Latest Ebola Science Archive 

Oxford Ebola vaccine study moves to next phase

Oxford Vaccine Group to carry out phase II study of an Ebola vaccine regimen

UNIVERSITY OF OXFORD
Oxford University doctors and scientists are performing the second phase of clinical studies of an experimental Ebola vaccine regimen. The study is part of the EBOVAC2 project, a collaborative programme involving the University of Oxford, French Institute of Health and Medical Research (INSERM) as project coordinator, London School of Hygiene & Tropical Medicine (LSHTM), Le Centre Muraz (CM), Inserm Transfert (IT) and the Janssen Pharmaceutical Companies of Johnson & Johnson (Janssen).

The EBOVAC2 project is funded under a grant from the European Commission's Innovative Medicine Initiative Ebola+ programme which was launched in response to the Ebola virus disease outbreak. The EBOVAC2 project aims to assess the safety and immunogenicity of a novel prime boost preventative vaccine regimen against Ebola Virus Disease (EVD).

The original development of the prime boost vaccine regimen was accelerated in response to the outbreak of Ebola virus disease in West Africa, which has now claimed more than 11,000 lives. Although the number of confirmed EVD cases has decreased in recent months, new cases of EVD in Liberia, which had been declared Ebola free, highlight that a preventative vaccine may still be needed to control the spread of disease.

The Oxford Vaccine Group, part of the University of Oxford Department of Paediatrics, has started enrolling volunteers for the phase II study this month, with additional French sites coordinated by Inserm anticipated to start recruitment in August. An additional study is planned to follow in several African countries.

The Phase II study aims to recruit more than 600 healthy adult volunteers in the UK and France.
In the UK, volunteers for the study, aged 18-65 years, are likely to come largely from the Oxfordshire region, and will be asked to make a maximum of 17 visits to the Oxford Vaccine Group site on the city's Churchill hospital site over a period of a year. The Oxford study is supported by the NIHR Oxford Biomedical Research Centre , a partnership between the University of Oxford and Oxford University Hospitals Trust, funded by the National Institute for Health Research.

The vaccine regimen used in the study involves two different components, given a few weeks apart. The first dose is intended to stimulate, or 'prime', an initial immune response. The second dose then is designed to 'boost' the level of the body's immune response further.

Neither vaccine component contains any replicating virus, so it is not possible to be infected with Ebola.
In pre-clinical studies of this vaccine regimen conducted in collaboration with the National Institutes of Health complete protection from death due to Ebola was achieved against the Kikwit variant - which is highly similar to the virus causing the current outbreak in Western Africa. Preliminary results from the first phase of the clinical study, conducted in Oxford and involving 87 volunteers, indicated that the prime-boost vaccine regimen is immunogenic, regardless of the order of vaccine administration, and only provoked temporary reactions normally expected from vaccination.

People interested in volunteering for the clinical study can find out more information at http://www.ebolavaccine.org.uk.
In addition to the Phase II study being conducted in the UK and France, similar studies are also starting in Africa to establish how robust the immune response is to the Ebola vaccine regimen. Given the compressed nature of this development program, the Phase II studies are anticipated to be conducted in parallel with the planned safety and immunogenicity study in Sierra Leone as part of EBOVAC1.

Prof Andrew Pollard, Director of the Oxford Vaccine Group, said: 'The devastating Ebola epidemic in Guinea, Liberia and Sierra Leone has shown how urgently we need a safe and effective vaccine. That goal has brought together manufacturers, public health bodies and research regulators to accelerate these studies of new Ebola vaccines. The results of the first phase, which are due to be published shortly, are encouraging. We are appealing, once again, for volunteers to come forward and help us in the second stage of this vital work.'

The objectives of the EBOVAC2 study are to determine further the vaccine regimen's safety profile and how well it stimulates the immune system to protect against Ebola infection. The team also want to work out the best timing for each of the vaccines. Volunteers will therefore be put on different schedules, where the gap between 'prime' and 'boost' dose will be 28, 56 or 84 days.
The immune responses that the vaccine generates - both antibodies and T cells - will also be measured over a period of one year.

Another team in the Jenner Institute has been studying a different Ebola vaccine (ChAd3 EBOZ) funded by the Wellcome Trust and the Department for International Development and developed with GSK/ US National Institutes of Health. Led by Professor Adrian Hill, preliminary results from the phase I studies conducted earlier this year have shown that this vaccine has a good safety profile and stimulates an immune response against the Ebola virus. Professor Hill's team has since started on a phase I trial of a boost to this vaccine and recruitment is ongoing.

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For more information please the University of Oxford news & information office on +44 (0)1865 280530 or news.office@admin.ox.ac.uk

Notes to editors
Images: A trial vaccination session is running on Thursday 18 July between 8.30am and 3.30pm. To arrange attendance please contact the News Office.

* The 'prime' and 'boost' vaccine regimen has two different components.
One component (Ad26.ZEBOV) makes use of technology from Crucell Holland B.V., one of the Janssen Pharmaceutical Companies of Johnson & Johnson. A non-replicating human adenovirus is used as a base for the vaccine, to which genes for a protein from the Zaire species of the Ebola virus is added
The other component (MVA-BN FILO ®), made by the company Bavarian Nordic in Denmark, is based on a non-replicating modified vaccinia Ankara (MVA) virus, to which genes for the protein from the Zaire species of Ebola virus are added, along with genes coding for proteins from the related viruses Marburg, Sudan virus, and Taï Forest virus.
Neither the adenovirus nor the MVA virus in the vaccines can cause disease, nor can anyone be infected with Ebola or the other related diseases from the vaccines.

* This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement EBOVAC2 (grant nr. 115861). This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA.

* The design of the study will see the volunteers allocated into three groups.
The first group of 30, recruited only in the UK, will receive both the 'prime' and 'boost' components of the vaccine regimen. They will receive the 'boost' dose 28 days after the 'prime' dose. Volunteers will also be asked if they are willing to take part in genetic tests to determine what genes are needed for a good vaccination response.
The second group of 270 will be recruited in the UK and France. This group will receive either the two components or a placebo. They will receive the 'boost' dose 56 days after the 'prime' dose. They too will be asked if they are will take part in genetic tests.
The third group of 312 volunteers will be recruited jointly in the UK and France and will also receive either the two components or a placebo. They will receive the 'boost' dose 84 days after the 'prime' dose.

* The Oxford Vaccine Group, part of the University of Oxford, is headed by Professor Andrew Pollard and conducts studies of vaccines in both adults and children. Over the last nine years the group has recruited over 7000 participants to clinical trials of vaccines. In addition to studying vaccines against meningitis and respiratory infections the Oxford Vaccine Group is currently conducting world-leading research on the vaccine prevention of typhoid and paratyphoid disease.

* The NIHR Oxford Biomedical Research Centre is a partnership between the research expertise of the Oxford University Hospitals NHS Trust and the University of Oxford. Its main aim is to enable clinical research for patient benefit and foster innovation to improve healthcare. It is funded by the National Institute for Health Research (NIHR). The NIHR provides the NHS with the support and infrastructure it needs to conduct first-class research funded by the Government and its partners alongside high-quality patient care, education and training. Its aim is to support outstanding individuals (both leaders and collaborators), working in world class facilities (both NHS and university), and conducting leading edge research focused on the needs of patients. http://www.oxfordbrc.org

* The National Institute for Health Research (NIHR) is funded by the Department of Health to improve the health and wealth of the nation through research. Since its establishment in April 2006, the NIHR has transformed research in the NHS. It has increased the volume of applied health research for the benefit of patients and the public, driven faster translation of basic science discoveries into tangible benefits for patients and the economy, and developed and supported the people who conduct and contribute to applied health research. The NIHR plays a key role in the Government's strategy for economic growth, attracting investment by the life-sciences industries through its world-class infrastructure for health research. Together, the NIHR people, programmes, centres of excellence and systems represent the most integrated health research system in the world. For further information, visit the NIHR website (http://www.nihr.ac.uk).

* EBOVAC2
The EBOVAC2 project is one of 8 research projects funded under IMI2 Ebola+ programme that was launched in response to the Ebola virus disease outbreak. The consortium brings together industrial and academic stakeholders: Janssen Pharmaceutical Companies of Johnson & Johnson (Janssen) as sponsor, French Institute of Health and Medical Research (Inserm) as coordinator, University of Oxford, London School of Hygiene & Tropical Medicine (LSHTM), La Centre Muraz (CM), and Inserm Transfert (IT). The project aims to assess the safety and efficacy of a novel prime boost preventive vaccine regimen against Ebola Virus Disease (EVD). The prime-boost vaccine regimen strategy requires two doses with two different vaccine components (Ad26.ZEBOV and MVA-BN-Filo). This is original in the Ebola context and different from other ongoing vaccination strategies with only one vaccination. For further information, visit the website (http://www.ebovac2.com).

Ebola vaccine trial begins in Senegal

Trial tests vaccine developed on new cell line with advantages for low cost large scale manufacturing

UNIVERSITY OF OXFORD
A trial to evaluate an Ebola vaccine has begun in Dakar, Senegal, after initial immunisations started at the Jenner Institute, Oxford University. The announcement comes as a conference in Oxford discusses the global response to Ebola and the implications for future drug and vaccine development.

The first volunteers of the trial at Centre Hospitalier Universitaire le Dantec in Dakar received an initial vaccination at the start of July, with a booster vaccination one week later. While this is a short timescale for immunisation, if proved successful it would provide an option to respond to an Ebola outbreak with a rapid vaccination programme. This new accelerated vaccination approach is now being tested in parallel in the UK and Senegal.

Dr Egeruan Babatunde Imoukhuede, who is coordinating the Senegal trial, said: 'The current Ebola outbreak has reinforced that speed of response is crucial. Outbreak diseases spread quickly, so any vaccination approach must be able to keep up.' There were 30 confirmed cases of Ebola virus disease in West Africa in the week to 5 July 2015 with transmission continuing in Guinea and Sierra Leone, and renewed transmission in Liberia.

The trial uses two vaccines tested first in people at the Jenner Institute at Oxford. The first vaccination, based on a chimpanzee adenovirus (known as ChAd3), is intended to stimulate, or prime, an initial immune response. The second vaccination, using modified vaccinia Ankara (MVA), is designed to boost the level of the body's immune response further. The ChAd3-EBO Z vaccine is being developed further by GlaxoSmithKline (GSK) and partners while the newly available MVA-EBO Z vaccine was manufactured through a collaboration between Oxford University, Emergent Biosolutions and GSK.

Each vaccine is based on genetically modifying safe viruses to carry just one part of the Ebola virus that will stimulate the body's immune system to fight the disease. Neither vaccine component contains any live Ebola virus, so it is not possible to be infected with Ebola.

While the Jenner Institute has trialled similar vaccines, this trial uses a refined booster vaccine, explained Professor Adrian Hill, Director of the Jenner Institute: 'We are using a new MVA, which has two advantages. Firstly, it matches exactly to the ChAd3 insert, which may improve immune responses. Secondly, it was produced on a new cell line that has many advantages for low cost large scale manufacturing. When you consider that Ebola affects some of the world's poorer countries and can spread rapidly, getting the scale of manufacturing up while keeping the cost down is key to delivering an effective response.'

In Senegal, Professor Souleymane Mboup is the Principal Investigator (PI) and Head of the Laboratoire de Bactériologie-Virologie (LBV) conducting the study. He said: 'A dedicated, experienced and seasoned clinical research team led by Dr Pierre Birahim Ndiye has been set in place to work with colleagues at Oxford University for the successful conduct of this Ebola vaccine trial.'

The trials will see around 38 volunteers given the vaccines in the UK, and a further 40 volunteers in Senegal, initially to check that the vaccines are safe and that they stimulate an immune response. The studies aim to complete enrolment by late August.

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For more information or to request an interviewee please contact the University of Oxford news & information office on +44 (0)1865 280530 or news.office@admin.ox.ac.uk

Notes to editors:
The conference: The Global Response to Ebola: Implications for Future Drug & Vaccine Development is a half day event at the Saïd Business School, Oxford, OX1 1HP and begins at 3pm. For more information, visit http://www.oxfordbiotech.org/event-ebola/ or email: info@oxfordbiotech.org

The trial uses two 'viral vectored' vaccines, where a safe virus is used as an effective way to get into the human body and stimulate its immune system, in what is known as a 'prime-boost regime'.

The first, or prime, vaccine is ChAd3-EBO Z, a chimpanzee adenovirus modified to carry elements of Ebola Zaire. The second, or boost, vaccine is MVA-EBO Z, modified vaccinia Ankara (based on Edward Jenner's original smallpox vaccine) altered to carry elements of Ebola Zaire. Both MVA and ChAd3 have excellent safety profiles.

The Dakar, Senegal trial is being carried out by the EbolaVac consortium, which includes pharmaceutical company GSK and research partners from the University of Oxford, Centre Hospitalier Universitaire Vaudois in Lausanne and the Bernhard-Nocht Institute, Hamburg. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 666085

Professor Souleymane Mboup is the Principal Investigator (PI) and Head of the Laboratoire de Bactériologie-Virologie (LBV) where the study is being conducted in Senegal. Prof Mboup is very involved in the fight against Ebola and has recently helped co-organize the African Voice and Leadership meeting to accelerate the evaluation of potential treatments and vaccines for Ebola in West Africa. His laboratory is one of the lead clinical and research centres in the West African region with over 20 years of experience in many aspects of HIV/AIDS, Malaria, TB and recently Ebola biomedical research. A dedicated, experienced and seasoned clinical research team lead by Dr Pierre Birahim Ndiye has been set in place to work with colleagues at Oxford University for the successful conduct of this Ebola vaccine trial.

The UK trial is being funded by a Wellcome Trust Enhancement Award to Oxford University with co-funding from the UK Department of International Development.
The trials are registered on ClinicalTrials.gov: NCT02451891 and NCT02485912.

TSRI team gets new close-up view of key part of Ebola virus life cycle

Findings add to 'blueprint' for developing effective treatments
SCRIPPS RESEARCH INSTITUTE

LA JOLLA, CA - June 25, 2015 - A new study led by scientists at The Scripps Research Institute (TSRI) reveals a key part of the Ebola virus life cycle at a higher resolution than ever before. The research sheds light on how Ebola virus assembles--and how researchers might stop the often-fatal infection.

"This higher resolution is critical for design of much-needed antiviral therapeutics," said Erica Ollmann Saphire, senior author of the new study, professor at TSRI and director of the Viral Hemorrhagic Fever Immunotherapeutic Consortium. "These structures provide the blueprints that we need to see key vulnerabilities to attack.

IMAGE: THE SCRIPPS RESEARCH INSTITUTE TEAM'S HIGH-RESOLUTION IMAGE REVEALED HOW A VIRAL PROTEIN CALLED VP35 HELPS PROTECT THE EBOLA VIRUS FROM THE BODY'S IMMUNE SYSTEM. view more
CREDIT: PHOTO COURTESY OF THE SCRIPPS RESEARCH INSTITUTE.

The new study, published online ahead of print today in the journal Cell Reports, builds on previous work in Saphire's lab showing that a viral protein called VP35 has a role in protecting both Ebola virus and its "cousin," the deadly Marburg virus, from the immune system. VP35 helps ("chaperones") a viral protein, helping it coil and form a protein shell (nucleocapsid) around the virus's genetic material. With a virus's genetic material blocked from view, the human immune system cannot mount an effective defense.

Until now, scientists had not been able to see the coiling process in great detail. But using an imaging technique called x-ray crystallography, Saphire and her colleagues were able to show exactly how VP35 helps the viral protein that creates the capsid.

The new structure also reveals how the VP35 protein prevents the nucleocapsid from assembling incorrectly. The researchers could even see key atoms and structures called side chains--crucial pieces for moving forward with structure-based drug design.

The researchers believe these findings could be significant for more than just Ebola virus. "The structure we revealed is likely conserved across all the filoviruses: Marburg, Sudan, Bundibugyo, Reston and Ebola," said Saphire.

TSRI Research Associate Robert Kirchdoerfer, first author of the new study, added that the new understanding of viral assembly could be applied to Mononegavirales, an order of viruses that includes measles and rabies.

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In addition to Saphire and Kirchdoerfer, authors of "Assembly of the Ebola virus nucleoprotein from a chaperoned VP35 complex" were Dafna M. Abelson and Malcolm R. Wood of TSRI and Sheng Li of the University of California, San Diego.

This study was supported by the Skaggs Institute of Chemical Biology, the Burroughs Wellcome Fund, the National Institutes of Health (NIH) (1R56 AI118016-01 and 5T32 AI007354-25), the NIH National Cancer Institute (ACB-12002) and NIH National Institute of General Medical Sciences (AGM-12006). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.

Three Ebola virus variants identified in Guinea

INSTITUT PASTEUR

Sequencing the genome of Ebola virus strains circulating in Guinea has allowed scientists at the Institut Pasteur in Dakar and in Paris, the CNRS and the University of Sydney to retrace the spread of the virus and monitor its evolution in the country where the outbreak started. This research reveals the co-circulation in Guinea, particularly in the urban regions of the capital and neighboring towns, of three distinct variants of the virus whose mutations are described in an article published in Nature. Characterization of the genetic variations of the virus is crucial to ensure the continued efficacy of diagnostic tools and for the development of effective treatments and vaccines.

The Ebola epidemic has been ongoing in West Africa for over a year, with 27,341 reported cases, of which 11,184 have been fatal (1). The source of the epidemic has been traced to a forested area in South-East Guinea, from where it rapidly spread to the capital, Conakry, and to neighboring countries. In March 2014, the Institut Pasteur of Dakar set up a mobile laboratory at Donka hospital (Conakry), to provide diagnostic services throughout Guinea. The involvement of volunteers from the Institut Pasteur and its network, in Conakry and other regions of Guinea such as Macenta, was constant during the entire epidemic.

IMAGE: THIS IS A MAP OF EBOLA VIRUS VARIANTS CIRCULATING IN GUINEA AND SIERRA LEONE. view more

CREDIT: CREATIVE COMMONS - NATURE

Monitoring the development of the Ebola virus genome is key for developing better treatment strategies, designing effective vaccines and ensuring the continued efficacy of diagnostic tools. To this end, scientists at the Institut Pasteur in Dakar and Paris, the CNRS and the University of Sydney contributed to the international efforts to combat the disease by characterizing the Ebola virus isolates circulating in Guinea between July and November 2014.

Sequencing of the virus from rare samples containing only small amounts of biological material was optimized in a collaborative effort with scientists from the Broad Institute (Cambridge, USA), who were already deployed in Sierra Leone. Analysis of these sequences reveals the existence of three distinct variants of the virus co-circulating in Guinea, and a very different dynamic than that observed in Sierra Leone and Liberia.

The first variant (GUI-1 - shown in red on the map) is closely related to viruses sampled at the start of the epidemic in March 2014. This variant is found only in Guinea, both in urban areas (Conakry) and forested regions.

The second variant (GUI-2 - shown in blue on the map) is related to the viruses circulating in Sierra Leone, but could correspond to parallel evolution in Guinea. These sequences represent the missing link that led to two separate introductions of Ebola in Mali, in October and November 2014.

The third variant (SLE-GUI-3 - shown in orange on the map) was identified in Conakry and the surrounding towns (Forecariah, Dalaba and Coyah). The marked similarities between this variant and the viruses found in Sierra Leone, combined with epidemiological data, highlight multiple reintroductions of Ebola from Sierra Leone to the region around Conakry.

Each variant is defined by a combination of mutations affecting different viral proteins, in particular the VP35 protein, which may be a virulence factor, the virus envelope glycoprotein, which may alter the immune system's perception of the virus, or the polymerase, which is usually a more conserved viral region.

While this study highlights the genetic diversity of the viruses circulating in Guinea during the epidemic's spread, it also shows that the mutation rate is well within the margins previously described for this type of virus. Monitoring viral variations is a strong complement to epidemiological studies retracing transmission chains, and will enable better targeting of response strategies in the face of potential new epidemics. Lastly, studies of the Ebola virus genetic variations, which have quickly been made available to the scientific community, will help optimize the treatments and vaccines under development.

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(1) WHO figures as of June 14, 2015

Source
Distinct lineages of Ebola virus in Guinea during the 2014 West African epidemic, Nature, June 24, 2015

Etienne Simon-Loriere1,2†*, Ousmane Faye3†, Oumar Faye3†, Lamine Koivogui4, Nfaly Magassouba5, Sakoba Keita6, Jean-Michel Thiberge7, Laure Diancourt7, Christiane Bouchier8, Matthias Vandenbogaert7, Valérie Caro7, Gamou Fall3, Jan P. Buchmann9, Christan B. Matranga10, Pardis C. Sabeti10,11, Jean-Claude Manuguerra7, Edward C. Holmes9‡* and Amadou A. Sall3‡*.

1 Institut Pasteur, Functional Genetics of Infectious Diseases Unit, 75724 Paris Cedex 15, France.
2 CNRS URA3012 Hôtes, vecteurs et agents infectieux : biologie et dynamique, Paris 75015, France.
3 Institut Pasteur in Dakar, Arbovirus and Viral Hemorrhagic Fever Unit, Dakar, Senegal.
4 National Institute of Public Health in Guinea, Conakry, Guinea.
5 Hemorrhagic Fever Project of Guinea, Gamal Abdel Nasser University, Conakry, Guinea.
6 Ministry of Health, Conakry, Guinea.
7 Institut Pasteur, Environment and Infectious Risks Unit, Laboratory for Urgent Response to Biological Threats, 75724 Paris Cedex 15, France.
8 Institut Pasteur, Genomic platform, 75724 Paris Cedex 15, France.
9 Marie Bashir Institute for Infectious Diseases and Biosecurity, Charles Perkins Centre, School of Biological Sciences and Sydney Medical School, The University of Sydney, Sydney, NSW 2006 Australia.
10 Broad Institute, 75 Ames Street, Cambridge 02142, MA, USA.
11 FAS Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, 52 Oxford Street, Cambridge 02138, MA, USA.
† These authors contributed equally to the work.
‡ These authors jointly supervised this work.

Generic heart disease medications offer promise for Ebola treatment

AMERICAN SOCIETY FOR MICROBIOLOGY

Generic medications used frequently in the management of heart disease patients also have the potential to bolster the immune systems of patients with Ebola virus and some other life-threatening illnesses, researchers report this week in mBio®, the online open-access journal of the American Society for Microbiology.

Unlike other medications in development for Ebola, which attack the virus, statins and angiotensin receptor blockers typically used for heart disease work on the host response, or a person's biological reaction to the virus, said lead study author David S. Fedson, MD, a retired professor of medicine at the University of Virginia and expert on influenza and pneumococcal vaccination, and pandemic preparedness. Specifically, the drugs stabilize or restore the integrity of endothelial cells lining the blood vessels. Endothelial cell dysfunction has been a central feature of human Ebola virus disease, he said, leading to severe fluid and mineral losses.

"This approach to Ebola treatment has two advantages," Dr. Fedson said. "First, it uses inexpensive generic drugs that are widely available in any country with a basic healthcare system, and most physicians who treat patients with cardiovascular diseases are familiar with these medications. Second, because this strategy targets the host response to infection, these drugs might be used to treat patients with any form of acute infectious disease in which a failure to overcome endothelial dysfunction could lead to multi-organ failure and death."

The statin/angiotensin receptor blocker combination was found to help improve survival in 100 Ebola patients treated in Sierra Leone, Dr. Fedson said. In a pilot study last fall, patients were given the drugs atorvastatin (40 mg/day) and irbesartan (150 mg/day) at several hospitals in West Africa. While study reports were not published, Dr. Fedson said, reports indicate that rapid clinical improvement was seen in almost all patients. Only two are known to have died: one was critically ill when first seen and died soon after; the other initially responded to three days of combination treatment but relapsed and died when combination treatment was stopped and he was instead given an antiviral agent. The study results need to be replicated, Dr. Fedson said.

When pandemics hit, "you have to have something that ordinary doctors in ordinary countries can use to treat ordinary patients," he said. "We have extraordinary medicines that cardiovascular scientists have developed which modify not just endothelial function but all kinds of things that are part of the host response to infectious disease. In combination they work even better than they do alone."

Treating the host response would not prevent or cure Ebola virus infection itself, Dr. Fedson said, "but it could allow individual patients to survive long enough to develop an immune response that eliminates the virus. These agents could be used in combination with antivirals if they are available."

To move forward, researchers should consider four courses of action, Dr. Fedson said: undertake research on the host response to Ebola virus infection, including involving scientists who understand endothelial cell biology; perform clinical studies in West Africa to test statin and angiotensin receptor blocker combination treatment in Ebola patients; incorporate any successful treatment of the host response in other clinical trials of interventions against Ebola; and recognize the implications of treating the host response for other diseases.

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mBio® is an open access online journal published by the American Society for Microbiology to make microbiology research broadly accessible. The focus of the journal is on rapid publication of cutting-edge research spanning the entire spectrum of microbiology and related fields. It can be found online at http://mbio.asm.org. The article can be found online at http://mbio.asm.org/content/6/3/e00716-15.

The American Society for Microbiology is the largest single life science society, composed of over 39,000 scientists and health professionals. ASM's mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.

Study of Ebola survivors opens in Liberia

Research to examine long-term health effects of Ebola virus disease

NIH/NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES

The Liberia-U.S. clinical research partnership known as PREVAIL has launched a study of people in Liberia who have survived Ebola virus disease (EVD) within the past two years. The study investigators hope to better understand the long-term health consequences of EVD, determine if survivors develop immunity that will protect them from future Ebola infection, and assess whether previously EVD-infected individuals can transmit infection to close contacts and sexual partners. The study, sponsored by the Ministry of Health of Liberia and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, will take place at various sites in Liberia and is expected to enroll approximately 7,500 people, including 1,500 people of any age who survived EVD and 6,000 of their close contacts.

"The clinical course of Ebola virus disease is reasonably well-understood, but we still have much to learn about the long-term health effects of the illness in those who recover," said NIAID Director Anthony S. Fauci, M.D. "To unravel the many unknowns, we have expanded the focus of our partnership with Liberia's Ministry of Health to include research on the long-term health effects of Ebola virus disease, in addition to our ongoing efforts to find an effective preventive vaccine and treatments for Ebola virus disease."

Mosaka Fallah, Ph.D., M.P.H., former Ebola emergency-response program manager for Action Against Hunger-Liberia; Michael C. Sneller, M.D., from NIAID's Laboratory of Immunoregulation; and Desmond Williams, M.D., Ph.D., from the U.S. Centers for Disease Control and Prevention, will serve as principal investigators for the study. Investigators from NIH's National Eye Institute, the Johns Hopkins University Wilmer Eye Institute, Baltimore; the Ministry of Health of Liberia and the John F. Kennedy Medical Center in Sinkor, Monrovia, will also collaborate on the research. Enrollment began today at the John F. Kennedy Medical Center, and the study will open at the following sites later in June: C.H. Rennie Hospital in Kakata, Duport Road Clinic in Paynesville, and Redemption Hospital in Monrovia. Additional sites in Liberia are expected to join the study in the future.

Participants who test positive for HIV infection during the course of the study will be counseled and referred to treatment in accordance with standard medical practice in Liberia.

Study participants will undergo a medical history and physical and vision examination and have blood samples collected so researchers can identify and track any health issues, monitor organ and ocular function and record Ebola antibody levels. Some participants may also be asked to provide samples of bodily fluids, such as sweat, tears, and for adults, semen or cervical secretions. Participants will be asked if they would like to identify up to five close contacts (household members at the time of Ebola diagnosis and sexual partners after recovery from Ebola virus disease). Close contacts who agree to participate in the study will undergo a physical examination, have blood samples taken, and asked to complete a questionnaire detailing their contact with the Ebola survivor, such as touching, sleeping in the same bed and sexual intercourse. Staff from the NIH's National Eye Institute have helped establish a new eye clinic at John F. Kennedy Medical Hospital, where ophthalmologists from NEI and Johns Hopkins will be evaluating study participants and their identified close contacts for visual problems.

Treatment will be provided by Liberian ophthalmologists partnering in the study. "There have been reports of inflammatory eye disease and vision loss among Ebola survivors," said NEI Clinical Director Frederick Ferris, M.D. "Our goal is to determine the incidence and extent of Ebola-related eye disease among survivors, risk factors contributing to its development, and optimal treatment strategies."

The research team will follow the Ebola survivors and their close contacts for up to five years with study visits occurring every six months. At each follow-up visit, participants will undergo a physical examination and additional blood draws, to allow study physicians to monitor and characterize any changes in Ebola antibody levels and to detect the presence of select medical conditions. This information will help scientists determine the evolution of Ebola antibodies and will provide insight on whether survivors can still transmit the virus and if so, whether these people get sick with Ebola virus disease.

Using data collected at these site visits, the researchers will calculate the incidence, prevalence and risk factors for various health issues experienced by survivors, such as vision problems; immune system changes; mental disorders; joint pain; diabetes; hypertension; and pregnancy complications. Close contacts will be used as a control group to assess whether the risks of these conditions are the same or different from those who have not had Ebola virus disease.

PREVAIL, or the Partnership for Research on Ebola Virus in Liberia, is a clinical research partnership between the U.S. Department of Health and Human Services and the Liberian Ministry of Health. The new study, an Ebola natural history study known as PREVAIL III, is one of three research projects launched by the partnership. In February 2015, PREVAIL initiated two other Ebola clinical studies. PREVAIL I is a clinical trial to assess the safety and efficacy of two experimental vaccines to prevent Ebola virus infection. A total of 1,500 participants continue to be followed in the Phase 2 segment of this study. PREVAIL II is a clinical trial designed to obtain safety and efficacy data on various investigational drugs for the treatment of Ebola virus disease. The trial is ongoing in Liberia, Sierra Leone and the United States.

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Additional information about the PREVAIL III Ebola natural history study is available at ClinicalTrials.gov using the identifier NCT02431923. For more information about NIAID's Ebola research, visit the NIAID Ebola webpage.

NIAID conducts and supports research--at NIH, throughout the United States, and worldwide--to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

NEI leads the federal government's research on the visual system and eye diseases. NEI supports basic and clinical science programs that result in the development of sight-saving treatments. For more information, visit https://www.nei.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

The Case for Improved Diagnostic Tools to Control Ebola Virus Disease in West Africa and How to Get There

The Ebola virus disease (EVD) outbreak in West Africa, with the widest and most intense transmission occurring in Guinea, Liberia, and Sierra Leone, has claimed more than 8,000 lives since it began in December 2013. It has had a massive impact on already fragile health systems and now threatens food security. The latest World Health Organization (WHO) report has shown that there has been a decrease in the cases in January 2015 [1].

Since the identification of Ebola in Guinea in March 2013, rapid deployment of international mobile laboratories through WHO networks—Global Outbreak Alert and Response Network (GOARN) [2] and Emerging and Dangerous Pathogens Laboratory Network (EDPLN) [3]—has been vital to outbreak control operations. Deployable laboratories from multiple international organizations have been established near Ebola treatment centers (ETC) in Guinea, Liberia, and Sierra Leone. The organizations providing laboratories are China Centers for Disease Control Lab, European Union Mobile Laboratory Consortium (EM Lab), Institute Pasteur Dakar, Institute Pasteur Lyon, Institute Pasteur Paris, Institut National de Recherche Bio-Médicale Mobile lab in Democratic Republic of Congo, National Institute for Communicable Diseases in South Africa, Public Health England Mobile lab, Public Health Canada Mobile Lab, Russian Rospotrebnadzor Mobile Lab, United States Centers for Disease Control (CDC), US First Area Medical Laboratory, US National Institutes of Health, and US Naval Medical Research Center Mobile Lab.

The primary function of these laboratories has been to confirm disease in patients with suggestive symptoms in order to trigger isolation and contact tracing and to document cure and/or non-infectiousness in survivors. Current diagnostic testing is performed exclusively using reverse transcription polymerase chain reaction (RT-PCR) on RNA extracted from venous blood samples collected by personnel wearing full personal protective equipment. In the absence of simpler methods, diagnosis of EVD in this outbreak has, until now, relied exclusively on testing conducted in these internationally run, mobile laboratories.

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West African Ebola virus strain less virulent than prototype 1976 strain

Link to CDC article here.

Comparison shows delayed disease progression
NIH/NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES

What: The Makona strain of Ebola virus (EBOV) circulating in West Africa for the past year takes roughly two days longer to cause terminal disease in an animal model compared to the original 1976 Mayinga strain isolated in Central Africa, according to a new National Institutes of Health (NIH) report. The results provide important information to scientists who have wondered if the Ebola virus in West Africa is becoming more severe. In fact, the new study suggests the current virus has a decreased ability to cause disease in their animal model compared to the 1976 strain.

Using cynomolgus macaques to model infection and disease in humans, scientists from NIH's National Institute of Allergy and Infectious Diseases (NIAID) infected three animals with 1976 EBOV-Mayinga and three with 2014 EBOV-Makona. While both groups of animals were shedding virus three days after being infected, those in the Mayinga group developed a rash on day four and became extremely ill at days five and six. Those in the Makona group did not develop a rash until six days after infection, and severe disease appeared on days seven and eight. Further, liver damage -- typical in Ebola disease -- was delayed by about two days in the Makona group compared to the Mayinga group.

Of note, the scientists reported that the immune system of animals in the Makona group produced about three times the amount of a virus-fighting protein, interferon gamma, compared to the Mayinga group. They plan more studies of the immune response, but believe that at least seven days are needed after Ebola infection to mount an effective response. This response does not seem to develop during EBOV-Mayinga infection in cynomolgus macaques because disease progression is too fast.

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Article: A Marzi et al. Delayed disease progression in cynomolgus macaques infected with Ebola virus Makona strain. Emerging Infectious Diseases DOI: 10.3201/eid2110.150259 (2015).

Who: NIAID Director Anthony S. Fauci, M.D., is available to comment on this study as are Heinz Feldmann, M.D., Ph.D., and Andrea Marzi, Ph.D., both experts in viral hemorrhagic fever research in NIAID's Laboratory of Virology.

Contact:
Ken Pekoc
kpekoc@niaid.nih.gov
301-402-1663

NIAID conducts and supports research -- at NIH, throughout the United States, and worldwide -- to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

About the National Institutes of Health
NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov/.

What Factors Might Have Led to the Emergence of Ebola in West Africa?

Full text available here.

Abstract:
An Ebola outbreak of unprecedented scope emerged in West Africa in December 2013 and presently continues unabated in the countries of Guinea, Sierra Leone, and Liberia. Ebola is not new to Africa, and outbreaks have been confirmed as far back as 1976. The current West African Ebola outbreak is the largest ever recorded and differs dramatically from prior outbreaks in its duration, number of people affected, and geographic extent. The emergence of this deadly disease in West Africa invites many questions, foremost among these: why now, and why in West Africa? Here, we review the sociological, ecological, and environmental drivers that might have influenced the emergence of Ebola in this region of Africa and its spread throughout the region. Containment of the West African Ebola outbreak is the most pressing, immediate need. A comprehensive assessment of the drivers of Ebola emergence and sustained human-to-human transmission is also needed in order to prepare other countries for importation or emergence of this disease. Such assessment includes identification of country-level protocols and interagency policies for outbreak detection and rapid response, increased understanding of cultural and traditional risk factors within and between nations, delivery of culturally embedded public health education, and regional coordination and collaboration, particularly with governments and health ministries throughout Africa. Public health education is also urgently needed in countries outside of Africa in order to ensure that risk is properly understood and public concerns do not escalate unnecessarily. To prevent future outbreaks, coordinated, multiscale, early warning systems should be
developed that make full use of these integrated assessments, partner with local communities in high-risk areas, and provide clearly defined response recommendations specific to the needs of each community

Study identifies Ebola virus's Achilles' heel

US ARMY MEDICAL RESEARCH INSTITUTE OF INFECTIOUS DISEASES

An international team including scientists from Albert Einstein College of Medicine of Yeshiva University and the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) has identified the molecular "lock" that the deadly Ebola virus must pick to gain entry to cells. The findings, made in mice, suggest that drugs blocking entry to this lock could protect against Ebola infection. The study was published in today's edition of the online journal mBio.

The researchers found that the Ebola virus can't infect cells unless it first attaches to a host protein called Niemann-Pick C1 (NPC1) in membrane compartments called lysosomes deep within cells. "Our study reveals NPC1 to be an Achilles' heel for Ebola virus infection," said co-study leader Kartik Chandran, Ph.D., associate professor of microbiology and immunology and the Harold and Muriel Block Faculty Scholar in Virology at Einstein. "Mice lacking both copies of the NPC1 gene, and therefore devoid of the NPC1 protein, were completely resistant to infection."

The other co-study leaders are Steven Walkley, D.V.M., Ph.D., professor of Dominick P. Purpura Department of Neuroscience, of pathology, and of the Saul R. Korey Department of Neurology at Einstein, and John M. Dye, Ph.D., Branch Chief of Viral Immunology at the U.S. Army Medical Research Institute of Infectious Diseases.

Ebola virus binds to the host cell's outer membrane, and a portion of host cell membrane then surrounds the virus and pinches off, creating an endosome -- a membrane-bound bubble inside the cell. Endosomes carry their viral stowaways deep within the cell and eventually mature into lysosomes -- tiny enzyme-filled structures that digest and recycle cellular components. The viruses captive in the lysosome manage to escape destruction by exploiting components of the cell to gain entry to the cytoplasm, the substance between the cell membrane and the nucleus where the virus can replicate. But the identities of many of these components have remained unknown.

In an earlier study, the Einstein and USAMRIID researchers, together with colleagues at the Netherlands Cancer Institute and Harvard Medical School, found evidence, in tissue culture, that Ebola takes advantage of the NPC1 protein to enter the cell's cytoplasm. NPC1 is embedded within cell membranes, where it helps transport cholesterol within the cell. People lacking NPC1 due to genetic mutations develop a fatal neurodegenerative disorder called Niemann-Pick disease, in which cells become clogged with cholesterol and eventually die.

The current animal study was aimed at confirming whether NPC1 is essential for Ebola infectivity. The researchers challenged both "wild type" mice (which have two intact copies of the NPC1 gene) and "knockout mice" (lacking both copies of the gene) with Ebola virus. "While the wild type mice succumbed to the infection, the knockout mice were entirely free of virus replication and completely protected against the disease," said Dr. Walkley. Even though such a treatment in humans would also block the cholesterol transport pathway, "We think patients would be able to tolerate the treatment, which would be needed for only a short time," said Dr. Andrew S. Herbert, PhD, senior research scientist in the Viral Immunology Branch at USAMRIID, and co-first author of the study.

"Carrier" mice -- those with just one working copy of NPC1 and therefore possessing half the normal complement of NPC1 receptors -- proved substantially but not totally resistant to Ebola infection. "This would suggest that drugs that interfere with Ebola's interaction with NPC1 -- even if some Ebola viruses are able to enter cells -- could probably still provide some benefit from lethal infection," said Dr. Dye. "Ideally," Dr. Chandran says, "future research in humans, based on these findings, will lead to the development of antiviral drugs that can effectively target NPC1 and prevent infection not just by Ebola, but also by other highly virulent filoviruses, which also require NPC1 as a receptor."

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The study is titled "Niemann-Pick C1 is essential for Ebola virus replication and pathogenesis in vivo." The other contributors are: Cristin Davidson and Stephen Z. Braigen at Einstein; Andrew S. Herbert, Ph.D., Russell Bakken, Nancy A. Twenhafel, D.V.M., and Ana I. Kuehne, all at USAMRIID; Kathryn E. Gunn, Ph.D. at Mount St. Mary's University, Emmittsburg, MD; Sean P. Whelan, Ph.D., at Harvard Medical School, Boston, MA; and Thijn R. Brummelkamp, Ph.D., at 5Netherlands Cancer Institute, Amsterdam, The Netherlands.

"How Ebola Virus Infects a Cell"
This 3-D animation shows how the Ebola virus exploits a naturally occurring protein in our cells called NPC1 to cause infection and spread in the body.
Courtesy Albert Einstein College of Medicine

About Albert Einstein College of Medicine
Albert Einstein College of Medicine of Yeshiva University is one of the nation's premier centers for research, medical education and clinical investigation. During the 2014-2015 academic year, Einstein is home to 742 M.D. students, 212 Ph.D. students, 102 students in the combined M.D./Ph.D. program, and 292 postdoctoral research fellows. The College of Medicine has more than 2,000 full-time faculty members located on the main campus and at its clinical affiliates. In 2014, Einstein received $158 million in awards from the National Institutes of Health (NIH). This includes the funding of major research centers at Einstein in aging, intellectual development disorders, diabetes, cancer, clinical and translational research, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Its partnership with Montefiore Medical Center, the University Hospital and academic medical center for Einstein, advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. Through its extensive affiliation network involving Montefiore, Jacobi Medical Center--Einstein's founding hospital, and three other hospital systems in the Bronx, Brooklyn and on Long Island, Einstein runs one of the largest residency and fellowship training programs in the medical and dental professions in the United States. For more information, please visit www.einstein.yu.edu, read our blog, follow us on Twitter, like us on Facebook, and view us on YouTube.

About USAMRIID
USAMRIID's mission is to provide leading-edge medical capabilities to deter and defend against current and emerging biological threat agents. The Institute plays a key role as the lead military medical research laboratory for the Defense Threat Reduction Agency's Joint Science and Technology Office for Chemical and Biological Defense. USAMRIID is a subordinate laboratory of the U.S. Army Medical Research and Materiel Command. For more information, visit USAMRIID

Additional Media Contact:
Deirdre Branley
Albert Einstein College of Medicine
office (718) 430-2923
cell (347) 266-9204
deirdre.branley@einstein.yu.edu

Experimental Ebola treatment boosts survival in mice

AMERICAN CHEMICAL SOCIETY

The number of new Ebola cases is tapering off, but the search for new treatments continues. Now, one research team has found potential drug candidates that successfully treated up to 90 percent of mice exposed to the Ebola virus. They report their findings in the journal ACS Infectious Diseases.

Bogdan A. Solaja, Rekha G. Panchal and colleagues note that the U.S. Food and Drug Administration has yet to approve any therapeutic drugs or vaccines against the Ebola virus that, since December 2013, has infected more than 25,000 people and taken the lives of more than 10,000. While some researchers are developing vaccines to prevent Ebola infections, others are focusing on treatments for the disease. They are investigating a number of compounds, including existing malaria and flu drugs. Solaja's team has been looking into possible treatments by studying a class of small molecules called diazachrysenes, which they've found in lab tests to be non-toxic and effective against the most potent bacterial toxin, botulinum neurotoxin. They wanted to screen this family of compounds for possible anti-Ebola drug candidates.

The researchers narrowed down their search to a handful of diazachrysenes. In their study, 70 to 90 percent of the mice that received one of three of the experimental compounds survived infection and didn't show any obvious side effects.

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The authors acknowledge funding from the Ministry of Science and Technological Development of Serbia and the Defense Threat Reduction Agency.

The American Chemical Society is a nonprofit organization chartered by the U.S. Congress. With more than 158,000 members, ACS is the world's largest scientific society and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.

Ebola vaccine trial in west Africa faces criticism

WHO has come under fire for its running of the Ebola ring vaccine trial in Guinea, with critics highlighting inadequate care of participants and patients. Miriam Shuchman reports.

As the incidence of Ebola falls in west Africa, with Liberia declared Ebola free on May 9 and total cases in Sierra Leone and Guinea dipping to the lowest this year, investigators testing Ebola vaccines are racing to complete their studies. “Instead of a scramble for Africa, you have a scramble for patients, and the fear is that sometimes the patient gets lost”, Rebecca Freeman Grais, director of research at Médecins Sans Frontières' (MSF) Epicentre and a coinvestigator on a vaccine trial in Guinea, told The Lancet. In Guinea, the racing comes amid simmering criticisms that the so-called ring vaccine trial run by WHO is not adequately protecting participants.

There are two trials in Guinea testing Merck's rVSV-EBOV vaccine: Grais is leading an MSF team assessing it in front-line workers in the Ebola response, and WHO investigators are testing it in groups of contacts of individuals newly diagnosed with Ebola, including community members living in those individual's villages. MSF has a target of 1200 workers, and the WHO trial is targeting 190 rings—half receiving the vaccine immediately and the other half 3 weeks later, and both groups are collaborating on the trials with each other and with the Guinean Ministry of Health and the Norwegian Institute of Public Health.

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Genomics laboratory capability in Liberia supports Ebola virus outbreak response

US ARMY MEDICAL RESEARCH INSTITUTE OF INFECTIOUS DISEASES

Army scientists working to support the Ebola virus outbreak response in West Africa have established the first genomic surveillance capability in Liberia, enabling them to monitor genetic changes in the virus within one week of sample collection. An article describing their work was recently published ahead of print in the online edition of Emerging Infectious Diseases. In the paper, the team offers a concise evaluation of the potential impact of the evolution of Ebola virus Makona, the strain responsible for the current outbreak, based on genome reconstruction of 25 isolates from Liberia obtained during September 2014-February 2015.

These sequences were consistent with a single virus introduction to Liberia; however, shared ancestry with isolates from Mali indicated at least one additional instance of movement into or out of Liberia, according to senior author Gustavo Palacios, Ph.D., who directs the Center for Genome Sciences at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). Until now, efforts to sequence the genome of Ebola virus Makona have been hampered by the time it took to send samples back to the United States for analysis, according to first author Jeffrey Kugelman, Ph.D. "It just wasn't happening fast enough," said Kugelman, a viral geneticist at USAMRIID. "We need answers in days, rather than in weeks or months."

Kugelman recently returned from Liberia, where he spent four months setting up the genomics laboratory at the Liberian Institute for Biomedical Research (LIBR). The laboratory, a collaborative effort between LIBR and USAMRIID, was established to characterize Ebola viral genomes to assess for erosion of diagnostic and therapeutic targets, as well as to provide the scientific and public health communities working in Liberia with viral genomic information.

According to the authors, evaluating changes in the virus in real time is essential to determining whether those changes could have an impact on diagnostics and therapeutics. "The pace of change is generally consistent with previous estimates of mutation rate," they noted. "Six of the changes we observed are within known binding sites for sequence-based Ebola virus medical countermeasures. However, the diagnostic and therapeutic impact of Ebola virus evolution within Liberia appears to be low at this time." Palacios said the research team's work would not have been possible without the establishment of the genomic surveillance laboratory in Liberia, emphasizing the need for global sequencing capabilities to be part of the first response during future virus outbreaks. "It's absolutely essential, with this type of viral infection, to have this capability," said Palacios. "To be able to help establish lines of infection...to be able to look for target erosion in diagnostics and therapeutics...all of these are very important."

USAMRIID's experience with moving laboratory capabilities into a field setting proved invaluable, according to Kugelman. "We had already established a working relationship with LIBR, thanks to the Ebola virus diagnostics capability that was established by USAMRIID, the Navy and the National Institutes of Health last year," Kugelman said. "And because the diagnostics laboratory is already extracting nucleic acid from patient samples, we knew we would be able to use those isolations to perform our sequencing studies without the need for additional biocontainment considerations."

Several approvals had to be obtained before proceeding with setup, and the team faced numerous logistical challenges in operating the laboratory, Kugelman said. Electrical power must be provided by generators, internet capability is via satellite, and the instrument, an Illumina MiSeq sequencing platform, needs purified water to operate. Kugelman also had to complete a two-week training program to become a certified Illumina technician so he could make needed repairs to the instrument on the spot. "The sequencing process takes about three days, so a power failure or a fuel shortage can complicate the process even further," Kugelman said. "But it's a fully functional genomics lab--and the fact that we've been able to put next-generation sequencing into the outbreak area has made quite an impact."

Now that the genomics center at LIBR has been established, Palacios said, it will be supporting surveillance projects across the country to investigate reservoir animals and insect vectors of disease to identify potential threats. In addition, the center will support ongoing assessment of samples from patients with severe diseases of unknown origin, providing a key public health asset to West Africa. Key to this transition is Suzanne Mate, Ph.D., who is currently serving as the genomics laboratory lead for USAMRIID in Liberia.

Mate and her colleagues are working closely with public health officials to understand Ebola virus disease transmission, merging epidemiological reporting and genomic surveillance of virus nucleic acids extracted from patient samples in a transmission chain. The newly established genomics laboratory at LIBR has been instrumental in helping to trace the source of Liberia's most recent case of Ebola virus infection, which is reported to be linked to sexual contact with an EVD survivor, as described in an article published May 1 in the Morbidity and Mortality Weekly Report. In response to this case report, the World Health Organization and the Centers for Disease Control and Prevention have recommended consistent condom use by male survivors until additional studies are performed to determine how long Ebola virus is present in body fluids and whether it can be transmitted through sexual contact.

Ebola virus causes severe hemorrhagic fever in humans and nonhuman primates with high mortality rates and continues to emerge in new geographic locations, including West Africa, the site of the largest outbreak to date. Over 26,500 confirmed, probable and suspected cases have been reported in Guinea, Liberia and Sierra Leone, with more than 11,000 reported deaths, according to the World Health Organization.

USAMRIID's mission is to provide leading-edge medical capabilities to deter and defend against current and emerging biological threat agents. The Institute plays a key role as the lead military medical research laboratory for the Defense Threat Reduction Agency's Joint Science and Technology Office for Chemical and Biological Defense. USAMRIID is a subordinate laboratory of the U.S. Army Medical Research and Materiel Command.

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This work was supported by the Defense Threat Reduction Agency, the Global Biosurveillance Technology Initiative, the U.S. Agency for International Development, and Illumina.

References:
1. Kugelman JR, Wiley MR, Mate S, Ladner JT, Beitzel B, Fakoli L, et al. Monitoring of Ebola virus Makona evolution through establishment of advanced genomic capability in Liberia. Emerg Infect Dis. 2015 Jul. http://dx.doi.org/10.3201/eid2107.150522
2. Possible sexual transmission of Ebola virus--Liberia, 2015. (2015, May 8). MMWR: Morbidity and Mortality Weekly Report, 64(17), 479-481. Retrieved from http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6417a6.htm?s_cid=mm6417a6_w

Tekmira and Collaborators Publish Positive Preclinical Ebola Survival Data in Nature Journal

Findings Validate Adaptability of siRNA-LNP to Rapidly Target Emerging Viral Strains

VANCOUVER, British Columbia, April 22, 2015 (GLOBE NEWSWIRE) -- Tekmira Pharmaceuticals Corporation (Nasdaq:TKMR), an industry-leading therapeutic solutions company focused on developing a cure for chronic hepatitis B virus infection (HBV), announced today the publication of preclinical data highlighting positive results against Ebola virus Makona infection using a newly adjusted siRNA cocktail. The paper is titled, "Lipid Nanoparticle siRNA Treatment of Ebola Virus Makona-infected Nonhuman Primates," (Thi et al., Nature April 22, 2015, doi:10.1038/nature14442).

Tekmira, along with its collaborators at the University of Texas Medical Branch at Galveston, USA, jointly conducted a preclinical study demonstrating 100% survival of nonhuman primates infected with the West Africa Makona strain of Ebola virus, previously referred to as the Guinea strain. Complete survival was observed even when treatment did not begin until three days after viral exposure, a time point at which animals were five to six days away from death.

"We are pleased to report these preclinical efficacy results. As far as we are aware, these data are the first successful demonstration of anti-Ebola virus therapeutic efficacy against the Makona strain in nonhuman primates," said Dr. Mark Murray, Tekmira's President and CEO. "These results underscore the adaptability of our siRNA-LNP technology in response to emerging infections. In this case, we rapidly went from new viral sequence data availability, to clinical product adapted to the new Makona strain."

TKM-Ebola-Guinea (targeting the Makona strain), containing the adjusted siRNA cocktail used in the pre-clinical study, is currently being evaluated in a Phase II clinical study in Sierra Leone with results expected in the second half of 2015. The study is being conducted by the University of Oxford on behalf of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), with funding by the Wellcome Trust.

About TKM-Ebola-Guinea, an Anti-Ebola RNAi Therapeutic Targeting Ebola-Guinea
The Ebola virus Makona variant responsible for the current outbreak in West Africa shows sequence divergence from Central African Ebola virus variants, the original target of TKM-Ebola. The genomic sequence of Ebola virus Makona was determined from several viral isolates and published in the New England Journal of Medicine in October 2014. Tekmira developed a modified RNAi therapeutic, based on the Company's original TKM-Ebola investigational therapeutic, to specifically target the Makona variant. The new product, termed TKM-Ebola-Guinea, is designed to match the genomic sequence exactly, with two RNAi triggers. The ability to rapidly and accurately match the evolving genetic sequences of emerging infectious agents is one of the powerful features of RNAi therapeutics.

About University of Texas Medical Branch
Texas' first academic health center opened its doors in 1891 and today comprises four health sciences schools, three institutes for advanced study, a research enterprise that includes one of only two national laboratories dedicated to the safe study of infectious threats to human health, and a health system offering a full range of primary and specialized medical services throughout Galveston County and the Texas Gulf Coast region. UTMB Health is a component of the University of Texas System and a member of the Texas Medical Center.

About Oxford University's Medical Sciences Division
Oxford University's Medical Sciences Division is one of the largest biomedical research centres in Europe, with over 2,500 people involved in research and more than 2,800 students. The University is rated the best in the world for medicine, and it is home to the UK's top-ranked medical school. From the genetic and molecular basis of disease to the latest advances in neuroscience, Oxford is at the forefront of medical research. It has one of the largest clinical trial portfolios in the UK and great expertise in taking discoveries from the lab into the clinic. Partnerships with the local NHS Trusts enable patients to benefit from close links between medical research and healthcare delivery. A great strength of Oxford medicine is its long-standing network of clinical research units in Asia and Africa, enabling world-leading research on the most pressing global health challenges such as malaria, TB, HIV/AIDS and flu. Oxford is also renowned for its large-scale studies which examine the role of factors such as smoking, alcohol and diet on cancer, heart disease and other conditions.

About Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to improving health. It provides more than £700 million a year to support bright minds in science, the humanities and the social sciences, as well as education, public engagement and the application of research to medicine. Its investment portfolio provides independence to support such transformative work as the sequencing and understanding of the human genome, research that established front-line drugs for malaria, and Wellcome Collection, its free venue for the incurably curious that explores medicine, life and art. www.wellcome.ac.uk.

About Tekmira
Tekmira Pharmaceuticals Corporation is a biopharmaceutical company dedicated to discovering, developing and commercializing a cure for patients suffering from chronic hepatitis B infection (HBV). Our strategy is to target the three pillars necessary to develop a curative regimen for HBV, including suppressing HBV replication within liver cells, stimulating and reactivating the body's immune system so that it can mount an effective defense against the virus and, most importantly, eliminating the reservoir of viral genomic material known as covalently closed circular DNA, or cccDNA, that is the source of HBV persistence. Our portfolio of assets includes eight drug candidates for use in combination to develop a cure for HBV, and includes our product TKM-HBV currently in Phase 1 clinical studies.

We also have a pipeline of non-HBV assets in oncology, anti-viral and metabolic therapeutics that leverage our expertise in RNA interference (RNAi) therapeutics and leading Lipid Nanoparticle (LNP) technology. RNAi and LNP technology have the potential to generate new therapeutics that take advantage of the body's own natural processes to silence disease causing genes, or more specifically, to eliminate specific gene-products, from the cell. We intend to maximize the value of our non-HBV assets in the clinic, namely: TKM-PLK1 for advanced gastrointestinal neuroendocrine tumors, adrenocortical carcinoma and hepatocellular carcinoma; and TKM-Ebola, and TKM-Ebola-Guinea for Ebola virus disease; as well as our preclinical programs in metabolic disorders and other filoviruses.

Tekmira is headquartered in Vancouver, BC, Canada with offices in Doylestown, PA, USA. For more information, visit www.tekmira.com.

Forward-Looking Statements and Information
This press release contains forward-looking statements within the meaning of the Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, and forward looking information within the meaning of Canadian securities laws (collectively, "forward-looking statements"). Forward-looking statements in this press release include statements about adapting a pre-existing siRNA drug to emerging viral strains and manufacturing a clinical product in as little as eight weeks; the expectation of results in the second half of 2015 from a TKM-Ebola-Guinea Phase II clinical study in Sierra Leone; Tekmira's LNP technology being the most advanced and widely adopted delivery technology for the systemic delivery of RNAi triggers; Tekmira's strategy for discovering, developing and commercializing a cure for HBV; and Tekmira's intent to maximize the value of their non-HBV assets.

With respect to the forward-looking statements contained in this press release, Tekmira has made numerous assumptions regarding, among other things: the continued approval of the FDA; the effectiveness of pre-clinical and clinical studies; and continued economic and market stability. While Tekmira considers these assumptions to be reasonable, these assumptions are inherently subject to significant business, economic, competitive, market and social uncertainties and contingencies.

Additionally, there are known and unknown risk factors which could cause Tekmira's actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements contained herein. Known risk factors include, among others: the FDA may place restrictions on further clinical trials; other organizations may have made advancements in RNAi delivery technology that Tekmira is not aware of; anticipated pre-clinical and clinical trials may be more costly or take longer to complete than anticipated, and may never be initiated or completed, or may not generate results that warrant future development of the tested drug candidate; and economic and capital market conditions may worsen.

A more complete discussion of the risks and uncertainties facing Tekmira appears in Tekmira's Annual Report on Form 10-K and Tekmira's continuous disclosure filings, which are available at www.sedar.com and at www.sec.gov. All forward-looking statements herein are qualified in their entirety by this cautionary statement, and Tekmira disclaims any obligation to revise or update any such forward-looking statements or to publicly announce the result of any revisions to any of the forward-looking statements contained herein to reflect future results, events or developments, except as required by law.

CONTACT:
Investors
Adam Cutler
Senior Vice President, Corporate Affairs
Phone: 604.419.3200
Email: acutler@tekmira.com

Julie P Rezler
Director, Investor Relations and Corporate Communications
Phone: 604.419.3200
Email: jrezler@tekmira.com

Media
Please direct all media inquiries to media@tekmira.com

Study examines long-term adverse health effects of Ebola survivors

Largest long-term study to date examines survivors of 2007-2008 outbreak in Bundibugyo, Uganda
THE U.S. MILITARY HIV RESEARCH PROGRAM (MHRP)

April 22, 2014 (SILVER SPRING, Md.) - Ebola survivors experienced negative health effects that persisted more than two years after the 2007-2008 Bundibugyo ebolavirus (BDBV) outbreak in Uganda that claimed 39 lives. These findings are detailed in a paper published online today in Lancet ID. This represents the largest long-term study to-date on Ebola survivors, and examines health events more than two years after initial exposure to BDBV. "Defining EVD-related health consequences could help improve patient care for survivors," said Dr. Hannah Kibuuka, the principal investigator on the study in Uganda with the Makerere University Walter Reed Project.

Researchers studied forty-nine probable and confirmed BDBV adult survivors and 157 of their seronegative contacts in this observational study that enrolled volunteers 29 months after the outbreak. Information on health status, functional limitations and demographics was collected, along with blood samples for analysis. Researchers found that survivors were at significantly increased risk of ocular deficits, blurred vision, hearing loss, and neurologic abnormalities such as difficulty swallowing and sleeping. Survivors also reported more chronic health problems and limitations due to memory loss or confusion.

Limitations in the ability to perform routine functions were more prevalent among BDBV survivors. In addition, survivors were twice as likely to report having chronic health problems lasting more than a year. These included pain in the abdomen, back, and large joints, fatigue, impotence and severe headaches. Limitations due to memory problems or confusion were approximately six times more prevalent among BDBV survivors than uninfected participants of similar age and sex. "Many diseases, such as Ebola, severe sepsis, dengue, and others are thought to put survivors at increased risk of persistent health problems, but further research is needed," said Dr. Danielle Clark, lead author on the paper and deputy director of the Austere Environments Consortium for Enhanced Sepsis Outcomes at the Naval Medical Research Center.

This study was limited to adult survivors. Since the long-term health effects experienced by children following severe disease likely differs from that of adults, researchers said that additional studies are needed to determine the health needs for children who survive EVD. "The ongoing Ebola virus disease outbreak in West Africa has resulted in thousands of fatalities, but also thousands of survivors. The limited evidence from this study and the work of others indicates that strategies to address the long-term health needs of survivors are needed," said COL Nelson Michael, director of the US Military HIV Research Program at the Walter Reed Army Institute of Research.

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Makerere University Walter Reed Project (MUWRP) of Kampala, Uganda conducted this long-term retrospective cohort study in collaboration with the Uganda Ministry of Health and the district health care workers in Bundibugyo. Initially established to study HIV vaccines by the US Military HIV Research Program at the Walter Reed Army Institute of Research, MUWRP also conducted the first Ebola vaccine study in Africa and is currently testing a Chimpanzee Adenovirus Ebola vaccine candidate with the NIAID. For more information, visit http://www.muwrp.org

This research was supported by the Chemical Biological Technologies Directorate from the Department of Defense Chemical and Biological Defense program through the Defense Threat Reduction Agency (DTRA) and Division of Global Emerging Infections Surveillance and Response System (GEIS) Operations at the Armed Forces Health Surveillance Center (RJS).

About MHRP
The US Military HIV Research Program (MHRP) at the Walter Reed Army Institute of Research conducts research to develop an effective HIV vaccine and integrates prevention, treatment, diagnosis and monitoring as part of a global effort to protect troops and reduce the impact of HIV worldwide. MHRP has developed six state-of-the-art international research sites in the Africa and Asia. In 2009, MHRP announced results of an Army-sponsored clinical trial in Thailand that demonstrated for the first time a modest ability to protect against HIV infection, reducing the number of infections by 31.2 percent. The program successfully collaborates on HIV prevention care and treatment services, funded by the President's Emergency Plan for AIDS Relief (PEPFAR), with African militaries and in the communities where it conducts research. For more information, visit http://www.hivresearch.org or find MHRP on Facebook, http://www.facebook.com/hivresearch, and Twitter at @MHRPInfo.

About the Walter Reed Army Institute of Research (WRAIR)
WRAIR is a leader in global efforts against the world's most pervasive and high impact infectious diseases, such as malaria, HIV/AIDS, Ebola, and dengue. Infectious diseases pose a significant and persistent threat to force protection and readiness and while the primary mission of Army medical research is protection of the U.S. Service and their family members, vaccines and treatments developed by Army researchers also benefit global public health. For more information on WRAIR, visit: http://wrair-www.army.mil/

How best to test Ebola treatment

PLOS

An unconventional clinical trial design might have advantages over classical trials for testing treatments for Ebola virus disease (EVD), suggests a study published this week in PLOS Medicine. The work of an international team led by John Whitehead of Lancaster University, UK and Ben Cooper of Oxford University, UK, provides much-needed data to inform a debate on the scientific and ethical justification for non-randomized EVD trials that has taken place in the editorial pages of a number of medical journals in past months.

The researchers compared three different scenarios using analytic methods and computer simulations and report that, compared with two different approaches using all randomized trials, a multi-stage approach (MSA) that includes a component without randomization has the potential under certain circumstances to reduce patient harm and the time to roll-out of an effective treatment for EVD.

Although alternative evaluation designs are possible, the researchers suggest that beginning with a non-randomized phase II stage can be the quickest way to triage potential treatments and to decide how to test them further. For treatments that show strong evidence of benefit, it might even be possible to recommend the treatment without undertaking an RCT, they suggest.

While stressing that "RCTs are usually the best method for evaluating interventions", the researchers argue that "the current Ebola epidemic in west Africa is an unprecedented situation where there is substantial uncertainty that RCTs can be conducted successfully and safely". "Given these operational concerns and the results of our analysis", they say, "the MSA--which begins with a less operationally challenging design and yet retains the ability to provide robust and informative results--must be considered."

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Research Article
Funding: The work was supported by the Wellcome Trust of Great Britain (grant number 106491/ Z/14/Z and 089275/Z/09/Z) and by the EU FP7 project PREPARE (602525). BSC was supported by The Medical Research Council and Department for International Development (grant number MR/ K006924/1). MFB is supported by the Wellcome Trust (grant number 098511/Z/12/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: NJW is a member of the Editorial Board of PLOS Medicine. PO is a staff member of the World Health Organization (WHO); the authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy, or views of the WHO. The authors have declared that no other competing interests exist.

Citation: Cooper BS, Boni MF, Pan-ngum W, Day NPJ, Horby PW, Olliaro P, et al. (2015) Evaluating Clinical Trial Designs for Investigational Treatments of Ebola Virus Disease. PLoS Med 12(4): e1001815. doi:10.1371/journal.pmed.1001815

Author Affiliations:
Mahidol Oxford Tropical Medicine Research Unit, THAILAND
University of Oxford, UNITED KINGDOM
Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, VIETNAM
Mahidol University, THAILAND
UNICEF-UNDP-World Bank-WHO Special Programme for Research and Training in Tropical Diseases, SWITZERLAND
Lancaster University, UNITED KINGDOM

IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE FREELY AVAILABLE PAPER: http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001815

Contact:
Ben S. Cooper
Mahidol University
THAILAND
+66 (0)23549128 x110
ben@tropmedres.ac; ben.s.cooper@gmail.com

New Ebola study points to potential drug target

WASHINGTON UNIVERSITY SCHOOL OF MEDICINE

Opening the door to potential treatments for the deadly Ebola virus, scientists have found that a protein made by the virus plays a role similar to that of a coat-check attendant. The protein removes a protective coat from the virus's genetic material, exposing the viral genome so that it can be copied, and then returns the coat, according to new research led by scientists at Washington University School of Medicine in St. Louis. The research, in cell cultures, showed that interfering with this process kills the virus.

As part of the study, the researchers introduced rogue coat-check attendants into Ebola-infected cells. These rogue attendants carried a short chain of amino acids that forms the part of the protein that removes the coat. But they lacked the ability to return the coat, disrupting the emergence of newly created viruses from infected cells. Consequently, the virus did not survive. "This coat-check protein, known as VP35, has a great deal of potential as a new target for Ebola treatments," said senior author Gaya Amarasinghe, PhD, assistant professor of pathology and immunology at the School of Medicine. "If we can block this process, we can stop Ebola infection by blocking viral replication." The study appears April 9 in Cell Reports.

The Ebola outbreak that began last year in West Africa has infected nearly 25,000 people and killed more than 10,000, according to the Centers for Disease Control and Prevention. Ebola and other viruses like it are made of a single strand of RNA, a genetic material closely related to DNA. Higher organisms use RNA to copy protein-building instructions from their DNA, but Ebola stores such instructions -- the virus's genetic self -- directly in RNA.

RNA is less stable than DNA and can set off immune defenses that destroy viruses. So Ebola keeps its RNA covered with a protective coat called the nucleoprotein. To replicate, however, the virus has to partially remove the nucleoprotein and expose its RNA to the viral copying machinery. Amarasinghe and first author Daisy Leung, PhD, together with colleagues at the Icahn School of Medicine at Mount Sinai, University of Texas Southwestern Medical Center, Texas Biomedical Research Institute and Baylor University, have spent the past seven years studying the role of VP35, a viral protein involved in the replication process,

"One of the major challenges was that the part of VP35 involved in this interaction is an intrinsically disordered peptide," said Leung, an assistant professor of pathology and immunology at Washington University. "This means that it may not take on a definite structure until it binds to another protein. That made structural studies of VP35 difficult because the structure, which plays a critical role in determining function, doesn't form without its specific binding partner."

The researchers showed that VP35 binds to the virus's nucleoprotein -- which forms part of the protective coat worn by the virus' RNA. They found that this binding removes the nucleoprotein from the viral RNA prior to replication. And while the viral RNA is being copied, VP35 keeps newly synthesized nucleoproteins from attaching to other RNA in the host cell. New copies of the virus require new protein coats. So VP35 also ensures that new nucleoproteins -- made by the host cell's protein-making machinery -- bind only to Ebola RNA, allowing the virus to complete replicating. Disabling or disrupting VP35 could stop the virus in its tracks, according to Amarasinghe.

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The research was supported by the U.S. Department of Defense, grants DTRA 1-21-1-0002, DTRA-HDTRA1-12-1-0051, DTRA HDTRA1-14-1-0013; the National Institutes of Health (NIH), grants R01AI107056, R01GM053163, R01AI077519, R01AI059536, U19AI109945, U19AI109664, U19AI070489, P41GM103832, P50 GM1003297, R01Ai081914; the National Institute of General Medical Sciences, grant P41GM103399; and the Center for Structural Genomics of Infectious Diseases, contract number HHSN272201200026.

Leung DW, Borek DM, Luthra P, Binning JM, Anantpadma M, Liu G, Harvey IB, Su Z, Endlich-Frazier A, Pan J, Shabman RS, Chiu W, Davey R, Otwinowski Z, Basler CF, Amarasinghe GK. An intrinsically disordered peptide from Ebola virus VP35 controls viral RNA synthesis by modulating nucleoprotein-RNA interactions. Cell Reports, April 9, 2015.

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Ebola test vaccines appear safe in phase 2 Liberian clinical trial

Liberia-US partnership planning Phase 3 trial and study of Ebola survivors

NIH/NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES

Two experimental Ebola vaccines appear to be safe based on evaluation in more than 600 people in Liberia who participated in the first stage of the Partnership for Research on Ebola Vaccines in Liberia (PREVAIL) Phase 2/3 clinical trial, according to interim findings from an independent Data and Safety Monitoring Board review. Based on these findings, the study, which is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, may now advance to Phase 3 testing.

"We are grateful to the Liberian people who volunteered for this important clinical trial and encouraged by the study results seen with the two investigational Ebola vaccine candidates," said NIAID Director Anthony S. Fauci, M.D. "Now we must move forward to adapt and expand the study so that ultimately we can determine whether these experimental vaccines can protect against Ebola virus disease and therefore be used in future Ebola outbreaks."

The PREVAIL trial, which began on Feb. 2, 2015 in Monrovia, Liberia, is testing the safety and efficacy of the cAd3-EBOZ candidate vaccine co-developed by NIAID scientists and GlaxoSmithKline, and the VSV-ZEBOV candidate vaccine developed by the Public Health Agency of Canada and licensed to NewLink Genetics Corporation and Merck. Volunteers are assigned at random to receive a single injection of the NIAID/GSK (cAd3-EBOZ) vaccine, the VSV-ZEBOV vaccine, or a placebo (saline) injection. The trial is also double-blinded, meaning that neither study subjects nor staff know whether a vaccine or placebo was administered. A randomized, double-blind, placebo-controlled trial is considered the "gold standard" in clinical research.

While the initial enrollment goal in the Phase 2 study has been met and the vaccines proven safe, the researchers are continuing Phase 2 study enrollment at Redemption Hospital in Monrovia, Liberia, through late April 2015. This would boost enrollment in the Phase 2 portion of the trial to approximately 1,500 people and would be done, in part, to increase the percentage of women (currently, about 16 percent) in the study for a more robust data set overall. The study follow-up period would be at least one year, and two additional blood samples would be obtained from all volunteers at six and 12 months post-vaccination to determine the durability of the immune responses. These proposed changes will be discussed with the U.S. Food and Drug Administration and are under review by the institutional review boards in Liberia and the United States.

Investigators planned to enroll 27,000 people in Liberia at risk of Ebola infection in the Phase 3 portion of the trial. However, there has been only one new confirmed case of Ebola infection in the country since Feb. 19, 2015. Given this decline in Ebola infection incidence, the trial leaders--H. Clifford Lane, M.D., NIAID deputy director for clinical research, and Liberian co-principal investigators Stephen Kennedy, M.D., and Fatorma Bolay, Ph.D.--have determined that it is scientifically appropriate to expand the trial to additional sites in other West African countries. Discussions are underway to explore that possibility.

The Liberia-U.S. research team also plans to launch a separate natural history study of Ebola survivors to better understand the after-effects of Ebola virus disease. Four sites in Monrovia, Liberia and locations in the United States may begin enrollment into this study in the coming months, pending regulatory review and approval. More information on this study will be provided when the trial launches.

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NIAID conducts and supports research--at NIH, throughout the United States, and worldwide--to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

Ebola whole virus vaccine shown effective, safe in primates

UNIVERSITY OF WISCONSIN-MADISON
MADISON, Wis. -- An Ebola whole virus vaccine, constructed using a novel experimental platform, has been shown to effectively protect monkeys exposed to the often fatal virus. The vaccine, described today (March 26, 2015) in the journal Science, was developed by a group led by Yoshihiro Kawaoka, a University of Wisconsin-Madison expert on avian influenza, Ebola and other viruses of medical importance. It differs from other Ebola vaccines because as an inactivated whole virus vaccine, it primes the host immune system with the full complement of Ebola viral proteins and genes, potentially conferring greater protection. "In terms of efficacy, this affords excellent protection," explains Kawaoka, a professor of pathobiological sciences in the UW-Madison School of Veterinary Medicine and who also holds a faculty appointment at the University of Tokyo. "It is also a very safe vaccine."

The vaccine was constructed on an experimental platform first devised in 2008 by Peter Halfmann, a research scientist in Kawaoka's lab. The system allows researchers to safely work with the virus thanks to the deletion of a key gene known as VP30, which the Ebola virus uses to make a protein required for it to reproduce in host cells. Ebola virus has only eight genes and, like most viruses, depends on the molecular machinery of host cells to grow and become infectious. By engineering monkey kidney cells to express the VP30 protein, the virus can be safely studied in the lab and be used as a basis for devising countermeasures like a whole virus vaccine. The vaccine reported by Kawaoka and his colleagues was additionally chemically inactivated using hydrogen peroxide, according to the new Science report.

Ebola first emerged in 1976 in Sudan and Zaire. The current outbreak in West Africa has so far claimed more than 10,000 lives. There are no proven treatments or vaccines, although several vaccine platforms have been devised in recent years, four of which recently advanced to the clinical trial stage in humans. The new vaccine reported by Kawaoka has not been tested in people. However, the successful tests in nonhuman primates conducted at the National Institutes of Health (NIH) Rocky Mountain Laboratories, a biosafety level 4 facility in Hamilton, Montana, may prompt further tests and possibly clinical trials of the new vaccine. The work at Rocky Mountain Laboratories was conducted in collaboration with a group led by Heinz Feldmann of NIH.
Those studies were conducted with cynomolgus macaques, which are very susceptible to Ebola. "It's the best model," Kawaoka says. "If you get protection with this model, it's working."

Ebola vaccines currently in trials include:
--A DNA-based plasmid vaccine that primes host cells with some of the Ebola proteins.
--A vaccine based on a replication incompetent chimpanzee respiratory virus engineered to express a key Ebola protein.
--A live attenuated virus from the same family of viruses that causes rabies, also engineered to express a critical Ebola protein.
--A vaccine based on a vaccinia virus and engineered to express a critical Ebola protein.

Each of those strategies, Kawaoka notes, has drawbacks in terms of safety and delivery. Whole virus vaccines have long been used to successfully prevent serious human diseases, including polio, influenza, hepatitis and human papillomavirus-mediated cervical cancer. The advantage conferred by inactivated whole virus vaccines such as the one devised by Halfmann, Kawaoka and their colleagues is that they present the complete range of proteins and genetic material to the host immune system, which is then more likely to trigger a broader and more robust immune response. Early attempts to devise an inactivated whole virus Ebola vaccine through irradiation and the preservative formalin failed to protect monkeys exposed to the Ebola virus and were abandoned. Although the new vaccine has surpassed that hurdle, human trials are expensive and complex, costing millions of dollars.

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The Ebola vaccine study conducted by Kawaoka was supported by the National Institutes of Health and by the Japanese Health and Labour Sciences Research Grants. In addition to Kawaoka, co-authors of the new Science report include Halfmann, Lindsay Hill-Batorski and Gabriele Neumann of UW-Madison and Andrea Marzi, W. Lesley Shupert and Feldmann of the National Institute of Allergy and Infectious Diseases.

CONTACT: Yoshihiro Kawaoka, kawaokay@svm.vetmed.wisc.edu
Terry Devitt, 608-262-8282, trdevitt@wisc.edu

Study announces a durable vaccine for Ebola

A cytomegalovirus-based vaccine provides long-lasting protective immunity against Ebola virus, and has potential for development as a disseminating vaccine strategy to prevent ebolavirus infection of wild African ape populations

UNIVERSITY OF PLYMOUTH
A cytomegalovirus (CMV)-based vaccine provides long-lasting protective immunity against Ebola virus, and has potential for development as a disseminating vaccine strategy to prevent ebolavirus infection of wild African ape populations. A new study shows the durability of a novel 'disseminating' cytomegalovirus (CMV)-based Ebola virus (Zaire ebolavirus; EBOV) vaccine strategy that may eventually have the potential to reduce ebolavirus infection in wild African ape species.  The multi-institutional study is led by Dr Michael Jarvis at Plymouth University, and is published today, 25th March 2015, in Vaccine.

African apes serve as a main source of ebolavirus transmission into the human population. As a consequence, the prevention of ebolavirus infection in African apes could reduce the incidence of future human ebolavirus outbreaks. Ebola virus is also highly lethal to African apes, and is regarded as a major threat to the survival of these populations in the wild. Such a 'disseminating' vaccine offers hope for both stabilizing these endangered ape populations and protecting humans against the devastating effects of Ebola.

The innovative approach may overcome the major hurdle to achieving high vaccine coverage of these animals. They live in of some of the most remote, inaccessible regions of the world which makes conventional, individual vaccination near impossible. Apart from being very immunogenic (able to provoke an immune response) and species-specific, CMV can also spread easily from individual to individual, a process which remains remarkably unaffected by prior CMV immunity. This is the basis of the team's current innovative strategy of using a CMV-based ebolavirus vaccine that can spread through wild ape populations as a means to provide high levels of protective ebolavirus-specific immunity without the need for direct vaccination.

The current publication expands on a 2011 study, in which the same collaborative research team first showed the ability of a CMV-based vaccine to provide protection against Ebola virus in a mouse challenge model. Most Ebola virus vaccine mouse studies, including this earlier 2011 study, have only assessed protection against Ebola virus infection shortly after vaccination (generally within six weeks post-vaccination). The present study showed that immunity induced by CMV is extremely long-lasting, with Ebola virus-specific immune responses being maintained for greater than 14 months (equivalent to half the life span of a mouse) following only a single dose of the vaccine.

Importantly, immunity induced by the CMV vaccine was able to provide protection against Ebola virus at least until 119 days (approximately four months) post-vaccination. Long-lasting immunity will be critical for the eventual success of this disseminating vaccine approach. It is also an attractive characteristic for a (albeit non-disseminating) CMV-based Ebola virus vaccine for direct use in humans, which is an additional area of development of the current collaborative research group.

The next step, which is nearing completion, is to trial the vaccine using CMV in the macaque EBOV challenge model (regarded as the 'gold standard' for testing vaccines in a model translatable to Ebola infection in great apes and humans). The results from this study further support the utility of this approach and will be published in the next few months. Many questions clearly remain, including the nature of the immunity conferred by disseminated CMV vaccines (in the current study mice were directly inoculated).

"We must walk before we can run, but this study provided a little skip," said Dr. Michael Jarvis, corresponding author on the study from Plymouth University Peninsula Schools of Medicine and Dentistry. "However, this disseminating approach does potentially provide a workable solution to a currently intractable problem of achieving high vaccine coverage in inaccessible ape populations. Given the impact of ebolavirus on African ape numbers in the wild, and the role of apes as a route of ebolavirus transmission to humans via the bush meat trade, such a vaccine would be a win-win for humans and wild apes alike."

To this end the project has been incorporated as a component of an international research program, which includes key players such as the World Wildlife Fund and National Institutes of Health, which are dedicated to driving the project forward to mobilization.

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For more information about this press release please contact Andrew Gould, andrew.gould@plymouth.ac.uk

Article reference: "A cytomegalovirus-based vaccine provides long-lasting protection against lethal Ebola virus challenge after a single dose" by Yoshimi Tsuda, Christopher J. Perkins, Patrizia Caposio, Friedericke Feldmann, Sara Botto, Susan Ball, Ilhem Messaoudi, Luka Cicin-Sain, Heinz Feldmann, Michael A. Jarvis. DOI: 0.1016/j.vaccine.2015.03.029. It appears in Vaccine published by Elsevier.

Copies of this paper are available to credentialed journalists upon request; please contact Elsevier's Newsroom at newsroom@elsevier.com or +31 20 4853564

About Plymouth University Peninsula Schools of Medicine and Dentistry
Plymouth University Peninsula Schools of Medicine and Dentistry focuses on medical, dental and biomedical education and research. In education it takes the lead in using innovative, evidence-based learning techniques which nurture future doctors, dentists and biomedical scientists who are clinically excellent, have immense empathy for those in their care, and who are well-prepared for roles in an ever-changing health service. Research covers the areas of clinical neurosciences; cancer; inflammation, infection and immunity; diagnostics; genomics; stratification; prevention; personalised integrated care; and novel health technologies. The Research Excellence Framework 2014 ranked the organisation top in the UK for the quality of its research outputs, above medical schools at the Universities of Oxford and Cambridge. It is one of the lead academic partners in the Alzheimer's Research UK South West Research Network, and one of four Research Centres of Excellence for charity Brain Tumour Research.

About Vaccine
Vaccine is the pre-eminent journal for those interested in vaccines and vaccination. It is the official journal of The Edward Jenner Society, The International Society for Vaccines and The Japanese Society for Vaccinology and is published by Elsevier. http://www.elsevier.com/locate/vaccine

TKM-Ebola-Guinea Enters Phase II Clinical Study in Sierra Leone

Patient Recruitment Initiated

VANCOUVER, British Columbia, March 11, 2015 (GLOBE NEWSWIRE) -- Tekmira Pharmaceuticals Corporation (Nasdaq:TKMR), an industry-leading therapeutic solutions company focused on developing a cure for chronic hepatitis B virus infection (HBV), announced today that TKM-Ebola-Guinea will be evaluated for efficacy in Ebola virus infected patients in Sierra Leone, West Africa. Patient recruitment has been initiated.

The Phase II single arm trial called RAPIDE (Rapid Assessment of Potential Interventions & Drugs for Ebola) is open-label with a concurrent observational study of Ebola virus disease in Sierra Leone. Study results are expected in the second half of 2015. The University of Oxford, which is the representative of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) is responsible for conducting the Phase II study, with funding provide by the Wellcome Trust.

"We have been working judiciously these last few months to finalize a suitable clinical trial protocol and to receive all the necessary ethics and regulatory approvals to enable TKM-Ebola-Guinea to be clinically evaluated in patients in Sierra Leone," said Dr. Mark J. Murray, Tekmira's President and CEO. "This study will enable us to gather important clinical data that may help us to determine whether TKM-Ebola-Guinea is a promising treatment for patients infected with Ebola virus disease. We expect the results of the study to help inform us on the potential further development of this important therapeutic."

Dr. Murray added, "New cases of Ebola virus disease infections are still occurring, and many people remain infected, which reinforces the critical need for effective therapeutics against this deadly disease. If we are eventually successful in obtaining market approval of TKM-Ebola-Guinea, the company would provide patients a therapeutic option for this terrible disease and in addition this may place the company on a path to receive a Tropical Disease Priority Review Voucher from the US FDA that we can apply to another product in development to support expedited approval."

About TKM-Ebola-Guinea, an Anti-Ebola RNAi Therapeutic Targeting Ebola-Guinea
The Ebola-Guinea strain is known as "Ebola virus Makona" the virus responsible for the current outbreak in West Africa. This strain diverges slightly from the Kikwit strain, which was the original target of TKM-Ebola. The genomic sequence of the Ebola-Guinea strain was determined from several viral isolates and published in the New England Journal of Medicine in October 20141. Tekmira developed a modified RNAi therapeutic, based on the Company's original TKM-Ebola investigational therapeutic, to specifically target Ebola-Guinea. The new product, termed TKM-Ebola-Guinea, is designed to match the genomic sequence exactly, with two RNAi triggers. The ability to rapidly and accurately match the evolving genetic sequences of emerging infectious agents is one of the powerful features of RNAi therapeutics.

About the Neglected Tropical Disease Priority Review Voucher Program
Developed by the U.S. FDA in 2007 under the Food and Drug Administration Amendments Act ("FDAAA"), a Priority Review Voucher (PRV) is an incentive for companies to invest in new drugs and vaccines for neglected tropical diseases. Ebola virus disease was recently added to the PRV program. A PRV entitles the holder to a "priority review" reducing the target review time for a New Drug Application from 10 months to 6 months. Plus, the PRV permits a voucher to be sold—"transferred"—an unlimited number of times, before eventual use.

About RNAi and Tekmira's LNP
RNAi therapeutics have the potential to treat a number of human diseases by "silencing" disease causing genes. The discoverers of RNAi, a gene silencing mechanism used by all cells, were awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi trigger molecules often require delivery technology to be effective as therapeutics. Tekmira believes its LNP technology represents the most advanced and widely adopted delivery technology for the systemic delivery of RNAi triggers. Tekmira's LNP platform is being utilized in multiple clinical trials in various disease areas by Tekmira and its partners. Tekmira's LNP technology (formerly referred to as stable nucleic acid-lipid particles or SNALP) encapsulates RNAi triggers with high efficiency in uniform lipid nanoparticles that are effective in delivering these therapeutic compounds to disease sites. Tekmira's LNP formulations are manufactured by a proprietary method which is robust, scalable and highly reproducible, and LNP-based products have been reviewed by multiple regulatory agencies for use in clinical trials. LNP formulations comprise several lipid components that can be adjusted to suit the specific application.

About Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to improving health. We provide more than £700 million a year to support bright minds in science, the humanities and the social sciences, as well as education, public engagement and the application of research to medicine. Our investment portfolio gives us the independence to support such transformative work as the sequencing and understanding of the human genome, research that established front-line drugs for malaria, and Wellcome Collection, our free venue for the incurably curious that explores medicine, life and art. www.wellcome.ac.uk.

About Oxford University's Medical Sciences Division
Oxford University's Medical Sciences Division is one of the largest biomedical research centres in Europe, with over 2,500 people involved in research and more than 2,800 students. The University is rated the best in the world for medicine, and it is home to the UK's top-ranked medical school. From the genetic and molecular basis of disease to the latest advances in neuroscience, Oxford is at the forefront of medical research. It has one of the largest clinical trial portfolios in the UK and great expertise in taking discoveries from the lab into the clinic. Partnerships with the local NHS Trusts enable patients to benefit from close links between medical research and healthcare delivery. A great strength of Oxford medicine is its long-standing network of clinical research units in Asia and Africa, enabling world-leading research on the most pressing global health challenges such as malaria, TB, HIV/AIDS and flu. Oxford is also renowned for its large-scale studies which examine the role of factors such as smoking, alcohol and diet on cancer, heart disease and other conditions.

About Tekmira
Tekmira Pharmaceuticals Corporation is a biopharmaceutical company dedicated to discovering, developing and commercializing a cure for patients suffering from chronic hepatitis B infection (HBV). We believe this goal will only be accomplished with multiple agents and multiple mechanisms of action targeting various aspects of the virus in combination. Our strategy is to target the three pillars necessary to develop a curative regimen for HBV, including suppressing HBV replication within liver cells, stimulating and reactivating the body's immune system so that it can mount an effective defense against the virus and, most importantly, eliminating the reservoir of viral genomic material known as covalently closed circular DNA, or cccDNA, that is the source of HBV persistence. Our portfolio of assets includes eight drug candidates for use in combination to develop a cure for HBV.

We also have meaningful non-HBV assets including key development partnerships and product candidates in oncology (TKM-PLK1), anti-viral (TKM-Ebola and TKM-Ebola-Guinea) and metabolic programs (TKM-HTG) that leverage our expertise in RNA interference (RNAi) therapeutics and leading Lipid Nanoparticle (LNP) delivery technology. RNAi and LNP technology have the potential to generate new therapeutics that take advantage of the body's own natural processes to silence disease causing genes, or more specifically, to eliminate specific gene-products, from the cell. Our plan is to maximize the value of these programs while ensuring the primary focus and resource allocation within the company remains weighted on HBV.

Forward-Looking Statements and Information
This press release contains forward-looking statements within the meaning of the Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, and forward looking information within the meaning of Canadian securities laws (collectively, "forward-looking statements"). Forward-looking statements in this press release include statements about an evaluation of TKM-Ebola-Guinea; the timing of expected results of the Phase II clinical (Rapid Assessment of Potential Interventions & Drugs for Ebola) RAPIDE study; the University of Oxford as the conductor of the study; the funding provided by the Wellcome Trust; the ability to gather useful clinical data from the study; market approval of TKM-Ebola-Guinea; receipt and subsequent use of a Tropical Disease Priority Review Voucher; curing HBV through a combination mechanism; and Tekmira's plan to maximize the value of its non-HBV assets while ensuring a primary focus and resource allocation on HBV.

With respect to the forward-looking statements contained in this press release, Tekmira has made numerous assumptions regarding, among other things: the continued ability of the University of Oxford to conduct the Phase II clinical RAPIDE study; the availability of funding from the Wellcome Trust; the availability of patients for the study; the ability to carry out the study effectively and obtain useful data; the continuation of the Neglected Tropical Disease Priority Review Voucher Program; and the continued suitability of Tekmira's asset strategy. While Tekmira considers these assumptions to be reasonable, these assumptions are inherently subject to significant business, economic, competitive, market and social uncertainties and contingencies.

Additionally, there are known and unknown risk factors which could cause Tekmira's actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements contained herein. Known risk factors include, among others: the University of Oxford may no longer be willing or able to conduct the study; the Wellcome Trust may not be willing or able to provide the necessary funding; there may be insufficient patients in Sierra Leone to enroll into the study; the results may be delayed, or not useful in evaluating the efficacy of TKM-Ebola-Guinea; the Neglected Tropical Disease Priority Review Voucher Program may be discontinued; anticipated pre-clinical and clinical trials may be more costly or take longer to complete than anticipated, and may never be initiated or completed, or may not generate results that warrant future development of the tested drug candidate; Tekmira may not receive the necessary regulatory approvals for the clinical development of Tekmira's products; and market shifts may require a change in strategic focus.

A more complete discussion of the risks and uncertainties facing Tekmira appears in Tekmira's Annual Report on Form 10-K and Tekmira's continuous disclosure filings, which are available at www.sedar.com and at www.sec.gov. All forward-looking statements herein are qualified in their entirety by this cautionary statement, and Tekmira disclaims any obligation to revise or update any such forward-looking statements or to publicly announce the result of any revisions to any of the forward-looking statements contained herein to reflect future results, events or developments, except as required by law.

Reference
1 Baize S., Pannetier D., Oestereich L., et al. "Emergence of Zaire Ebola Virus Disease in Guinea." New England Journal of Medicine. October 9, 2014 Vol. 371 No. 15

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Emergency Ebola response: a new approach to the rapid design and development of vaccines against emerging disease

Claire M Tully, Teresa Lambe, Sarah C Gilbert, Adrian V S Hill

The epidemic of Ebola virus disease has spread at an alarming rate despite containment eff orts. As a result, unprecedented large-scale international response efforts have been made in an attempt to gain control of the outbreak and reduce transmission. Several international consortia have been formed in a remarkable worldwide collaborative effort to expedite trials of two candidate Ebola virus vaccines: cAd3-EBOZ and rVSV-EBOV. In parallel, both vaccines are being manufactured in large amounts to enable future rapid deployment for management of the crisis.

Introduction
On March 23, 2014, WHO reported a rapidly emerging outbreak of Ebola virus disease in Guinea in west Africa. Zaire ebolavirus (referred to hereafter as Ebola virus) was quickly identified as the cause, by which time, suspected cases were being investigated in border areas of neighbouring Liberia and Sierra Leone. By June, the situation was described as “out of control” by front-line Médecins Sans Frontières health workers who had been treating patients since March. WHO declared a public health emergency of international concern on Aug 8, and priority response protocols and implementation strategies were quickly published in the Ebola Response Roadmap.

The outbreak has since become a major humanitarian crisis. Eight countries have been affected so far, and more than 8000 deaths—a fi gure widely thought to be under estimated—have been recorded. Conservative forward projections estimating that more than 20 000 people would be infected before the disease could be contained have already been surpassed.5,6 As the crisis
has escalated, extraordinary measures to contain and treat infections have been implemented.
read more

Chains of transmission and control of Ebola virus disease in Conakry, Guinea, in 2014: an observational study

Ousmane Faye, PhD*, Pierre-Yves Boëlle, PhD*, Emmanuel Heleze, MD, Oumar Faye, PhD, Cheikh Loucoubar, PhD, N'Faly Magassouba, PhD, Barré Soropogui, MD, Sakoba Keita, MD, Tata Gakou, MD, El Hadji Ibrahima Bah, MD, Lamine Koivogui, PhD, Dr Amadou Alpha Sall, PhD†correspondenceemail, Dr Simon Cauchemez, PhD†correspondenceemail
DOI: http://dx.doi.org/10.1016/S1473-3099(14)71075-8

Background
An epidemic of Ebola virus disease of unprecedented size continues in parts of west Africa. For the first time, large urban centres such as Conakry, the capital of Guinea, are affected. We did an observational study of patients with Ebola virus disease in three regions of Guinea, including Conakry, aiming to map the routes of transmission and assess the effect of interventions.

Methods
Between Feb 10, 2014, and Aug 25, 2014, we obtained data from the linelist of all confirmed and probable cases in Guinea (as of Sept 16, 2014), a laboratory database of information about patients, and interviews with patients and their families and neighbours. With this information, we mapped chains of transmission, identified which setting infections most probably originated from (community, hospitals, or funerals), and computed the context-specific and overall reproduction numbers.

Findings
Of 193 confirmed and probable cases of Ebola virus disease reported in Conakry, Boffa, and Télimélé, 152 (79%) were positioned in chains of transmission. Health-care workers contributed little to transmission. In March, 2014, individuals with Ebola virus disease who were not health-care workers infected a mean of 2·3 people (95% CI 1·6–3·2): 1·4 (0·9–2·2) in the community, 0·4 (0·1–0·9) in hospitals, and 0·5 (0·2–1·0) at funerals. After the implementation of infection control in April, the reproduction number in hospitals and at funerals reduced to lower than 0·1. In the community, the reproduction number dropped by 50% for patients that were admitted to hospital, but remained unchanged for those that were not. In March, hospital transmissions constituted 35% (seven of 20) of all transmissions and funeral transmissions constituted 15% (three); but from April to the end of the study period, they constituted only 9% (11 of 128) and 4% (five), respectively. 82% (119 of 145) of transmission occurred in the community and 72% (105) between family members. Our simulations show that a 10% increase in hospital admissions could have reduced the length of chains by 26% (95% CI 4–45).

Interpretation
In Conakry, interventions had the potential to stop the epidemic, but reintroductions of the disease and poor cooperation of a few families led to prolonged low-level spread, showing the challenges of Ebola virus disease control in large urban centres. Monitoring of chains of transmission is crucial to assess and optimise local control strategies for Ebola virus disease.

Funding
Labex IBEID, Reacting, PREDEMICS, NIGMS MIDAS initiative, Institut Pasteur de Dakar.

NIH Ebola study in macaques provides timeframes for post-mortem viral stability

NIH/NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES

WHAT: To determine how long Ebola virus could remain infectious in a body after death, National Institutes of Health (NIH) scientists sampled deceased Ebola-infected monkeys and discovered the virus remained viable for at least seven days. They also detected non-infectious viral RNA for up to 70 days post-mortem. The study, published in Emerging Infectious Diseases, suggests that Ebola transmission from deceased individuals may be possible for an extended period of time following death, underscoring the importance of using safe practices for handling corpses. The research also highlights oral swabbing of bodies as a reliable and safer alternative to riskier procedures for obtaining diagnostic samples.

To conduct this study, scientists at NIH's National Institute of Allergy and Infectious Diseases tested samples from five deceased macaques used in Ebola virus studies and euthanized after showing signs of disease. To assess the stability of the virus post-mortem, the scientists placed the bodies in a chamber to mimic environmental conditions in West Africa. After the scientists sampled seven different body surfaces and removed tissue from four internal organs, they measured the amount of live Ebola virus and viral RNA, and compared test results at various times. The group determined that live virus was detectable in surface swabs up to seven days after death, and in the tissue samples up to three days post-mortem. Viral RNA was detectable in several swab and tissue types for up to 10 weeks.

The scientists believe these findings are likely to be consistent for non-human primates such as gorillas and monkeys. In fact, they designed the study to test animals found dead in the wild, but shifted the timing and emphasis to human implications related to the ongoing West Africa Ebola outbreak.

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ARTICLE:
J Prescott et al. Post-mortem stability of Ebola virus. Emerging Infectious Diseases DOI: 10.3201/eid2105.150041 (2015).

Grant awarded to test new wireless approach to improve Ebola care

Scripps Translational Science Institute to lead team developing innovative technology program

SAN DIEGO - Scripps Translational Science Institute will lead a consortium of four partners to develop a program through which wearable, wireless health sensors, a wireless vital signs monitoring platform and advanced analytics technology will be tested in a new "precision medicine" approach designed to improve health outcomes for Ebola patients, increase the safety of health care workers and reduce risk of spreading the virus to others. The program will be funded by a grant that was announced today by the U.S. Agency for International Development.

Joining STSI in the new program are wireless vital signs monitor developer Sotera Wireless, Inc., wireless health sensor developer Rhythm Diagnostic Systems, and personalized predictive analytics technology company PhysIQ. The program is dubbed STAMP2, short for Sensor Technology and Analytics to Monitor, Predict and Protect Ebola Patients. STAMP2 will test the effectiveness of the novel technology to monitor and analyze multiple vital signs of patients either suspected or confirmed to be infected with the Ebola virus.

STAMP2 represents a potential solution to current shortcomings in the management of Ebola patients. For example, the existing approach for monitoring patients suspected of an infection detects the infection only after a patient has become contagious and the virus has the opportunity to spread. And for patients confirmed to be infected, important changes in health status can be missed in periodic vital sign checks, even when carried out every few hours. In both cases, continuous monitoring of multiple vital signs, coupled with sophisticated, personalized data analytics, can lead to much earlier warning and with it, earlier intervention.

"The new approach will provide unprecedented visibility into a patient's physiology that we believe will be invaluable in improving care in minimizing risk of exposure during an Ebola virus outbreak," said Steven Steinhubl, M.D., director of digital medicine at Scripps Health. "This will open the door to being able to identify warning signs very early on, when potentially lifesaving care can be provided."

Patient data will be collected using two innovative wireless monitors that will continuously and remotely monitor and transmit multiple vital signs. By incorporating the ViSi Mobile System from Sotera Wireless and a Band Aid-type sensor - the MultiSense device from Rhythm Diagnostic Systems - into systems of care, patients will be able to be monitored at all times, so that changes in their condition can be recognized sooner, and without needless exposure to health care workers.

Data from the monitors will be transmitted wirelessly to a personalized physiology analytics (PPA) platform developed by physIQ, which will use advanced machine learning algorithms to detect subtle changes in a patient's physiological profile over time, compared to the patient's physiological baseline. The PPA will also provide automated analysis, actionable information and guidance to clinical staff for multiple patients simultaneously. This offers the opportunity to detect and act upon changes in a patient's health status in real time, well before symptoms develop or conditions worsen.

Plans to develop, validate, refine and field test the STAMP2 program are currently under way. Following the completion of these processes, it is expected that a fully functioning turnkey STAMP2 system would be made available for deployment to the appropriate U.S. federal agencies. As currently envisioned, the system would include an appropriately scaled supply of ViSi Mobile and MultiSense wireless health monitoring devices, wireless rugged computers and smartphones and tablets with specially created apps.

The PPA analytic capability will be provided for either cloud-based or local storage and processing, along with a web portal for clinical access to patient status. As currently envisioned, the completed turnkey system would have the capability to accommodate the monitoring of up to 500 patients, but the program could be flexible enough to be ramped up or down as needed.

Ebola is a rare and deadly disease caused by infection with one of the Ebola virus strains. The disease was first discovered in 1976 near the Ebola River in what is now the Democratic republic of Congo. When an Ebola virus infection occurs in humans, the virus can be spread to others through direct contact with blood or body fluids, objects such as syringes, or infected fruit bats or primates.

According to the Centers for Disease Control and Prevention, the 2014 Ebola epidemic is the largest such outbreak in history, affecting multiple countries in West Africa, with more than 13,000 confirmed cases and more than 9,000 deaths. Two imported cases, including one death, and two locally acquired cases in health care workers have been reported in the United States, and one confirmed case has been reported in Spain.

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ABOUT SOTERA WIRELESS
Sotera Wireless, Inc. is a San Diego-based medical device company dedicated to the development, marketing and sale of a new generation of comprehensive vital signs monitoring. Sotera's mission is to improve patient safety by empowering clinicians to detect early signs of deterioration in virtually any care setting and enable early intervention and rapid response, all without limiting the patient's freedom of movement. Sotera's ViSi Mobile System is a platform for comprehensive vital signs monitoring that is designed to keep clinicians connected to their patients. ViSi Mobile is able to measure and display core vital signs (non-invasive blood pressure, heart rate, pulse rate, respiratory rate, skin temperature, electrocardiogram and more), with monitoring accuracy and resolution typically found in intensive care units, plus motion, posture and activity. More information on the company or its ViSi Mobile System can be obtained at soterawireless.com or by sending an email to info@soterawireless.com. Sotera® and ViSi® are registered trademarks of Sotera Wireless, Inc.

ABOUT RHYTHM DIAGNOSTIC SYSTEMS, INC.
Rhythm Diagnostic Systems is focused on developing and manufacturing a family of proprietary, wearable, small, unobtrusive, Band Aid-like strips, each capable of detecting simultaneously, and recording or transmitting, up to nine different physiological parameters. In this way, single, wireless strips can be tailored to detect and report just those parameters relevant to a particular disorder or study. Strips tailored to monitor various aspects of cardiac, cardiopulmonary, and sleep disorders are currently in clinical and other trials. These MultiSense™ strips, weighing less than 10 grams, integrate not only the ability to detect and measure any and all of these parameters, but also connectivity via direct reading of flash memory or low power Bluetooth. Rhythm Diagnostic Systems is based in the San Francisco Bay Area. More information on the company and the MultiSense strips can be obtained at http://www.rhythmdiagnostics.com, or by email to info@rhythmdiag.com.

ABOUT physIQ
Based in Naperville, Ill., PhysIQ is a company dedicated to making a difference in people's lives through its proprietary personalized physiology analytics technology. PhysIQ is a proven, first-of-its-kind data analytics platform designed to process multiple vital signs from wearable sensors to create a personalized normal baseline for each individual. By mapping personal physiology this way, we can then monitor and detect clinically significant departures from the norm to enable timely corrective action for patients. With applications in both the regulated healthcare and consumer health and fitness markets, physIQ is bringing the same technology used to monitor complex systems like jet aircraft engines to human health.

ABOUT SCRIPPS TRANSLATIONAL SCIENCE INSTITUTE
Part of the San Diego, Calif.-based Scripps Health, the Scripps Translational Science Institute (STSI) is a unique community collaboration that embraces precision medicine by initiating research to move basic science from the lab to the patient bedside. STSI is supported by the National Institutes of Health flagship program, Clinical and Translational Science Award, awarded to The Scripps Research Institute in conjunction with its collaboration with STSI. The San Diego Supercomputer Center also is a collaborator in the STSI consortium. More information can be found at http://www.stsiweb.org.

ABOUT SCRIPPS HEALTH
Founded in 1924 by philanthropist Ellen Browning Scripps, Scripps Health is a nonprofit integrated health system based in San Diego, Calif. Scripps treats a half-million patients annually through the dedication of 2,600 affiliated physicians and 13,750 employees among its five acute-care hospital campuses, hospice and home health care services, and an ambulatory care network of physician offices and 25 outpatient centers and clinics.

Recognized as a leader in the prevention, diagnosis and treatment of disease, Scripps is also at the forefront of clinical research, genomic medicine and wireless health care. With three highly respected graduate medical education programs, Scripps is a longstanding member of the Association of American Medical Colleges. In 2014, Truven Health Analytics named Scripps one of the top five large health systems in the nation for the third year, and Scripps hospitals are consistently ranked by U.S. News & World Report among the nation's best. Scripps is regularly recognized by Fortune, Working Mother magazine and AARP as one of the best places in the nation to work. More information can be found at http://www.scripps.org.

Ebola: New studies model a deadly epidemic

ARIZONA STATE UNIVERSITY

On Dec. 26, 2013, a two-year-old boy living in the Guinean village of Meliandou, Guéckédou Prefecture was stricken with a rare disease, caused by the filament-shaped Ebola virus. The child is believed to be the first case in what soon became a flood-tide of contagion, ravaging the West African countries of Guinea, Sierra Leone and Liberia, infecting, according to the World Health Organization, over 21,000 cases as of Jan. 21, with nearly 9000 confirmed deaths--the actual toll likely much higher.

Now, researchers from Arizona State University and Georgia State University are trying to better understand the epidemiology and control of Ebola Virus Disease in order to alleviate suffering and prevent future disease outbreaks from reaching the catastrophic proportions of the current crisis. In reports appearing in the February 2015 issue of the prestigious British medical journal The Lancet Infectious Disease, ASU researchers report on new efforts to model the impact of timely diagnostic testing on the spread of Ebola across populations. A better understanding of viral dissemination and techniques for disease management are vital if a similar calamity is to be avoided in the future. Researchers from the Biodesign Institute, and the Simon A. Levin Mathematical, Computational and Modeling Sciences Center present a new study: Modelling the effect of early detection of Ebola. The study examines the levels of detection and patient isolation required to shut down transmission of Ebola.

In related research, Gerardo Chowell, a newly appointed faculty member in the School of Public Health at Georgia State University and adjunct faculty member in the ASU's Simon A. Levin Mathematical, Computational and Modeling Sciences Center, together with Cécile Viboud from the from the National Institutes of Health discuss recent large-scale modeling efforts to explain the spatial-temporal patterns of spread of the epidemic in Liberia. Chowell is also co-author of Ebola control: rapid diagnostic testing, which appears in the Lancet's correspondence section.

Wave of destruction
The Ebola virus has become notorious, not only for its highly contagious and lethal nature, but for the nightmarish assortment of symptoms collectively known as hemorrhagic fever. These may include vomiting of blood, bleeding from the eyes, ears, nose, mouth, rectum, internal bleeding, excruciating pain and the liquidization of internal organs. The three West African nations centrally affected by the epidemic were acutely unprepared for the crisis. Treatment centers were rapidly swamped with severely ill patients. Resources for proper care, isolation of infected patients and even basic means of sterilization were soon depleted. Health care workers were especially vulnerable to infection.

A number of exacerbating factors contributed to the outbreak and rapid spread of Ebola in the region. Timber and mining activities have impacted densely forested regions and brought fruit bats--believed to be a natural reservoir for the virus--in closer contact with humans. Infected animals consumed as bush meat may also have planted early seeds of the disease in the vulnerable population. Long periods of civil unrest have left the area deeply impoverished and the health infrastructure fractured.

Meliandou, the town identified as ground zero, is situated in a forested area at the convergence point of Guinea, Liberia and Sierra Leone. Populations move fluidly across these porous borders, as impoverished residents are often on the move in search of work. These conditions created a perfect storm for the aggressive virus. An additional factor fueling the explosive spread of Ebola in West Africa was the delayed and inadequate response to the crisis on the part of developed countries and global health organizations.

Time is the enemy
As the authors of the Lancet modeling study emphasize, breaking the chain of Ebola transmission presents intimidating challenges. After the development of symptoms, the virus is highly contagious and each new contact presents an opportunity for further spread of the disease. Tracking all contacts of infected individuals can be a daunting challenge, even in first world settings, with low case numbers. In the absence of a vaccine or reliable therapeutic for Ebola, diagnosis of the disease at a pre-symptomatic stage and rapid isolation of infected individuals are the surest means for arresting further disease transmission.

According to Biodesign's Karen Anderson, PhD., "Early detection of Ebola infection provides the opportunity and time to safely isolate and treat individuals before they become contagious. Our findings show two key things: first, that the predicted impact of early diagnostic tests depends on existing public health measures. Second, there appears to be a tipping point, where early diagnosis of high-risk individuals, combined with adequate isolation, can markedly decrease the predicted number of infected individuals."

Stopping an epidemic in its tracks requires a reduction in a critical value known as the reproductive ratio or R0-- a measure of new infections generated by a single case over the course of the infectious period. The higher the number for R0, the more difficult an epidemic is to contain. A technique known as polymerase chain reaction (PCR) can be used for pre-symptomatic identification of the Ebola virus. The current study models the expected outcomes on viral transmission of Ebola using PCR-based pre-symptomatic diagnosis and isolation of infected patients within 3 days of the onset of symptoms. "Our results underscore the dramatic impact that diagnostic capacity can bring about during an Ebola epidemic to quickly identify Ebola cases before these start new chains of transmission in the community or health care settings," according to Diego Chowell, lead author of the study.

Carlos Castillo-Chavez, director of the Simon A. Levin Mathematical, Computational and Modeling Sciences Center, emphasises the power of mathematical modeling for understanding and limiting the scale of epidemics: "Finding that small differences in isolation effectiveness may have a large impact on epidemic size highlights the importance of evaluating novel diagnostic technologies at the population level using mathematical models," he says. "An intervention may not work or be effective unless it is effectively used beyond a tipping point."

The authors urge the implementation of the strategy of pre-symptomatic diagnosis and rapid isolation, targeting high-risk individuals, including care givers and health care workers. In his comment to the Lancet, Geraldo Chowell examines another mathematical model, put forward by Merler and his colleagues. This study models the course of the Ebola epidemic in Liberia, based on population structure and geography, including location of households, hospitals, and Ebola treatment units. Chowell notes that the establishment of new treatment centers, isolation of new patients and distribution of household protection kits all likely played a role in curtailing the spread of Ebola in Liberia, relative to neighboring states of Guinea and Sierra Leone.

"Carefully calibrated mathematical models have potential to guide public health authorities to effectively respond to disease epidemics," Chowell says. "In the context of the Ebola epidemic in West Africa, several key factors, including delays in responding to the epidemic, behavior changes and increased public health infrastructure in the region in order to trace contacts of infected individuals and break chains of transmission through effective isolation have played a major role in shaping the trajectory of this epidemic."

The desperate need for early diagnosis of Ebola was further emphasized in Chowell's correspondence, which points out that most West African Ebola patients remained undiagnosed in their communities and the average time from symptom onset to diagnosis was about 5 days--a prescription for rapid, far-flung transmission of the disease. While underscoring the diagnostic power of PCR, Chowell notes that such tests presently require transportation to a laboratory or transit center, causing critical delays in diagnosis and treatment and heightening transmission risks. His recommendation is to supplement these efforts with the distribution of point-of-care rapid tests that could be used in households for early protection.

Chowell and his colleagues conducted a simulation based on reducing the time between symptom onset and diagnosis, using rapid testing. The results were dramatic. If 60 percent of Ebola patients can be rapidly diagnosed and isolated (within 1 day of symptom onset), the proportion of the population eventually infected (known as the attack rate) drops from 80 percent to nearly zero.

A vaccine for Ebola?
While authors of the current Lancet papers model Ebola transmission and propose strategies to address future epidemics, ASU has also been on the forefront of efforts toward Ebola therapeutics and eventual vaccines. Charles Arntzen, Ph.D., offered a prescient warning back in 2011 that the next outbreak of Ebola could be far more devastating than those in the past, if sufficient resources were not immediately brought to bear. Regrettably, Arntzen's prediction became a reality with the recent epidemic, far surpassing in death toll and geographic extent all previous Ebola outbreaks combined. Arntzen's earlier study in the Proceedings of the National Academy of Science described an experimental cocktail of monoclonal antibodies produced from tobacco plants, which showed considerable promise in animal studies.

The recent West African epidemic provided an unprecedented opportunity to test the effectiveness of the drug formula, developed with Arntzen's longtime collaborators at San Diego based MAPP Pharmaceuticals. Two health care workers returning to the U.S. after having been stricken with Ebola in Africa were treated with the drug, known as ZMapp. Both survived, offering the tantalizing potential for a safe, highly effective vaccine against the disease.

Arntzen's efforts also highlighted the potential of similar plant-made pharmaceuticals. A number of these are currently being investigated at the Biodesign Institute by Qiang "Shawn" Chen, Ph.D., a researcher in the Center for Infectious Diseases and Vaccinology. Chen hopes to apply similar techniques to produce therapeutics against other diseases, including West Nile Fever, a focus of current research.

According to the latest reports from the World Health Organization, the Ebola epidemic appears to be weakening its grip on the region. For the first time since June 2014, there have been fewer than 100 new weekly cases reported in the 3 countries most affected, signaling what health care workers hope is the final phase of Ebola's devastating reign. Increased vigilance and new tools at both the epidemiological and therapeutic ends of the spectrum are vitally needed, if another epidemic--perhaps of even greater scale--is to be prevented.

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Modelling the effect of early detection of Ebola
Diego Chowell, Carlos Castillo-Chavez, Sri Krishna, Xiangguo Qiu, Karen S Anderson
The Lancet Infectious Diseases, Vol. 15, No. 2, p148-149
Published in issue: February 2015

Controlling Ebola: key role of Ebola treatment centres (Comment)
Gerardo Chowell, Cécile Viboud
The Lancet Infectious Diseases, Vol. 15, No. 2, p139-141

Ebola control: rapid diagnostic testing (correspondence)
Ranu S Dhillon, Devabhaktuni Srikrishna, Robert F Garry, Gerardo Chowell
The Lancet Infectious Diseases, Vol. 15, No. 2, p147-148

Carlos Castillo-Chavez is a Distinguished Sustainability Scientist, Julie Ann Wrigley Global Institute of Sustainability; Regents' and Joaquin Bustoz Jr. Professor, School of Human Evolution and Social Change/School of Mathematical and Statistical Sciences, College of Liberal Arts and Sciences and the Executive Director, Mathematics and Theoretical Biology Institute.

Written by: Richard Harth
Science Writer: Biodesign Institute
richard.harth@asu.edu

In pursuit of next-generation Ebola stockpile vaccines

BY KATE KELLAND AND BEN HIRSCHLER
LONDON Sun Feb 1, 2015 6:51am EST

(Reuters) - As West Africa's devastating Ebola outbreak begins to dwindle, scientists are looking beyond the endgame at the kind of next-generation vaccines needed for a vital stockpile to hit another epidemic hard and fast. Determined not to lose scientific momentum that could make the world's first effective Ebola interventions a reality, researchers say the shots, as well as being proven to work, must be cheap, easy to handle in Africa and able to hit multiple virus strains.

That may mean shifting focus from the stripped-down, fast-tracked vaccine development ideas that have dominated the past six months, but it mustn't mean the field gets bogged down in complexities. "We need a stockpile because there will be other outbreaks," said Seth Berkley, chief executive of the GAVI global immunization alliance, which helps bulk-buy vaccines for poor countries. The experimental vaccines now moving into large clinical trials in West Africa target the current Ebola Zaire virus strain, but the next outbreak may be different. "We need to work with the pharmaceutical industry to create second-generation vaccines that would cover not just Ebola Zaire but also Ebola Sudan and perhaps Marburg, perhaps Lassa. The idea is to have vaccines that will work across different places," Berkley said.

Right now, scientists are grappling with several tricky issues -- partly due to success in cutting new infections in the vast Ebola outbreak. With relatively few new cases, big trials in Liberia and Sierra Leone to test the first generation single-dose one strain vaccines may not have the statistical power needed to show whether the shots work. And already, early data from safety trials in humans suggest a single-dose vaccination with the most advanced vaccine, from GlaxoSmithKline, may not provoke an immune response strong enough to protect people exposed to the virus. "We now know you get around 10 times fewer antibodies in humans (than in monkeys) and probably five times fewer T-cells," said Adrian Hill of Oxford's Jenner Institute, referring to two key elements of the immune system. This strongly suggests that a two-dose regime, or a so-called "prime-boost" approach, is the one likely to prove effective, Hill said.

Sizeable Challenge
These and other issues add up to a sizeable to do list for scientists focusing on vaccines for future stockpiles. Producing multi-strain, or multivalent, vaccines that could protect against different types of Ebola and other hemorrhagic fevers will be more time consuming than making today's monovalent shots, but it is by no means impossible. In fact, several of the candidate Ebola vaccines being fast-tracked through testing started out as multivalents before being stripped back to deal with the current outbreak.

Another challenge is ensuring vaccines have a long shelf-life and can be easily transported in the tropics. At the moment, test shots are kept at -70 or -80 degrees Celsius, although Johnson & Johnson says its Ebola vaccine can be stored at normal fridge temperature for many weeks. Producing adequate volumes, however, looks manageable. Hopefully, the next time Ebola emerges from Africa's forests it will be spotted earlier and immunization will be needed for perhaps tens of thousands of people -- nothing like the tens of millions who would need vaccines in a worldwide flu pandemic.

Finally companies still need a regulatory green light, which gets tricky if large-scale trials fail to produce clear proof that the shots are both safe and effective in people. Researchers and drugmakers say, however, that regulators have made clear stockpile Ebola vaccines could be approved on efficacy data from tests in monkeys or other non-human primates plus proof of safety and immune response in humans, reflecting contingency plans for vaccines designed for bioterror attacks.

Pursuing tomorrow's vaccines is not to say one of today's monovalent shots from GSK, Merck or J&J might not yet have a role in ring-fencing lingering pockets of infection in the current epidemic, and perhaps finally stamping it out. "I'm pretty optimistic there's still a role for vaccination in ending this outbreak," said Hill. "And I'm certainly optimistic that we'll learn for the next outbreak which of these vaccine approaches is the most likely to work, and be ready to tackle it early on."

(Editing by Anna Willard)

First trial results show GSK/NIH Ebola candidate vaccine has acceptable safety profile

A Monovalent Chimpanzee Adenovirus Ebola Vaccine — Preliminary Report

Abstract:

Background">BACKGROUND
The West African outbreak of Ebola virus disease has caused more than 8500 deaths. A vaccine could contribute to outbreak control in the region. We assessed a monovalent formulation of a chimpanzee adenovirus 3 (ChAd3)–vectored vaccine encoding the surface glycoprotein of Zaire ebolavirus (EBOV), matched to the outbreak strain.

METHODS
After expedited regulatory and ethics approvals, 60 healthy adult volunteers in Oxford, United Kingdom, received a single dose of the ChAd3 vaccine at one of three dose levels: 1×10¹⁰ viral particles, 2.5×10¹⁰ viral particles, and 5×10¹⁰ viral particles (with 20 participants per group). Safety was assessed over the next 4 weeks. Antibodies were measured on enzyme-linked immunosorbent assay (ELISA) and T-cell responses on enzyme-linked immunospot (ELISpot) and flow-cytometry assays.

RESULTS
No safety concerns were identified at any of the dose levels studied. Fever developed in 2 of the 59 participants who were evaluated. Prolonged activated partial-thromboplastin times and transient hyperbilirubinemia were observed in 4 and 8 participants, respectively. Geometric mean antibody responses on ELISA were highest (469 units; range, 58 to 4051; 68% response rate) at 4 weeks in the high-dose group, which had a 100% response rate for T cells on ELISpot, peaking at day 14 (median, 693 spot-forming cells per million peripheral-blood mononuclear cells). Flow cytometry revealed more CD4+ than CD8+ T-cell responses. At the vaccine doses tested, both antibody and T-cell responses were detected but at levels lower than those induced in macaques protected by the same vaccine.

CONCLUSIONS
The ChAd3 monovalent vaccine against EBOV was immunogenic at the doses tested. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT02240875.)

Full Text of Discussion...

Scientists ask if Ebola immunises as well as kills

By Kate Kelland and Emma Farge
LONDON/DAKAR (Reuters) - A recent sharp drop in new Ebola infections in West Africa is prompting scientists to wonder whether the virus may be silently immunising some people at the same time as brutally killing their neighbours. So-called "asymptomatic" Ebola cases - in which someone is exposed to the virus, develops antibodies, but doesn't get sick or suffer symptoms - are hotly disputed among scientists, with some saying their existence is little more than a pipe dream.

Yet if, as some studies suggest, such cases do occur in epidemics of the deadly disease, they may be a key factor in ending outbreaks more swiftly by giving secret protection to those lucky enough to be able to bat the infection away. "We wonder whether 'herd immunity' is secretly coming up - when you get a critical mass of people who are protected, because if they are asymptomatic they are then immune," Philippe Maughan, senior operations administrator for the humanitarian branch of the European Commission, told Reuters. "The virus may be bumping into people it can't infect any more."

Latest World Health Organization data show new cases of infection in West Africa's unprecedented Ebola epidemic dropping dramatically in Guinea, Sierra Leone and particularly in Liberia. Most experts are sure the main driver is better control measures reducing direct contact with contagious patients and corpses, but there may also be other factors at work. So-called herd immunity is a feature of many infectious diseases and can, in some cases, dampen an outbreak if enough people get asymptomatic, or "sub-clinical" cases and acquire protective antibodies. After a while, the virus - be it flu, measles, polio - can't find non-immune people to be its hosts. But some specialists with wide experience of disease outbreaks are highly sceptical about whether this phenomenon happens in Ebola, or whether it could affect an epidemic. "There is some suggestion there may be cases that are less severe... and there may even be some that are asymptomatic," said David Heymann, an infectious disease expert and head of global health security at Chatham House. "But herd immunity is just the wrong term. There could be household immunity developing, but even that is only hypothesis."

Others are more hopeful and are urging researchers in West Africa to seek out and test possible asymptomatic cases with a view to using the secrets of their silent immunity. Steve Bellan of the University of Texas in the United States argues that if scientists can reliably identify asymptomatic people, they could help with disease-control tasks like caring for patients and conducting burials, reducing the number of non-immune people exposed in these risky jobs. Bellan points to two studies in particular. One, conducted after an Ebola outbreak in Gabon in 1997, found that 71 percent of "seropositive" people - those with traces of the Ebola virus in their blood - did not have the disease. The other, published in April 2002, found 46 percent of asymptomatic close contacts of patients with Ebola were seropositive.

With the largest Ebola epidemic on record raging through three of Africa's most under-resourced countries, scientists and medics have, understandably, focussed all efforts on the sick and dying and not on testing people with no symptoms. If they do, however, and if they were to find what Bellan and some others suspect, it could prompt a reappraisal of what jolted a relatively sudden downturn in new cases. Some researchers say they have identified a few cases in the current outbreak with mild symptoms and low concentrations of Ebola virus in the blood. One was a Guinean student who travelled to Senegal and is not known to have infected anyone else, despite having contact with dozens of people.

Ian MacKay, a virologist at Australia's University of Queensland, agrees that possible sub-clinically-acquired immunity is one of many unexplored mysteries of the Ebola virus. "One thing that this particular outbreak shows is that we really don't know an awful lot about these kinds of infectious diseases," he said. "We tend to think we can answer all the questions, but this is one of those things we may end up being taught by the virus itself."

© Thomson Reuters 2015 All rights reserved

CWRU researcher on the clock to improve early Ebola detection

CASE WESTERN RESERVE UNIVERSITY
CLEVELAND--Health care workers must diagnose and isolate Ebola victims at an early stage to have a chance to save them and prevent the virus from spreading. But the most sensitive and quickest diagnostic test produces a small percentage of false negative results that undermine efforts to control the deadly agent.

Case Western Reserve University researchers have been awarded a $100,000 National Science Foundation (NSF) grant to--within a year--develop a method to reduce the risk of the virus going undetected. Different forms of Ebola virus have killed 25 percent to 90 percent of those who became infected, according to the World Health Organization. The current outbreak has left more than 8,400 dead in Guinea, Liberia and Sierra Leone, according to recent Centers for Disease Control figures. Among the dead are surgeon Martin Salia, whose family lives in Maryland. After he fell ill in Sierra Leone, an early test for the disease was negative. By the time he was flown to an Omaha, Neb., hospital for treatment in November, he was in advanced stages of the fast-moving disease and died soon after.

"While Ebola is declining in West Africa, there remains a strong risk of outbreaks in the future," said Nicole Steinmetz, an assistant professor of biomedical engineering at Case Western Reserve University. With no vaccine or cure on the horizon, the NSF sought proposals that could quickly improve the status quo. Steinmetz, the principal investigator of the grant and an appointee of the university's School of Medicine, is not an expert in human viruses, but has extensive experience in manipulating nanoparticle-sized plant viruses for the benefit of human health.

The problem with the current method, called the reverse transcription polymerase chain reaction test, is that there is no reliable control available to ensure the target of the test is not being destroyed during processing. The test is designed to detect the presence of Ebola ribonucleic acid, RNA, a key component of the virus' molecular biology. To extract the viral RNA from the tissue for testing, health care workers have to process the tissues, and the target RNA may be destroyed during the harsh conditions of the assay. These processing errors may remain undetected, resulting in a false negative result.

Steinmetz's lab plans to build a positive control through a bio-inspired nanomanufacturing protocol. The team will make a synthetic, safe form of the Ebola RNA and insert it in a plant virus nanoparticle. The plant virus has a protective protein coat similar to the Ebola virus coat that protects its RNA. This control will mimic Ebola virus realistically and can be added to test samples for detection and monitoring of the processing steps.

The safe RNA will also include a type of marker that can be detected by enzymatic activity, as long as the RNA remains intact. Not detecting the marker at any point would indicate that the processing has degraded the plaint virus RNA and would have also degraded any Ebola virus RNA present, Steinmetz said. "It tells us a mistake was made and the assay needs to be repeated to rule out a false negative result," she said. Otherwise, the test could fail to detect the Ebola virus. Therefore, the patient might not be quarantined and treated, and those with whom the patient had close contact would not be tested.

Working with Steinmetz will be Ruth Keri, a professor of pharmacology at the School of Medicine, and the University of Stuttgart's Christina Wege. As part of the project, the lab will develop a high-tech test to use in a clinic and a low-tech test for use in the field. "For the low-tech assay, we'll need a different process where you don't have computers or refrigeration," Steinmetz said. "We hope to develop low-tech kits that can be taken to high-risk areas of Africa and be used to detect the disease earlier rather than waiting on U.S. or European health care workers to fly in and run diagnostics."

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The NSF has awarded nearly 60 Ebola rapid response grant since the outbreak. More information is at:. http://www.nsf.gov/news/news_summ.jsp?cntn_id=133531.

LSU Health New Orleans identifies toxic Ebola protein fragment

New Orleans, LA - William Gallaher, PhD, Emeritus Professor of Microbiology, Immunology & Parasitology at LSU Health New Orleans School of Medicine, has discovered a fragment of an Ebola virus protein that is toxic to cells and may contribute to infection and illness. The findings were published online January 20, 2015, in the open access journal, Viruses, available at http://www.mdpi.com/1999-4915/7/1/285.

The fragment was found within a grouping of amino acids that is made in parallel with the protein involved in attachment of the virus to cells. Called the "Delta peptide," it has been shown recently to block the Ebola virus from attaching to already-infected cells. The new findings suggest that Delta peptide possibly functions by changing membrane permeability.

Following his discovery, Dr. Gallaher contacted Robert Garry, PhD, Professor of Microbiology and Immunology at Tulane University School of Medicine, a longtime collaborator, to produce a structural model and potential mechanism of action. The results of that modeling work were fashioned into a manuscript that was subjected to rigorous peer view by experts in the field and are being made public only after acceptance into a special issue on "Advances in Ebolavirus, Marburgvirus, and Cuevavirus Research 2014-2015" in Viruses.

Although preliminary studies using synthetic peptides have confirmed the potential of the fragment, its specific role and potency in its natural environment within Ebola virus-infected cells are yet to be determined. However, Dr. Gallaher and his colleagues have determined how to deactivate the toxic properties of the Ebola protein fragment in the laboratory environment. He and his colleagues are also developing inhibitors of the toxic mechanism, which may ultimately be useful as drugs, should a role for Delta peptide in Ebola virus disease become established by future studies.

According to the Centers for Disease Control and Prevention (CDC), the 2014 Ebola epidemic is the largest in history, affecting multiple countries in West Africa. Two imported cases, including one death, and two locally acquired cases in healthcare workers have been reported in the United States. As of January 16, 2015, the CDC and World Health Organization report 13,510 laboratory-confirmed cases and 8,483 deaths worldwide.

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This discovery is the latest in a series of discoveries by Dr. Gallaher during a long career, spanning 32 years of active service in the Department of Microbiology, Immunology and Parasitology, at LSU Health New Orleans School of Medicine. He was the first to identify and publish the entry peptide sequence of HIV-1 in 1987, and he and his colleagues, including Dr. Garry, were first to model the structure of the HIV-1 entry protein in 1989. Those studies defined a superfamily of viral entry proteins subsequently named by others as "Class I fusion/entry glycoproteins." The "Gallaher model" of HIV-1 also directly led to the development of the drug Fuzeon, an inhibitor of HIV-1 entry used as therapy for HIV disease. He was also the first to identify and model the entry peptide loop and entry protein of Ebola virus in 1996. He has remained professionally active during retirement, in teaching, research and writing.

The work was supported, in part, by grants from the National Institutes of Health.

LSU Health Sciences Center New Orleans educates Louisiana's health care professionals. The state's health university leader, LSUHSC includes a School of Medicine, the state's only School of Dentistry, Louisiana's only public School of Public Health, and Schools of Allied Health Professions, Nursing, and Graduate Studies. LSUHSC faculty take care of patients in public and private hospitals and clinics throughout the region. In the vanguard of biosciences research in a number of areas in a worldwide arena, the LSUHSC research enterprise generates jobs and enormous economic impact. LSUHSC faculty have made lifesaving discoveries and continue to work to prevent, advance treatment, or cure disease.

How Innovation Is Transforming the Fight Against Ebola

How Innovation Is Transforming the Fight Against Ebola

POSTED BY RAJIV SHAH Link
JANUARY 17, 2015

A few weeks ago, in the midst of the holiday season, President Obama showcased some cutting-edge gadgets in the Roosevelt Room of the White House. But they were not new tablets, smartphones, or digital cameras. They were protective suits, state-of-the-art cooling vests, and germ-killing gels -- all tools that could make the difference between life and death in the fight against the Ebola epidemic in West Africa.

Designed in partnership with the U.S. Global Development Lab, these innovations will not only speed up our response on the ground, but also protect health workers on the frontlines of the epidemic. They embody our Agency’s new model of development -- one grounded in mobilizing the energy and creativity of a new generation of students, inventors, and entrepreneurs to bend the curve of progress.

Today, the United States is helping to lead a global response in West Africa with a strategy driven by evidence, innovation, and data. As the epidemic has evolved, so too has our response -- adapting our strategy to be highly mobile and scalable and allowing for a quick response to flare-ups in rural and hard-to-reach areas. The rapid deployment of safe burial teams, alongside widespread community awareness campaigns, has contributed to a significant reduction in transmission. In Liberia, new cases have dropped from more than 30 a day to as few as one. But much more must still be done to keep up our momentum and eliminate the virus at its source.

That’s why President Obama announced Fighting Ebola: A Grand Challenge for Development, a grant competition designed to challenge the world to invent better tools to tackle this disease in a matter of months, not years. In just two months, it received more than 1,500 ideas from a global community of innovators -- from re-engineered personal protective suits to lotions that repel the virus.

One award nominee is Johns Hopkins University, which created a protective suit prototype with easy-to-open zippers and a built-in cooling fan that runs off a cell phone charger. While the old suits took 22 steps and 15 minutes to take off safely, these new ones come off in less than 60 seconds -- all in one fluid motion. Another nominee is Qore Performance, a Virginia startup that produces wearable cooling packs for athletes. By repurposing their technology to fit protective suits, frontline health care workers can provide better care.

With just a small amount of seed funding, these innovations have the potential to improve the speed and impact of our response. In addition to improved designs for personal protective equipment, we are exploring advances in diagnostics to test patients on the spot -- eliminating the need to transport blood samples over rough roads. We are also working to improve real-time data, empowering local teams to better predict the spikes and valleys in active cases.

Our nation’s life-saving response to the worst Ebola epidemic in history represents an impressive display of American values, commitment, and ingenuity. Even as the headlines have slowed, the tireless work of thousands of frontline health care workers and disasters responders has not. In a year marked by an unprecedented number of humanitarian crises -- from South Sudan to Syria -- we remain committed to providing help in an emergency, regardless of danger or difficulty. It is one of the most profound expressions of who we are as the American people.

As President Obama said recently, “America has never been defined by fear. We are defined by courage and passion and hope and selflessness and sacrifice and a willingness to take on challenges when others can’t and others will not…all in the constant pursuit of building a better world not just for ourselves but for people in every corner of the Earth.”

About the Author: Dr. Rajiv Shah serves as the Administrator of the U.S. Agency for International Development (USAID).

Editor's Note: This entry originally appeared on the White House Blog.

Genetic changes in Ebola virus in West African outbreak could hinder potential treatments

AMERICAN SOCIETY FOR MICROBIOLOGY

WASHINGTON, DC--January 20, 2015--Researchers have tracked the genetic mutations that have occurred in the Ebola virus during the last four decades. Their findings, published in mBio®, the online open-access journal of the American Society for Microbiology, identified changes in the current West African outbreak strain that could potentially interfere with experimental, sequence-based therapeutics.

"We wanted to highlight an area where genomic drift, the natural process of evolution on this RNA virus genome, could affect the development of therapeutic countermeasures," says Gustavo Palacios, senior author of the study and director of the Center for Genome Sciences at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) in Frederick, Maryland.

Many of the most promising drugs being developed to fight Ebola are therapeutics that bind to and target a piece of the virus's genetic sequence or a protein sequence derived from that genetic sequence. If that sequence changes due to genetic drift, the natural evolution of the virus over time, then the drugs may not work effectively.

"Our work highlights the genetic changes that could affect these sequence-based drugs that were originally designed in the early 2000's based on virus strains from outbreaks in 1976 and 1995," says Palacios.

The team compared the entire genomic sequence of the current outbreak strain, called EBOV/Mak, with two other Ebola virus variants--one from an outbreak in Yambuku, Zaire (now the Democratic Republic of the Congo) in 1976 called EBOV/Yam-May, and one from an outbreak in Kikwit, Zaire in 1995 called EBOV/Kik-9510621. They found changes, called single nucleotide polymorphisms, or SNPs, in more than 600 spots, or about 3% of the genome.

The sequence-based drugs currently offer the best hope for future treatment of Ebola outbreaks, but have not yet been approved by the US Food and Drug Administration or any other regulatory agency. Because the World Health Organization adopted emergency containment measures for the ongoing West African outbreak, these drugs are currently being used to treat a few handfuls of patients in experimental testing. A clinical trial for one of the therapies will begin in Sierra Leone in the coming months.

The team, which included researchers from USAMRIID and Harvard University and the Massachusetts Institute of Technology, both in Cambridge, Massachusetts, then narrowed their search to only those mutations that changed the genetic sequences targeted by the various drugs. Of those, they found 10 new mutations that might interfere with the actions of monoclonal antibody, siRNA (small-interfering RNA), or PMO (phosphorodiamidate morpholino oligomer) drugs currently being tested.

The authors conclude that drug developers should check whether these mutations affect the efficacy of the therapeutic drug.

"The virus has not only changed since these therapies were designed, but it's continuing to change," says US Army Captain Jeffrey Kugelman, lead author and a viral geneticist at USAMRIID. Three of the mutations the team found appeared during the ongoing West African epidemic. "Ebola researchers need to assess drug efficacy in a timely manner to make sure that valuable resources are not spent developing therapies that no longer work."

Kugelman is currently in Charlesville, Liberia at the Liberian Institute for Biomedical Research, working with the local government to set up onsite genomics sequencing of Ebola patient samples to get a real-time picture of how the virus changes as it is transmitted from human to human. He'll be analyzing whether the virus's genetic sequences that are key for diagnostic tests and drug interventions change over time. "The virus mutates rapidly and it's an ongoing concern."

New model predicts Ebola epidemic in Liberia could be ended by June

UNIVERSITY OF GEORGIA

Athens, Ga. - The Ebola epidemic in Liberia could likely be eliminated by June if the current high rate of hospitalization and vigilance can be maintained, according to a new model developed by ecologists at the University of Georgia and Pennsylvania State University.

The model includes such factors as the location of infection and treatment, the development of hospital capacity and the adoption of safe burial practices and is "probably the first to include all those elements," said John Drake, an associate professor in the UGA Odum School of Ecology who led the project. The study appears in the open access journal PLOS Biology Jan. 13.

Drake said that the UGA model should be useful to public health officials as they continue to combat the Ebola epidemic because it offers both general insights and realistic forecasts, something few models are able to do.

During the fall of 2014, the authors ran the model for five different hospital capacity scenarios. For the worst case, with no further increase in hospital beds, the median projection was for 130,000 total cases through the end of 2014; for the best case--an increase of 1,400 more beds, for roughly 1,700 total or an 85 percent hospitalization rate--the median projection was 50,000 cases. After the authors updated it with more recent information collected through Dec. 1, the model projected that, if an 85 percent hospitalization rate can be achieved, the epidemic should be largely contained by June.

"That's a realistic possibility but not a foregone conclusion," Drake said. "What's needed is to maintain the current level of vigilance and keep pressing forward as hard as we can."

Epidemic modeling is an important tool that helps public health officials design, target and implement policies and procedures to control disease transmission, and several models of the 2014 Ebola epidemic have already been published. According to Drake, many of these models seek to estimate the disease's reproductive number--the number of new cases that one infected individual can generate.

"This is useful because it says how far transmission must be reduced to contain the epidemic," he said. "Our model does this too, but it does other stuff as well. It aims to be intermediate in complexity--it captures all the things we think to be most important and ignores the rest."

Those important variables include infection and treatment setting, individual variation in infectiousness, the actual build-up of hospital capacity over time and changing burial practices. The researchers used a mathematical formulation known as branching processes--a method for keeping track of all possible epidemic outcomes in proportion to their probabilities--calibrated with newly developed methods.

To build this more complex model, Drake and his colleagues started with information gleaned from earlier Ebola outbreaks. They included data about variables such as the numbers of patients hospitalized health care workers infected, which allowed them to estimate the level of under-reporting; rates of transmission in hospitals, the community and from funerals; and the effectiveness of infection control measures.

Once they had a working model with plausible parameters, they fine-tuned it using data from the World Health Organization and the Liberia Ministry of Health for the period from July 4 through Sept. 2, 2014. This included information about new cases as well as changes in behavior and public health interventions during that time, such as the addition of roughly 300 hospital beds and the adoption of safer burial practices.

Liberia continued to add hospital beds after Sept. 2, so in mid-December, Drake and his team updated the model to include information collected through Dec.1. Using reported data rather than estimates from the earlier version of the model significantly cut down on the range of future possibilities, showing that the response by the Liberian government and international groups had greatly reduced the likelihood of a massive epidemic.

The model should prove useful beyond the current Ebola crisis, Drake said. "We introduced a new method for model fitting--the method of plausible parameter sets--that could be used in future rapid response scenarios."

Plausible parameter sets use recorded data that falls within the range of possibilities generated by the model at least 500 times, meaning that the model "fits" the data closely. This keeps the model's projections in line with observed reality, making it particularly useful for investigating a wide range of realistic potential interventions and accounting for the impacts of human behavior on disease transmission.

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The study is available online at http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002056.

Model coauthors were RajReni B. Kaul, Laura W. Alexander, Suzanne M. O'Regan, Andrew M. Kramer, J. Tomlin Pulliam and Andrew W. Park of UGA's Odum School and Matthew J. Ferrari of Pennsylvania State University. The research was conducted under the auspices of the Ebola Modeling Working Group of the National Institutes of Health Institute of General Medical Sciences Models of Infectious Disease Agent Study.

For more information about the Odum School of Ecology, see http://www.ecology.uga.edu.

Draft road map for Ebola vaccine development

A draft road map for the expedited development, testing, manufacture, delivery and financing of Ebola vaccines has today been published by a global group of experts supported by the Wellcome Trust. The development and delivery of safe and effective vaccines would make a huge contribution to containing Ebola in Guinea, Liberia and Sierra Leone, as well as improving responses to future outbreaks and providing a model for vaccine development against other emerging infectious disease, the expert group has concluded.

The panel of 26 international experts, convened by the Wellcome Trust and the Centre for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota, explains how the substantial scientific, financial, social and logistical challenges to rapid Ebola vaccine development and deployment can be overcome through collaboration between governments, industry and philanthropic bodies.

It highlights the potential need for multiple Ebola vaccines with different characteristics, which might enable different vaccination strategies such as ring-vaccination to prevent an outbreak from spreading, and prophylactic vaccination of high-risk individuals such as healthcare workers. It sets out the qualities that a successful vaccine should have and a set of principles for trial design. The road map also emphasises the importance of community engagement so that vaccine trials and delivery programmes are positively received, and the need for such engagement campaigns to be adapted to national and local circumstances.

The recommendations are made in the interim report of Team B, which is co-chaired by Dr Jeremy Farrar, Director of the Wellcome Trust, and Professor Michael Osterholm, Director of CIDRAP. A full report will be published in the coming weeks, and the guidance will be a “living document” that evolves over time. The group is called “Team B” in recognition of the principal role played by the World Health Organisation and national governments in leading the international Ebola response.

Dr Jeremy Farrar, Director of the Wellcome Trust and co-chair of Team B, said: “As Guinea, Liberia and Sierra Leone make encouraging progress in containing Ebola, we must not lose sight of the immense contribution that a safe and effective vaccine would make towards controlling both this and future epidemics. We need urgent global collaboration between governments, industry and philanthropy to ensure candidate vaccines progress through trials to manufacture and delivery as swiftly as possible.

“The draft road map we publish today, agreed by a global group of experts, offers solutions to the great scientific, social, logistical and financial challenges of delivering an Ebola vaccine on this urgent timescale. It is a living document that will evolve as we learn more about Ebola and the candidate vaccines that are available. As well as being of great value in the present crisis, it will enable vaccine strategies to begin without delay in future outbreaks, and provide a model for vaccine development in response to other emerging infectious diseases.”

The draft roadmap can be viewed here.

Contact

Clare Ryan
Senior Media Officer, Wellcome Trust
T: +44 (0)20 7611 8866
E: c.ryan@wellcome.ac.uk

Caroline Marin
Media Relations Coordinator, University of Minnesota
T: + 1 (0) 612 624 5680
E: crmarin@umn.edu

The Wellcome Trust is a global charitable foundation dedicated to improving health. We support bright minds in biomedical science, the humanities and the social sciences, as well as education, public engagement and the application of research to medicine.

The Wellcome Trust has provided approximately £10 million funding in response to the Ebola epidemic, which has enabled unparalleled international collaboration across the public, private and not-for-profit sectors to tackle the crisis. This includes trials of potential vaccines and treatments, in addition to public health, social and humanitarian research.

U.S. Government Contributes $1 Million to IAEA in Ebola Fight

Media Note
Office of the Spokesperson
Washington, DC
January 8, 2015

The U.S. Government has contributed $1 million to the International Atomic Energy Agency for a new project that will improve and streamline efforts to diagnose the Ebola virus in Africa. Of the total U.S. contribution, $650,000 is provided through the IAEA’s Peaceful Uses Initiative and $350,000 through other extra-budgetary contributions to the IAEA.

The IAEA’s project will provide high-quality training and cutting-edge equipment based on nuclear science applications to teams of virologists in 11 African countries—Cote d’Ivoire, Guinea, Liberia, Mali, Mauritania, Niger, Nigeria, Senegal, Sierra Leone, South Africa, and Uganda—to help them more quickly and safely diagnose emerging diseases, including Ebola.

Since the launch of the IAEA peaceful uses initiative in May 2010, the United States has contributed more than $50 million in the last five years and allocated more than $45 million of this amount to specific projects. This initiative, announced at the 2010 Nuclear Nonproliferation Treaty Review Conference, reinforced the commitment of the United States and other donors to IAEA activities that promote peaceful uses of nuclear technology in areas such as human health, water resource management, food security and agriculture, environmental protection, and nuclear power infrastructure development. To date the United States,17 other donor countries, and the European Union have contributed approximately $77 million to the PUI, which funds IAEA projects that benefit more than 120 countries. This is in addition to annual voluntary contributions from member states, including the United States, averaging more than $85 million to the IAEA’s Technical Cooperation program.

Pivotal Ebola vaccine trials to start this month or next: WHO

(Reuters) - Final-stage trials of experimental Ebola vaccines will begin in January or February in the worst-hit West African countries as scientists and drugmakers race to block the deadly disease, the World Health Organization said on Thursday. If effective, the shots will be available for deployment a few months later.

Nearly 90 experts from vaccine manufacturers, regulatory agencies and health ministries met at WHO headquarters to review data from initial safety trials and finalise plans for pivotal Phase III clinical trials in Liberia, Sierra Leone and Guinea. "It is my understanding that no major safety signals have been reported to date," WHO director-general Margaret Chan told the talks in opening remarks obtained by Reuters. "We all want the momentum and sense of urgency to continue," she said. "Too many health care workers are still getting infected, including nationals and doctors and nurses from foreign medical teams." The meeting is discussing three different large-scale clinical trial designs using the most advanced vaccines to fight a disease that has killed more than 8,000 people in the past year.

Two vaccines from GlaxoSmithKline and another from a collaboration between NewLink Genetics and Merck started initial clinical testing in the autumn. A third one from Johnson & Johnson and Bavarian Nordic has just reached the first-in-human testing stage. Officials from GSK, Merck and J&J all addressed the closed-door meeting. In addition, officials heard from developers of earlier-stage vaccines, including U.S.-based Novavax and Russia's Influenza Research Institute.

The talks also assessed the funding situation, after the GAVI global vaccines alliance said last month it was committing up to $300 million to buy Ebola shots. Sierra Leone, the country worst affected by Ebola, plans to start vaccine trials in the second half of January, Samuel Kargbo of its health ministry told Reuters Television on the sidelines of the Geneva talks. Ebola continues to spread in the Liberian capital of Monrovia, with cases scattered throughout the city, making it hard to identify distinct chains of transmission, Chan said. "Many believe that the virus has moved from the cities into extremely remote rural areas, making it difficult to see what is really happening in Liberia," she said. Keiji Fukuda, WHO Assistant-Director for Health Security, told Reuters: "There are ups and downs. We have to be very cautious. We don't want people to get the idea this is over."

(Additional reporting by Marina Depetris and Ben Hirschler; Editing by Andrew Heavens)

Ebola outbreak: 2-shot vaccine trial begins at University of Oxford

Experimental vaccine being tested in U.K. includes a booster, is 3rd in safety testing

A third experimental Ebola vaccine will start safety testing in humans, a British university says. Oxford University said Tuesday it aims to vaccinate 72 healthy adults with the experimental vaccine, developed by Johnson & Johnson, by the end of January. Some of the subjects will receive a placebo. Unlike two other experimental vaccines, the J&J vaccine uses two separate injections. The "prime-boost" approach gives one shot to stimulate the immune system and a booster a few weeks later aims to enhance immune response over time.

The vaccine does not contain any replicating virus and can’t infect people with the Ebola virus that has killed more than 8,100 people, mainly in Guinea, Sierra Leone and Liberia. "The main aim is to understand the safety profile of the vaccines," the study’s leader, Dr. Matthew Snape of the Oxford Vaccine Group, said in a release.

While public health measures remain the best way to bring the outbreak under control, Snape said, a safe and effective vaccine could start to help later this year. Further tests are planned later this month in the U.S. and soon after in Kenya, Uganda and Tanzania. Earlier studies showed the prime-boost approach offered non-human primates complete protection against the Kikwit Zaire strain of Ebola that is similar to the virus causing the current outbreak, the university said.

J&J said it has produced enough vaccine to treat more than 400,000 people, which could be used in large-scale clinical trials by April. How many doses are needed depends on how quickly the epidemic is brought under control.Currently, experts project between 100,000 and 12 million doses could be needed.

A second experimental Ebola vaccine partly developed by researchers from Canada’s National Microbiology Laboratory is undergoing safety tests in Halifax and Geneva. The vaccine is licensed to NewLink and Merck.Another experimental vaccine developed by GlaxoSmithKline and the U.S. National Institutes of Health is also in clinical development, including at Oxford. Other vaccines are in development in Russia, the university said.

With files from Reuters

Study identifies 53 approved drugs that may block Ebola infection

Compounds may keep virus from entering cells; may accelerate drug development

Researchers found 53 existing drugs that may keep the Ebola virus from entering human cells, a key step in the process of infection, according to a study led by researchers at the Icahn School of Medicine at Mount Sinai and the National Institutes of Health (NIH), and published today in the Nature Press journal Emerging Microbes and Infections. Among the better known drug types shown to hinder infection by an Ebola virus model: several cancer drugs, antihistamines and antibiotics. Among the most effective at keeping the virus out of human cells were microtubule inhibitors used to treat cancer.

"In light of the historic and devastating outbreak of Ebola virus disease, there is an urgent need to rapidly develop useful treatments against Ebola infection, and our study results argue that repurposing existing drugs may be among the fastest ways to achieve this," said lead author Adolfo García-Sastre, PhD, Director of the Global Health and Emerging Pathogens Institute within the Icahn School of Medicine at Mount Sinai. "Many of the compounds identified in this study promise to become lead compounds in near-future drug development efforts studies targeting this virus," said Dr. García-Sastre, also the Fishberg Chair and Professor of Medicine (Infectious Diseases) within the School.

There is no approved treatment for Ebola virus infection, and the estimated mortality rate of the current Ebola outbreak is nearly 70 percent in many areas. Antibody-based therapy (e.g. ZMapp) has proven effective in animal studies, and has been used for the treatment of a few patients, but has not been confirmed in clinical trials. It is also expensive to make and in short supply. Ebola vaccine trials are getting underway as well, but vaccines will not be available for some time.

"NCATS is all about getting more treatments to more patients more quickly, and this is never more urgent than in the case of a public health emergency like Ebola," said Christopher P. Austin, MD, Director of the National Center for Advancing Translational Sciences (NCATS), part of the NIH, which also led the study. "This remarkable team of scientists combined NCATS' expertise in drug screening and development with Mt. Sinai's expertise in Ebola virology to rapidly identified candidate treatments for Ebola infection."

Specifically, the research team used a miniaturized, high-speed technology to screen through sample libraries of 2,816 compounds already approved by the US Food and Drug Administration for other uses. Their assay was designed to identify compounds that blocked the ability of the Ebola virus to enter and infect human cells by at least 50 percent.

While fully intact Ebola virus is a biosafety level (BSL) 4 pathogen and dangerous to work with, the team created a virus-like particle comprised of the Ebola proteins (glycoproteins and matrix proteins) that enable the virus to enter cells, but without many of the genes and proteins that make the virus deadly. When they inserted a fluorescent reporter protein in this virus-like shell, their test became capable of high-speed screening to see which drugs blocked the entry of Ebola-like viral particles into cells as measured by fluorescence. These Ebola mimics can be studied in a BSL-2 facility, making them much safer to work with.

The team's screen yielded 53 drugs that block Ebola virus-like particles from entering human cells. Along with the drug types mentioned above, other categories that blocked viral entry included estrogen receptor modulators used against cancer and serotonin reuptake inhibitors used to treat depression. Some of the compounds had been shown by previous studies to counter Ebola lifecycle steps. Next steps include testing of the re-purposed drug candidates in animal studies to see if useful doses against the virus come with toxic side effects. If any of prove to be safe and effective, the "government may opt to deploy them in the outbreak areas," said Dr. García-Sastre.

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Carles Martínez-Romero, PhD, an instructor in the Department of Microbiology within the Icahn School of Medicine, also led the research at Mount Sinai. NCATS study authors were Wei Zheng, Jennifer Kouznetsova, Wei Sun, Gregory Tawa, Paul Shinn, Catherine Chen, Philip Sanderson, and John McKew. Aaron Schimmer of Princess Margaret Cancer Centre, part of the University Health Network in Toronto, was also a study author. This work was supported by grants from NCATS and the NIH. The development of antiviral screen assays in Dr. García-Sastre's lab was also supported by NIH grants (R01AI079110 and R01AI089539).

About the Mount Sinai Health System
The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven member hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services--from community‐based facilities to tertiary and quaternary care.

The System includes approximately 6,600 primary and specialty care physicians, 12‐minority‐owned free‐standing ambulatory surgery centers, over 45 ambulatory practices throughout the five boroughs of New York City, Westchester, and Long Island, as well as 31 affiliated community health centers. Physicians are affiliated with the Icahn School of Medicine at Mount Sinai, which is ranked among the top 20 medical schools both in National Institutes of Health funding and by U.S. News & World Report.

Contest Seeks Novel Tools for the Fight Against Ebola

By DONALD G. McNEIL Jr. Text with links

The well-prepared Ebola fighter in West Africa may soon have some new options: protective gear that zips off like a wet suit, ice-cold underwear to make life inside the sweltering suits more bearable, or lotions that go on like bug spray and kill or repel the lethal virus.Those ideas are among the contenders to win the Ebola “Grand Challenges” contest announced in October by the United States Agency for International Development, or among those being considered by the agency without having formally entered the contest. All still need to undergo testing, and some may prove impractical, but the 1,500 contest submissions “blew the roof off the number of responses we’ve ever had,” said Wendy Taylor, director of U.S.A.I.D.’s Center for Accelerating Innovation and Impact.

The agency’s Grand Challenges, modeled on those begun a decade ago by the Bill & Melinda Gates Foundation, have produced some nifty inventions, the best known of which is a device for helping women in obstructed labor that was invented by an Argentine auto mechanic after he saw a YouTube video on using a plastic bag to get a cork out of a wine bottle. The preliminary results of the Ebola challenge were revealed Friday, and Ms. Taylor said the agency would spend about $1.7 million testing the most promising possibilities.

Some, including various brands of cooling undergarments, are repurposed off-the-shelf products. The heavy-duty SteeleVest, for example, is used by the military, some industrial workers and, according to the company’s website, vacationers and fishermen. Technologically, it is simple: a fabric vest with pockets into which gel packs fresh out of the freezer are inserted. A higher-tech alternative is Qore athletic gear, which includes compression sleeves and shorts that press cooling packs to the forearm and groin, where arteries run close to the surface. Testing is needed, Ms. Taylor said, to see if the vest is comfortable enough and the sleeves cooling enough. Doctors and nurses working in midday tropical heat are often near collapse after 45 minutes. Prolonging that period would let them see more patients.

Other contenders include Zylast, an antiseptic skin gel that its makers claim kills microbes for up to six hours, even after hand washing. To see if it might be effective during the slow, dangerous process of taking off a protective suit, Zylast must be tested specifically against the Ebola virus and for its durability on skin running with sweat, Ms. Taylor said. A spray-on barrier to repel microbes with electrostatic fields will also be tested, in the hope that it will let protective gear be fashioned out of breathable fabrics. However, whether it can repel infectious vomit and diarrhea remains to be seen.

A joint team of engineering and medical students from Johns Hopkins University and the Under Armour clothing company, both based in Baltimore, are refining a new type of protective suit. It is meant to be cooler than current versions and removable in 60 seconds because it uses a wet-suit-style back zipper and breakaway leg seams. It also has a big built-in face shield, which would help wearers see better and make them look less scary. “You can see their smile,” Ms. Taylor said.

Unexpected Joint Pain Seen In Test Of Experimental Ebola Vaccine

By Richard Harris Text link.
Two potential Ebola vaccines are currently being tested in people, to see if they're safe and to figure out the best dose. Both trials have encountered some of the typical travails of vaccine research. One vaccine, which uses a modified chimpanzee virus, was associated with some mild fevers at its highest dose. And today, the University Hospitals of Geneva said that four healthy volunteers receiving a second potential vaccine, called VSV-ZEBOV, had experienced unexpected joint pain.

The hospital has already given the vaccine to 59 people, and was about to inject another 15. But researchers there decided to hold off on those next 15 people for a week or so, while they pause to take a closer look at the people who experienced mild pain in their hands and feet. All told, the Geneva hospital plans to inoculate 115 volunteers. Despite this side effect, "Initial results show that the vaccination is very well tolerated," the hospital said in a statement. The hospital says joint pain is a common side effect of vaccines, but it had not listed this as a potential side effect for this particular study. The hospital says it will update its list of potential side effects before proceeding.

The vaccine was developed by the Canadian government and then licensed to a small U.S. biotech company called NewLink Genetics, which teamed up with pharmaceutical giant Merck for testing, manufacturing and distribution. Merck told NPR that the vaccine will continue to be tested at other sites using lower doses.

Three major manufacturers have been pursuing Ebola vaccines, and the World Health Organization says Russia has something in the works as well. In the best of circumstances, it will take many months of study to figure out whether the vaccine is safe and effective. But assuming one or more of these vaccines can protect people from Ebola, GAVI the Vaccine Alliance, says it's ready to commit $300 million to buy vaccines for Africa.

GAVI is a public-private partnership that includes U.N. agencies, the World Bank, foundations and private companies. "Up to an additional $ 90 million could be used to support countries to introduce the vaccines and to rebuild devastated health systems and restore immunisation services for all vaccines in Ebola-affected countries," Gavi said in a statement.

Inside the lab: The race to create an Ebola vaccine

By Brian Dowling
Rick Chubet paces from machine to machine inside a clean, white lab at Protein Sciences. The vaccine scientist pulls up to a monitor displaying fresh results from a test. Two lines, one blue, one red, cut across a graph. He walks to another area, where more data waits. "This is good news," he says, pointing to a cluster of blue lines that tells him he is zeroing in on the protein he wants.

Tasks and projects at Protein Sciences differ depending on the day. Sometimes, Chubet wakes up at his home in Middletown, drives to Meriden and launches into work on a vaccine for influenza, an illness that still kills more than 30,000 in the United States each year despite the widespread use of vaccines. Other days, it might be rabies, which results in a similar number of deaths worldwide, mostly in Africa and Asia. This early November morning, the target is Ebola.

Protein Sciences Corp., a pharmaceutical company of 130 employees, jump-started work on the virus in July after discussions with officials from the National Institutes of Health and the U.S. Biomedical Advanced Research and Development Authority. In so doing, it joined a handful of other biotechnology companies racing toward a vaccine or treatment of Ebola, which has taken more than 5,600 lives in West Africa. Protein Sciences had in cold storage a half-completed vaccine from 2010, when U.S. public health officials pushed Ebola research. The genetic work was done, leaving just the manufacturing and Chubet's job: purifying the vaccine to its essence.

"I have two weeks to figure it out, and we are damn close," he says. Chubet, 54, stands at a workstation, wearing a white lab coat over blue jeans and a gray pullover. He delves into the finer points of molecular biology and the behavior of viruses as if the world can keep up with him and see the scientific methods as clearly as he does. A man partly responsible for an innumerable number of people being stuck in the arm, Chubet says he avoids needles whenever possible.

Protein Sciences is becoming known for its influenza vaccine, Flublok, and in recent months landed a large distribution deal for the drug as well as an important decision from the U.S. Food and Drug Administration to extend its approval to older people. The company spent about two decades and more than $100 million on Flublok. Technical differences aside, the production of the flu vaccine mirrors the process Chubet and his team are following as they rush to get a vaccine for Ebola to next-stage clinical studies. Chubet needs to separate the exact vaccine proteins from a milkshake-like soup of broken cells, waste protein, shattered DNA, and other particles that the company's manufacturing division sends him.

His lab equipment works as a type of sieve that, when loaded with the right filters that strain out unwanted particles, can separate out the vaccine protein, called a glycoprotein. The plan for Chubet is to send doses of the purified protein to the NIH by early December. In the middle of a four-week push on the vaccine, Chubet seems content with his progress. "We have done pretty well for just two weeks. For flu, we worked on it for years." But Ebola, Chubet is finding, is a complex and fragile virus. And while Chubet battles in the lab, the possibility of a clinically tested Ebola vaccine faces more than just technical hurdles.

One, Protein Sciences is a private company and limited in how much of its own capital it will put toward this early work. Two, there is no formal market for an Ebola vaccine, so any feasible solution would require a governmental partnership or a deal with a pharmaceutical company that could find public financing. Also, Protein Sciences is not the only pharmaceutical company with an iron in the fire. At least half a dozen other vaccines or treatments are in various development stages, including one backed by British drug giant GlaxoSmithKline and another recently bought by Merck.

•

For Manon Cox, chief executive of Protein Sciences, the real worry is more than competition from pharmaceutical giants. The largest threat is that the now-strong push for a vaccine could fade. She sees support for an Ebola vaccine as fragile and fears that the public will misunderstand signs of improvement in Western Africa as success. If that happens, pressure to conquer the outbreak could wash away. "The complacency turns up," she says. "The virus is still out there. And it might come back much harder."

Cox studied business and microbiology in the Netherlands before joining Protein Sciences in 1998. She saw funding disappear from an Ebola vaccine project the company worked on in 2010. Protein Sciences also produced a bird-flu vaccine in eight weeks at the request of the public health officials in the United States. But then the need for that vaccine vanished. The Ebola virus is believed to live in African fruit bats. From there it is thought to jump straight to humans or mammals that are hunted for meat, known as bushmeat.

The current outbreak is West Africa's first, something that researchers have slowly begun to resolve. Researchers at Virginia Tech, Columbia University and elsewhere found that humans pushing into formerly forested areas where the virus lives in animals helped cause the outbreak. "These environmental changes in the outbreak region may provide the opportunity for direct exposure to infected bats, potentially creating transmission pathways that do not rely on exposure to bushmeat," researchers say. Greater urban populations and increased mobility also increased the spread of the disease, the researchers say in the paper, conditionally accepted by the journal Public Library of Science's Neglected Tropical Diseases.

The world lacks an Ebola vaccine mainly because of the way the virus has behaved in the past. Seventeen outbreaks since 2000 have come and gone, most resulting in only a small number of cases in rural areas. The short period from emergence to disappearance leaves little time for the clinical work to approve a vaccine before the demand fades. Researchers at Yale, in the Annals of Internal Medicine, say the time to deploy vaccines is now, and argued that vaccines should be able to reach approval from animal studies and other diagnostics. "The relentless epidemiologic trajectory and geographic dissemination represent a public health crisis that shows no signs of diminishing under current efforts," researchers at the Yale School of Public Health wrote. They also recommended vaccinating health workers in high-risk regions, a "ring" of likely exposed people, and close contacts of infected persons. They warned that these efforts should begin as quickly as possible. "Curtailing an outbreak is always easier in its earliest stages than after it has disseminated geographically," the researchers wrote. "That window of opportunity may be rapidly closing."

Reflecting on the public health community's past efforts to make a vaccine for Ebola, Cox says the virus was not on anyone's radar. Nobody thought Ebola would be a public health crisis, she says, "but as we infringe on the animal kingdom we will continue to have these viruses." In a way, Cox is torn about the Ebola vaccine. She and many of her colleagues say the work is a moral response to the situation in West Africa. "There is a thing called social responsibility," Cox says. But she is self-funding the effort, and her duty to shareholders limits what she is willing to put toward the project. Asked what Protein Sciences has spent on the vaccine, she says, "It is a limited expenditure." "It is possible with more resources, we could have done this quicker," Cox says. "We felt we had to step out on the boat, but there it stops." For Cox, "there" is in clinical trials, an expensive step in the development of any drug, one she hopes an official public health body, like the NIH, or another pharmaceutical company could pursue. "If you have a technology that could be used to deal with a public health crisis you have to make clear that show to make an effort but at the same time you have to be realistic," she says.

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The vaccine Protein Sciences is developing is not a weakened version of the Ebola virus. In fact, Protein Sciences is able to develop the vaccine without ever putting its employees' hands on a live version of the virus. Ebola virus is a filovirus, so named because of its filament- or thread-like shape. On the outside of the long virus are glycoproteins, little arms or branches that connect with cells. These proteins are what the immune system sees and, importantly, what it needs to recognize to launch an immune response.

Infections of Ebola accelerate and spread very quickly in the body, much faster than the time it takes the immune system to recognize the virus cells as foreign and dangerous. By the time the body catches up, the virus has spread far through the body, causing internal hemorrhaging and organ failure. The vaccine introduces the immune system to what Ebola looks like, giving it weeks to learn that the glycoprotein is a foreign particle and requires a serious response. Producing the glycoprotein involves some genetic hijacking. Protein Sciences starts with a virus that is native to worms called a baculovirus. Researchers reprogram the virus' genetic code by rewriting specific parts of its genes, giving the virus a new set of instructions — that is, to produce as many copies as it can of the glycoprotein that pockmarks the outside of Ebola.

Researchers then introduce the baculovirus to cells of the Fall armyworm, known asSpodoptera frugiperda, and the mixture produces a soup of material, a small amount of which is the treasured vaccine protein. Research has shown that the proteins need a helper called an adjuvant to trigger the strong immune response needed with Ebola. The adjuvant acts as a structure for the proteins to hang on. Cox is in talks to acquire an adjuvant for the company's vaccine. Having the adjuvant, Cox says, gives the company the best chance for its vaccine to get approval from the FDA.

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The person at Protein Sciences who has had closest contact with the Ebola virus is Alex Neverov. Neverov, 33, guides Protein Sciences' products though the numerous approvals needed from the U.S. Food and Drug Administration. A decade ago, he worked at Russia's State Research Center for Virology and Biotechnology, commonly known as Vector. During the Cold War era, the site was a center for the development of biological weaponry. In recent years, with funding from the United States, its work has shifted to biodefense and vaccines.

Neverov's research at Vector focused on the safety of viral vaccines, using animal models and molecular biology. The goal of his research was to better understand the safety of widely used vaccines for measles, mumps and other diseases. "Ebola was not the major topic of my laboratory," he says, sitting across a glass-topped wooden conference table at Protein Sciences headquarters. "My next-door neighbors, that is what they were dealing with 24 hours, seven days a week."

One day in 2004, a technician in the lab next to Neverov's, Antonina Presnyakova, was working with the Ebola virus. "We use special protective suits, like spacesuits, when working with infected cell culture," Neverov says. The lab is a Biosafety Level Four facility, the highest level. Special cabinets with thick rubber gloves let researchers conduct dangerous experiments from a safer distance. "There are two philosophies: The first is to protect the researcher from virus and second is to protect the virus and other stuff from the outside," he says. "How you use it depends on what kind of work you do." Presnyakova, who had two other layers of gloves on, Neverov says, was working in the cabinet with material infected with the Ebola virus. With her hands in the cabinet holding a needle and infected material, she inadvertently punctured herself with the Ebola-infected needle, Neverov says, recounting the story, which was widely publicized at the time. Presnyakova quickly contracted the Ebola virus and weeks later died.

Neverov completed his doctorate the next year, then started working for the FDA. Protein Sciences hired him in 2013. "There are lot of unanswered questions" about Ebola, Neverov says. He speaks with an understandable, though thick, Russian accent, and punctuates his ideas with slices of his hands. "Where it comes from, there are sort of basic hints, and some people may think we know everything, but that's not true," he says. He says Protein Sciences is also producing the protein used in the vaccine for researchers doing basic studies on the virus or for applications such as treatments or diagnostics for the virus. "We are in the business of helping people. We are in the business of improving human health. It's very rewarding. Instead of working with pure empirical things like financial derivatives, you are potentially improving lives."

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Last week, Chubet completed the first production run of the Ebola vaccine. From a tank of 495 liters filled with baculovirus culture, armyworm cells and other material, he was able to purify out half of one liter of protein. The hundreds of liters passed through three filters, called columns. Inside the columns are ions or other media that unwanted materials in the mix bind to, leaving the desired Ebola proteins. It was a battle to get the yield of just one-thousandth.

Initially, the vaccine proteins were falling apart as Chubet directed them through the columns to purify out the extra material. "It's breaking down. It's going somewhere. It's falling apart. We didn't know that for a week," he says. Sometimes in sorting the proteins from the fray, they would just disappear. Chubet, confused about the results, wrote off those proteins as going to the ether, never to be seen again. "I tried like every which way known to man to make this," he says. "And it actually came back to the flu process. It was really the only process that kind of worked and gave us any possible hope." Two of the three filters were nearly identical to what the company uses on its flu vaccine.

With the first production run a success, Protein Sciences is testing the potential vaccine for quality and efficacy. The company has asked the National Institutes of Health for a date that they want to take delivery of the vaccine. Chubet expects improvements to the process to increase the yield from 500 milliliters to 3 or 4 liters. Tweaks to both the manufacturing and purification stage will get him there, he says. Cox says Protein Sciences is in talks with the World Health Organization about offering doses for funded clinical trials in Africa, as well as for the U.S. Army Medical Research Institute of Infectious Diseases.

Neverov smiled when asked whether providing the world a vaccine for Ebola offers closure on his previous research in Russia. "Well, let's say you will be writing the last chapter when you will know that the vaccine it here and you can protect people and it is not such a dangerous threat to anybody. I think that will be the last chapter and let's move to that," he says. "But life is never a direct projectile, usually we are getting moved back and forth."

Copyright © 2014, Hartford Courant

Contact: Anne A. Oplinger
aoplinger@niaid.nih.gov
301-402-1663
NIH/National Institute of Allergy and Infectious Diseases
@NIAIDNews

NIAID/GSK experimental Ebola vaccine appears safe, prompts immune response

Results from NIH phase 1 clinical trial support accelerated development of candidate vaccine

An experimental vaccine to prevent Ebola virus disease was well-tolerated and produced immune system responses in all 20 healthy adults who received it in a Phase 1 clinical trial conducted by researchers from the National Institutes of Health. The candidate vaccine, which was co-developed by the NIH's National Institute of Allergy and Infectious Diseases (NIAID) and GlaxoSmithKline (GSK), was tested at the NIH Clinical Center in Bethesda, Maryland. The interim results are reported online in advance of print in the New England Journal of Medicine.

"The unprecedented scale of the current Ebola outbreak in West Africa has intensified efforts to develop safe and effective vaccines, which may play a role in bringing this epidemic to an end and undoubtedly will be critically important in preventing future large outbreaks," said NIAID Director Anthony S. Fauci, M.D. "Based on these positive results from the first human trial of this candidate vaccine, we are continuing our accelerated plan for larger trials to determine if the vaccine is efficacious in preventing Ebola infection."

The candidate NIAID/GSK Ebola vaccine was developed collaboratively by scientists at the NIAID Vaccine Research Center (VRC) and at Okairos, a biotechnology company acquired by GSK. It contains segments of Ebola virus genetic material from two virus species, Sudan and Zaire. The Ebola virus genetic material is delivered by a carrier virus (chimpanzee-derived adenovirus 3 or cAd 3) that causes a common cold in chimpanzees but causes no illness in humans. The candidate vaccine does not contain Ebola virus and cannot cause Ebola virus disease.

The trial enrolled volunteers between the ages of 18 and 50. Ten volunteers received an intramuscular injection of vaccine at a lower dose and 10 received the same vaccine at a higher dose. At two weeks and four weeks following vaccination, the researchers tested the volunteers' blood to determine if anti-Ebola antibodies were generated. All 20 volunteers developed such antibodies within four weeks of receiving the vaccine. Antibody levels were higher in those who received the higher dose vaccine.

The investigators also analyzed the research participants' blood to learn whether the vaccine prompted production of immune system cells called T cells. A recent study by VRC scientist Nancy J. Sullivan, Ph.D., and colleagues showed that non-human primates inoculated with the candidate NIAID/GSK vaccine developed both antibody and T-cell responses, and that these were sufficient to protect vaccinated animals from disease when they were later exposed to high levels of Ebola virus.

The experimental NIAID/GSK vaccine did induce a T-cell response in many of the volunteers, including production of CD8 T cells, which may be an important part of immune protection against Ebola viruses. Four weeks after vaccination, CD8 T cells were detected in two volunteers who had received the lower dose vaccine and in seven of those who had received the higher dose.

"We know from previous studies in non-human primates that CD8 T cells played a crucial role in protecting animals that had been vaccinated with this NIAID/GSK vaccine and then exposed to otherwise lethal amounts of Ebola virus," said Julie E. Ledgerwood, D.O., a VRC researcher and the trial's principal investigator. "The size and quality of the CD8 T cell response we saw in this trial are similar to that observed in non-human primates vaccinated with the candidate vaccine."

There were no serious adverse effects observed in any of the volunteers, although two people who received the higher dose vaccine did develop a briefly lasting fever within a day of vaccination.

Additional details about this trial, VRC 207, are available at ClinicalTrials.gov using the identifier NCT02231866.
For more information about early-stage Ebola vaccine clinical trials, see Questions and Answers: Phase 1 Clinical Trials of NIAID/GSK Investigational Ebola Vaccine.

NIAID conducts and supports research--at NIH, throughout the United States, and worldwide--to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

About the National Institutes of Health (NIH)
NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

References
JE Ledgerwood et al. Safety and immunogenicity of chimpanzee adenovirus vector Ebola vaccine: preliminary report. New England Journal of Medicine DOI: 10.1056/NEJMoa1410863 (2014).
DA Stanley et al. Chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge. Nature Medicine DOI: 10.1038/nm.3702 (2014).

Dynamics and control of Ebola virus transmission in Montserrado, Liberia: a mathematical modelling analysis

Joseph A Lewnard BA, Martial L Ndeffo Mbah PhD, Jorge A Alfaro-Murillo PhD,  Prof Frederick L Altice MD,  Luke Bawo MPH,  Tolbert G Nyenswah MPH,  Prof Alison P. Galvani

The Lancet Infectious Diseases, Volume 14, Issue 12, Pages 1189 - 1195, December 2014  doi:10.1016/S1473-3099(14)70995-8, Full text.

Background
A substantial scale-up in public health response is needed to control the unprecedented Ebola virus disease (EVD) epidemic in west Africa. Current international commitments seek to expand intervention capacity in three areas: new EVD treatment centres, case ascertainment through contact tracing, and household protective kit allocation. We aimed to assess how these interventions could be applied individually and in combination to avert future EVD cases and deaths.

Methods
We developed a transmission model of Ebola virus that we fitted to reported EVD cases and deaths in Montserrado County, Liberia. We used this model to assess the effectiveness of expanding EVD treatment centres, increasing case ascertainment, and allocating protective kits for controlling the outbreak in Montserrado. We varied the efficacy of protective kits from 10% to 50%. We compared intervention initiation on Oct 15, 2014, Oct 31, 2014, and Nov 15, 2014. The status quo intervention was defined in terms of case ascertainment and capacity of EVD treatment centres on Sept 23, 2014, and all behaviour and contact patterns relevant to transmission as they were occurring at that time. The primary outcome measure was the expected number of cases averted by Dec 15, 2014.

Findings
We estimated the basic reproductive number for EVD in Montserrado to be 2·49 (95% CI 2·38—2·60). We expect that allocating 4800 additional beds at EVD treatment centres and increasing case ascertainment five-fold in November, 2014, can avert 77 312 (95% CI 68 400—85 870) cases of EVD relative to the status quo by Dec 15, 2014. Complementing these measures with protective kit allocation raises the expectation as high as 97 940 (90 096—105 606) EVD cases. If deployed by Oct 15, 2014, equivalent interventions would have been expected to avert 137 432 (129 736—145 874) cases of EVD. If delayed to Nov 15, 2014, we expect the interventions will at best avert 53 957 (46 963—60 490) EVD cases.

Interpretation
The number of beds at EVD treatment centres needed to effectively control EVD in Montserrado substantially exceeds the 1700 pledged by the USA to west Africa. Accelerated case ascertainment is needed to maximise effectiveness of expanding the capacity of EVD treatment centres. Distributing protective kits can further augment prevention of EVD, but it is not an adequate stand-alone measure for controlling the outbreak. Our findings highlight the rapidly closing window of opportunity for controlling the outbreak and averting a catastrophic toll of EVD cases and deaths.

Funding
US National Institutes of Health.

Canadian Ebola vaccine development taken over by Merck

Public Health Agency of Canada, which originally developed the vaccine, will retain non-commercial rights
Thomson Reuters Posted: Nov 24, 2014 12:43 PM ET Last Updated: Nov 24, 2014 12:43 PM ET   Full text.

Merck & Co Inc on Monday said it would buy worldwide commercial rights to NewLink Genetics Corp's experimental vaccine against the Ebola virus. NewLink, whose subsidiary licensed commercial rights to the rVSV-EBOV vaccine in 2010, said it would receive $50 million US plus royalties from Merck. The deal between Merck and NewLink comes as other drugmakers are also racing to test and scale up production of potential treatments and preventive vaccines for Ebola, which has killed more than 5,400 people this year. (The Associated Press)

Large late-stage trials of the product could begin early next year, said Merck, the No. 2 U.S. drugmaker and one of the world's biggest makers of vaccines. Merck, which will be able to speed up and significantly boost production, will take over development of the vaccine and any follow-on products. The Public Health Agency of Canada, which originally developed the vaccine, will retain non-commercial rights to it. The deal between Merck and NewLink, a tiny biotechnology company based in Ames, Iowa, comes as other drugmakers are also racing to test and scale up production of treatments and preventive vaccines for Ebola, which has killed more than 5,400 people this year. It is the worst Ebola outbreak on record. Guinea, Sierra Leone and Liberia account for all but 15 of the deaths.

The Walter Reed Army Institute of Research and the U.S. National Institute of Allergy and Infectious Diseases, part of the U.S. National Institutes of Health, are conducting early-stage trials of the NewLink vaccine. The trials involve healthy volunteers and are testing whether the vaccine is safe and provokes a protective immune response. Should those Phase I studies prove favourable, the NIH plans to begin large late-stage trials early next year. The World Health Organization is also coordinating early-stage trials in Switzerland, Germany, Kenya and Gabon. In a regulatory filing on Monday, NewLink said Merck would pay it $30 million US upfront and $20 million US once larger formal trials begin. The company will also be eligible to receive royalties on sales in certain markets. Rival drugmaker GlaxoSmithKline Plc is developing its own Ebola vaccine with the NIH and plans to build a stockpile of thousands of doses for emergency deployment if results are good.

Elsewhere on Monday, the UN Ebola Emergency Response Mission said it will not fully meet its Dec. 1 target for containing the virus due to escalating numbers of cases in Sierra Leone and elsewhere, said Anthony Banbury, the head of UNMEER. The mission set the goal in September of having 70 per cent of Ebola patients under treatment and 70 per cent of Ebola victims safely buried. That target will be achieved in some areas, Banbury told Reuters. He cited progress in Liberia On Monday, Liberia's president urged a redoubling of efforts to reach the government's goal of having zero new Ebola cases by Dec. 25. "We've set a pretty tough target. But when you set a target it means that you stay focused on that target and on that goal and then you double your efforts," Sirleaf said during a ceremony marking the docking of a Dutch aid ship in the capital, Monrovia. "When you're running a race, as you get closer and closer to the finish line you pick up the speed because you want to make sure that that last mile you will give it your best bet," Sirleaf added. Italy's health ministry said Monday that an Italian doctor who has been working in Sierra Leone has tested positive for the Ebola virus and is being transferred to Rome for treatment. It is Italy's first confirmed case of Ebola.

With files from The Associated Press
© Thomson Reuters, 2014 

An Ebola virus protein can cause massive inflammation and leaky blood vessels

Ebola GP protein covers the virus' surface and is shed from infected cells during infection. A study published on November 20th in PLOS Pathogens reports that shed GP can trigger massive dysregulation of the immune response and affect the permeability of blood vessels

Ebola virus has seven genes. One of them, called GP, codes for two related proteins: a shorter secreted one and a longer one that spans the viral wall and sticks out of its surface. During virus infection, some of the surface GP is cut off by a human enzyme and is subsequently shed from infected cells. High levels of both shed and secreted GP are found in the blood of infected humans and animals.

Rather than working with intact Ebola virus, Viktor Volchkov and colleagues from the Claude Bernard University of Lyon, International Center for Infectiology Research (CIRI), INSERM, France, produced shed and secreted GP in tissue culture and used these proteins to test their effects on human cells.

They found that shed but not secreted GP can bind to immune cells, called macrophages and dendritic cells, both also targets of Ebola virus infection. Upon binding of shed GP, these immune cells start releasing massive quantities of immune-modulators. Both shed GP and these immune-modulators are soluble proteins that can travel in the blood stream, and this might explain how through continuing production and release of shed GP an initial immune response to the virus gets amplified and can spiral out of control, leading to high fever, massive inflammation, and possibly the shock that kills many Ebola patients.

The scientists also found that the effects of shed GP on the immune cells depends on a molecule called TLR-4. Blocking TLR-4 with specific antibodies prior to exposing immune cells to shed GP damped the cells' reaction and eliminated much of the release of immune modulators.

Besides massive and destructive inflammation, fatal Ebola disease is also associated with loss of blood vessel integrity--hence the name Ebola hemorrhagic fever. To examine a possible contribution of GP to these symptoms, the researchers examined the effects of secreted and shed GP on permeability of endothelial cells (which form blood vessels). They found that shed GP directly--as well as through the cocktail of immune-modulators produced by immune cells upon binding of shed GP--can increase permeability of endothelial cells.

While the results of the study need to be confirmed in the context of infected animals or humans, the authors conclude that their data "support a role for EBOV shed GP in the creation of excessive and dysregulated host inflammatory responses and an increased vascular permeability". They also speculate that "anti-TLR4 antibodies could be used to reduce the inflammatory reaction caused by shed GP".

Contact:
Viktor Volchkov
e-mail: viktor.volchkov@inserm.fr
phone: +33.4.37.28.24.50
Please use this URL to provide readers access to the paper (Link goes live upon article publication): http://dx.plos.org/10.1371/journal.ppat.1004509
Authors and Affiliations: Beatriz Escudero-Pérez, Valentina A. Volchkova, Olga Dolnik, Philip Lawrence, Viktor E. Volchkov
All authors are affiliated with INSERM U1111- CNRS UMR5308, Université de Lyon, France
Please contact plospathogens@plos.org if you would like more information.
Funding: This work was supported by the European Union FP7 project ANTIGONE (278976), Agence Nationale de la Recherche (ANR-07-MIME-006-01), Fondation pour la Recherche Medicale (DMI20091117323), the Direction Generale de l'Armement (DGA) and « La Caixa » Fondation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Citation: Escudero-Pérez B, Volchkova VA, Dolnik O, Lawrence P, Volchkov VE (2014) Shed GP of Ebola Virus Triggers Immune Activation and Increased Vascular Permeability. PLoS Pathog 10(11): e1004509. doi:10.1371/journal.ppat.1004509

Ebola control: rapid diagnostic testing

Full text.

[Selection] In their analysis of Ebola transmission,1 Joseph Lewnard and colleagues  emphasise the need for an  “acceleration of case ascertainment”, which so far has been a major challenge. Most patients with Ebola in west Africa remain undiagnosed in their communities,2 and the average delay from symptom onset to diagnosis is about 5 days.3 For a PCR-based diagnosis, patients need to attend a laboratory, or visit a transit centre where blood can be drawn and transported to a laboratory. This process introduces delays during which transmission can occur. Accurate, point-of-care, rapid tests could minimise this window of transmission. If Ebola is diagnosed at home when symptoms first appear, household members could use protective kits until the infected person is securely transported to a treatment centre. To investigate the eff ect of reducing the time between symptom onset and diagnosis with rapid testing, we used a standardised epidemic simulator4for a population of 10 million and basic reproduction rate of 2·0. The proportion of the population eventually infected (attack rate) is shown as a function of the proportion of patients infected with Ebola who are diagnosed and then isolated (effectiveness of the isolation strategy; fi gure). If 60% of patients infected with Ebola are diagnosed rapidly and isolated, the attack rate drops from 80% to nearly 0% because the delay is reduced from
5 days to 1 day.

This manuscript has been conditionally accepted by PLOS Neglected Tropical Diseases for publication prior to formal review, and was posted to Speaking of Medicine on October 31st, 2014. Following a successful outcome of independent peer review, a revised version will be formally published by PLOS Neglected Tropical Diseases, readers should check for updates to this manuscript here.

Full text.

Social pathways for Ebola Virus Disease in rural Sierra Leone, and some implications for containment

Paul Richards¹,*, Joseph Amara¹, Mariane C Ferme², Prince Kamara¹, Esther Mokuwa¹, Amara Idara Sheriff¹, Roland Suluku¹, and Maarten Voors³
1 Njala University, Sierra Leone
2 University of California, Berkeley, United States of America
3 Wageningen University, The Netherlands
*Corresponding author: paul.richards@wur.nl.

Abstract
The current outbreak of Ebola Virus Disease in Upper West Africa is the largest ever recorded. Molecular evidence suggests spread has been almost exclusively through human-to-human contact. Social factors are thus clearly important to understand the epidemic and ways in which it might be stopped, but these factors have so far been little analyzed. The present paper focuses on Sierra Leone, and provides data on the least understood part of the epidemic - the largely undocumented spread of Ebola in rural areas. Various forms of social networking in rural communities and their relevance for understanding pathways of transmission are described. Particular attention is paid to the relationship between marriage, funerals and land tenure. Funerals are known to be a high-risk factor for infection. It is suggested that more than a shift in awareness of risks will be needed to change local patterns of behavior, especially in regard to funerals, since these are central to the consolidation of community ties. A concluding discussion relates the information presented to plans for halting the disease. Local consultation and access are seen as major challenges to be addressed.

Contact: Michael Kennedy
m.kennedy@utoronto.ca
416-946-5025
University of Toronto
@UofTNews

University of Toronto launches search for new Ebola drug using artificial intelligence

TORONTO, ON - The University of Toronto, Chematria and IBM are combining forces in a quest to find new treatments for the Ebola virus.

Using a virtual research technology invented by Chematria, a startup housed at U of T's Impact Centre, the team will use software that learns and thinks like a human chemist to search for new medicines. Running on Canada's most powerful supercomputer, the effort will simulate and analyze the effectiveness of millions of hypothetical drugs in just a matter of weeks. "What we are attempting would have been considered science fiction, until now," says Abraham Heifets (PhD), a U of T graduate and the chief executive officer of Chematria. "We are going to explore the possible effectiveness of millions of drugs, something that used to take decades of physical research and tens of millions of dollars, in mere days with our technology."

Chematria's technology is a virtual drug discovery platform based on the science of deep learning neural networks and has previously been used for research on malaria, multiple sclerosis, C. difficile, and leukemia. Much like the software used to design airplanes and computer chips in simulation, this new system can predict the possible effectiveness of new medicines, without costly and time-consuming physical synthesis and testing. The system is driven by a virtual brain that teaches itself by "studying" millions of datapoints about how drugs have worked in the past. With this vast knowledge, the software can apply the patterns it has learned to predict the effectiveness of hypothetical drugs, and suggest surprising uses for existing drugs, transforming the way medicines are discovered.

The World Health Organization has projected that new cases of Ebola could reach 10,000 each week by December 2014, underscoring the urgent need for research to address the crisis. The unprecedented speed and scale of this investigation is enabled by the unique strengths of the three partners: Chematria is offering the core artificial intelligence technology that performs the drug research, U of T is contributing biological insights about Ebola that the system will use to search for new treatments and IBM is providing access to Canada's fastest supercomputer, Blue Gene/Q.

"Our team is focusing on the mechanism Ebola uses to latch on to the cells it infects," said Dr. Jeffrey Lee of the University of Toronto. "If we can interrupt that process with a new drug, it could prevent the virus from replicating, and potentially work against other viruses like Marburg and HIV that use the same mechanism."

While there are "broad spectrum" antibiotics that can treat multiple kinds of bacterial infections, most antiviral medications are only effective against a single kind of virus. The initiative may also demonstrate an alternative approach to high-speed medical research. While giving drugs to patients will always require thorough clinical testing, zeroing in on the best drug candidates can take years using today's most common methods. Critics say this slow and prohibitively expensive process is one of the key reasons that finding treatments for rare and emerging diseases is difficult. "If we can find promising drug candidates for Ebola using computers alone," said Heifets, "it will be a milestone for how we develop cures."

Contact: Gina DiGravio
ginad@bu.edu
617-638-8480
Boston University Medical Center

Study identifies pre-symptomatic markers for hemorrhagic viruses like Ebola

(Boston)--A new study has found it is possible to distinguish between different hemorrhagic fevers, including Marburg (Ebola cousin) and Lassa before the person becomes symptomatic.

The study, which appears in the journal BMC Genomics will allow for the development of better diagnostics, especially during the early stages of disease, when treatments have a greater chance of being effective. Hemorrhagic fevers include Lassa, which is endemic in Western Africa and Marburg, which causes sporadic outbreaks in Africa associated with high rates of mortality. The early symptoms of these viruses (fever, flu-like symptoms) are not unique, making it difficult to diagnose properly. More disease-specific symptoms and the ability to spread the virus from person to person, do not begin until virus has accumulated in the blood. Current diagnostics detect the virus after it spills out of primary sites of infection into the blood. The ability to identify the infection prior to this point would significantly aid early intervention and containment, and could improve outcomes.

Researchers from Boston University School of Medicine (BUSM) approached the diagnostic dilemma by trying to "see" infection prior to the point where viruses enter the blood stream. Collaborating with researchers at the U.S. Army Medical research Institute (USAMRIID), they used two experimental models: one that had involved Lassa virus, and one that involved Marburg virus infection. The researchers extracted genetic material (RNA) from a sample of white blood cells from each infection group at multiple times after the models were infected. Using next-generation sequencing techniques, gene expression changes in hosts cells that "recognize" early stages of infection were identified. This was seen prior to clinical symptom onset and before the models became infectious.

According to the researchers, distinguishing between these viruses early can guide treatment and containment efforts. "The ability to distinguish between different types of infection before the appearance of overt clinical symptoms has important implications for guiding triage and containment during epidemics," explained corresponding author Nacho Caballero, a PhD candidate at Boston University School of Medicine (BUSM). "We hope that our study will help in the development of better diagnostics, especially during the early stages of disease, when treatments have a greater chance of being effective," he added.

As exciting as the prospect of this testing is, the research team is setting a realistic time line. "We want to stress that this is not a finding that can be translated into a test tomorrow. This study supports the idea that early markers of infection are there, but significant work will still need to be done to extend these findings," said Caballero. This work was supported by the United States Army contracts W81XWH 100-02-0008 and 11-02-0130. NC was supported in part by the Fulbright Commission Spain and the Regional Government of Andalusia.

New WHO safe and dignified burial protocol - key to reducing Ebola transmission

Note for the media 7 November 2014  Full text.

A new WHO protocol for safe and dignified burial of people who die from Ebola virus disease emphasizes inclusion of family members and encouraging religious rites as an essential part of safe burials. “At least 20% of new Ebola infections occur during burials of deceased Ebola patients. By building trust and respect between burial teams, bereaved families and religious groups, we are building trust and safety in the response itself.” says Dr Pierre Formenty, one of WHO’s top Ebola experts. “Introducing components such as inviting the family to be involved in digging the grave and offering options for dry ablution and shrouding will make a significant difference in curbing Ebola transmission.”

How infections occur during burials
Ebola infections occur during burials when family and community members perform religious rites that require directly touching or washing the body, which still contains high levels of Ebola virus; and when family members distribute personal property of the loved one, which may be infected with the virus.

Step-by-step processes for safe burials
Developed by an interdisciplinary team at WHO, in partnership with the International Federation of Red Cross and Red Crescent Societies (IFRC) and faith-based organizations including World Council of Churches, Islamic Relief, Caritas Internationalis and World Vision, this updated protocol outlines step-by-step processes for safe and dignified burials. The protocol encourages inclusion of family and local clergy in the planning and preparation of the burial, as well as at the burial event itself, giving specific instructions for Muslim and Christian burials.

"We are becoming known for "dead body management", but we do not "manage" dead bodies. We safely, respectfully and in a dignified manner, accompany our deceased fellow human beings and help to prepare them, in accordance with their cultures, for their last resting places. It is in this spirit that our volunteers carry out their difficult work" says Elhadj As Sy, Secretary General, IFRC.

Safe alternatives
“It is clear from Islamic juristic ruling that the necessity of religious washing of the body before burial of patients who die from Ebola is over-ruled,” says Rehanah Sadiq, a Muslim chaplain with University Hospitals Birmingham NHS Foundation Trust who served as consultant to WHO on the protocol. “However, it is vital to help bereaved families grieve and find closure by ensuring that sacred rites, such as performing a dry ablution, shrouding the body, and praying over the deceased are represented in Muslim funerals. Providing safe alternatives for families to maintain deeply-cherished practices helps them be part of the decision-making process, which is critical particularly during a time when they may be feeling helpless.”

“Giving the family an opportunity to view the body of the deceased, ensuring that the grave is appropriately labelled, and allowing religious leaders to offer prayers and family members the option to throw the first soil – these are important incentives for encouraging families to continue to find strength in their faith, and to keep other family members safe from becoming infected,” said Rev. Msgr. Robert J. Vitillo, Head of Delegation, Caritas Internationalis.

A team of medical anthropologists also contributed meaningful, safe alternatives for touching and bathing dead bodies, developed from research into the cultural significance and values of burial practices in affected countries. Consultations were held with religious leaders in affected countries to define what is meant by “dignified burial” in both the Muslim and Christian context.

The protocol also includes ways for Ebola burial teams to carry out their work safely while respecting family sensitivities. These include abstaining from wearing personal protective equipment (PPE) when first meeting with the family, and asking the family if there are specific requests for managing the burial and personal effects of the deceased. As the protocol is applied in affected countries, feedback from religious leaders, communities and people managing burials will be used to update and improve the protocol.

WHO welcomes approval of a second Ebola vaccine trial in Switzerland

Statement 6 November 2014

WHO welcomes approval by Swissmedic, the Swiss regulatory authority for therapeutic products, of a second Swiss trial of an experimental Ebola vaccine. The trial will be led by the University Hospitals of Geneva (HUG). If judged safe, larger scale trials will be taken to African countries as early as January 2015. This trial approval means that the vaccine will be tested on approximately 115 volunteers in Geneva. The trial, which is receiving support from WHO, is the latest in a series of trials involving 2 different candidate Ebola vaccines that are ongoing in Switzerland, Mali, the United Kingdom, and the United States.

About the vaccine
The experimental VSV-ZEBOV vaccine has been developed by scientists at the Public Health Agency of Canada . It is based on the virus that causes vesicular stomatitis, a disease affecting animals. This virus has been weakened and genetically modified to express the glycoprotein of the Zaire Ebola virus (ZEBOV) so as to provoke an immune response against real Ebola viruses. The experimental vaccine will be tested on healthy volunteers, some of whom will be deployed as health care staff in the fight against the Ebola epidemic in West Africa. The trial will test the safety of the vaccine and its ability to provoke an immune response. VSV-ZEBOV is also being tested on healthy volunteers in the USA (the first trial started 13 October) and trials are planned to start very soon in Germany, Gabon and Kenya.

Vaccine trials
The trial is the second one organised in Switzerland and coordinated by WHO. The first vaccine, “ChAd3" - Chimpanzee-Adenovirus ChAd3-ZEBOV – started trials in Lausanne at the end of October. “These trials show an almost unprecedented mobilisation on the part of countries, health agencies and industry to pitch in and help to curb the Ebola epidemic,” says Dr Marie-Paule Kieny, Assistant Director-General for Health Systems and Innovation at WHO. “If the vaccines prove to be safe and effective and we move to production and distribution scale-up, this will be the fastest vaccine roll-out we have had in response to a public health emergency to date.” The trial in Geneva begins with the first vaccinations during the week of 10 November, with first results expected in December 2014.

For more information on the Geneva trial of the Ebola vaccine

WHO media contacts:

Fadéla Chaib
Communications Officer, World Health Organization
Telephone: +41 22 791 32 28
Mobile: +41 79 475 55 56
E-mail: chaibf@who.int

Tarik Jasarevic
WHO Department of Communications
Telephone: +41 22 791 50 99
Mobile: +41 79 367 62 14
E-mail: jasarevict@who.int

Telephone: +41 22 791 1646
E-mail: harrism@who.int

E-mail: Olga.De-Santis@hospvd.ch@who.int

New study sheds light on the importance of supportive care for Ebola patients

Ebola situation assessment - 6 November 2014

Evidence is mounting that earlier messages about Ebola virus disease having no treatment, cure, or vaccines are no longer entirely accurate. A number of candidate vaccines are currently undergoing clinical trials, with their manufacturers expressing determination to pursue work on all vaccines until they fail or one succeeds. Manufacturers have also expressed their willingness to include vaccines from competitor companies in their own clinical trials. The first clinical trials of therapeutic – possibly curative – transfusions of whole blood or blood plasma from recovered patients are scheduled to begin soon in Liberia, in line with WHO technical guidelines. The Organization’s country office is facilitating the importation of equipment needed for the study. This equipment, plus training of skilled staff for the study, are expected to strengthen the quality and safety of Liberia’s overall blood services. Today, a WHO-coordinated retrospective study, published in the New England Journal of Medicine, provides evidence that supportive care, especially rehydration and correction of metabolic abnormalities, may contribute to patient survival.

The WHO-coordinated Guinea study
The study analysed clinical data on 37 confirmed Ebola patients admitted for treatment at hospitals in Conakry, Guinea’s capital and most densely populated city. The cases occurred during the first month of West Africa’s first outbreak of Ebola virus disease. Fourteen of the patients were heath care workers. The majority (12) acquired their infection in a health care setting.
The study benefitted from careful and thorough daily data collection, laboratory records, and case histories put together by clinicians from the Ministry of Health, Médecins sans Frontières (MSF), and WHO.

One of the patients had negative results on an RT-PCR test, but was positive for IgG antibodies on ELISA. This finding underscores WHO recommendations for repeat testing before a suspected case can be discarded as “negative” or a recovered patient can be discharged from a treatment centre. The majority (65%) of patients were male, countering assumptions that women, who are more likely to provide home care for patients and prepare bodies for funerals and burials, are more frequently exposed and infected. Patients presented at hospital from 3 to 7 days after symptom onset, most commonly with fever (in 84%), fatigue (in 65%), diarrhoea (in 62%), vomiting in 21 patients (57%), and a heartbeat that was moderately faster than normal. Of these patients, 28% developed hiccups, a non-specific but distinctive feature of Ebola, at some point during their hospital stay.

More treatment, more survivors
To replace fluids lost through severe diarrhoea, 36 patients (97%) received oral rehydration solution. Additional intravenous fluid resuscitation was given to 28 (76%) patients.
One patient with acute kidney injury, probably caused by profound diarrhoea-related dehydration, improved following the administration of approximately 5 litres of intravenous crystalloid fluids per day for 3 days. As a precaution, antibiotics were administered to 37 patients (100%) to combat potential bacterial infections associated with their gastrointestinal illness. Seven patients received antimalarial medication and 4 had that diagnosis strengthened by a positive rapid diagnostic test. Despite this treatment, 16 patients (43%) died, on average within 5 days after hospitalization. This case fatality rate is lower than that recorded at other sites during the current outbreaks, also in Guinea, and in previous outbreaks caused by the Zaire species of Ebola virus.

For example, another retrospective study of 106 patients from Sierra Leone, published last week in the New England Journal of Medicine, documented a case fatality rate of 74%.

• Clinical illness and outcomes in patients with Ebola in Sierra Leone
  The New England Journal of Medicine

High-quality supportive care is thought to have contributed to the larger number of survivors. However, two limitations compromised the quality of bedside care: staff were too few in number; and the duration of time spent providing care at the bedside was too little, due to dehydration and over-heating of clinicians wearing personal protective equipment.These limitations suggest that survival rates, under more favourable hospital conditions, might be even higher.

Factors that may have influenced survival from Ebola
The study population was too small to allow firm conclusions about which specific interventions increased the prospects of survival.The amount of circulating viral load was higher in those who died than in survivors; those patients with the highest levels of virus were most likely to die. One of the strongest determinants of survival appears to be patient age. Patients older than 40 years were nearly 3.5 times more likely to die than those aged less than 40. The association between an older age and a higher risk of death was found regardless of whether the patient had co-morbidities or not.

Evidence of substantial fluid loss and profound electrolyte derangement associated with severe diarrhoea appears to increase the risk of a fatal outcome. More aggressive supportive care, especially intravenous rehydration, is thought to improve the prospects of survival. Along with fluid management, enhanced levels of clinical assessment and diagnostic testing may be ways to further improve survival beyond what has been seen elsewhere and in previous outbreaks of Ebola virus disease.

• Read the full article: Clinical presentation of patients with Ebola Virus Disease in Conakry, Guinea
  The New England Journal of Medicine, 5 November 2014

WHO updates personal protective equipment guidelines for Ebola response

News release  Full text.

31 OCTOBER 2014 ¦ GENEVA - As part of WHO’s commitment to safety and protection of healthcare workers and patients from transmission of Ebola virus disease, WHO has conducted a formal review of personal protective equipment (PPE) guidelines for healthcare workers and is updating its guidelines in context of the current outbreak.

About the PPE guidelines
These updated guidelines aim to clarify and standardize safe and effective PPE options to protect health care workers and patients, as well as provide information for procurement of PPE stock in the current Ebola outbreak. The guidelines are based on a review of evidence of PPE use during care of suspected and confirmed Ebola virus disease patients.

The Guidelines Development Group convened by WHO included participation of a wide range of experts from developed and developing countries, and international organizations including the United States Centers for Disease Control and Prevention, Médecins Sans Frontières, the Infection Control Africa Network and others.

“These guidelines hold an important role in clarifying effective personal protective equipment options that protect the safety of healthcare workers and patients from Ebola virus disease transmission,” says Edward Kelley, WHO Director for Service Delivery and Safety. “Paramount to the guidelines’ effectiveness is the inclusion of mandatory training on the putting on, taking off and decontaminating of PPE, followed by mentoring for all users before engaging in any clinical care.”

Guidelines were developed from an accelerated development process that meets WHO’s standards for scientific rigour and serves as a complement to the Interim infection prevention and control guidance for care of patients with suspected or confirmed filovirus haemorrhagic fever in health-care settings, with focus on Ebola, published by WHO in August 2014.

Use of the personal protective equipment
Experts agreed that it was most important to have PPE that protects the mucosae – mouth, nose and eyes – from contaminated droplets and fluids. Given that hands are known to transmit pathogens to other parts of the body, as well as to other individuals, hand hygiene and gloves are essential, both to protect the health worker and to prevent transmission to others. Face cover, protective foot wear, gowns or coveralls, and head cover were also considered essential to prevent transmission to healthcare workers.

"Although PPE is the most visible control used to prevent transmission, it is effective only if applied together with other controls including facilities for barrier nursing and work organization, water and sanitation, hand hygiene, and waste management," says Marie-Paule Kieny, Assistant Director-General of Health Systems and Innovation. Benefits derived from PPE depend not only on choice of PPE, but also adherence to protocol on use of the equipment.

A fundamental principle guiding the selection of different types of PPE was the effort to strike a balance between the best possible protection against infection while allowing health workers to provide the best possible care to patients with maximum ease, dexterity, comfort and minimal heat-associated stress.

In this situation where evidence is still being collected, to see what works best and on an effective sustainable basis, it was considered prudent to provide options for selecting PPE. In most cases, there was no evidence to show that any one of the options recommended is superior to other options available for healthcare worker safety.

Further work is needed to gather scientific experience and data from the field in systematic studies, in order to understand why some health workers are infected in the current outbreak and to increase effective clinical care. WHO is committed to working with international partners on these issues to build this evidence base.

WHO welcomes Swissmedic approval of Ebola vaccine trial at Lausanne University Hospital

Statement  Full text.
28 October 2014

The World Health Organization (WHO) welcomes the approval by Swissmedic, the Swiss regulatory authority for therapeutic products, for a trial with an experimental Ebola vaccine at the Lausanne University Hospital (CHUV). This marks the latest step towards bringing safe and effective Ebola vaccines for testing and implementation as quickly as possible. Approval means that the vaccine can be used on approximately 120 individuals in Lausanne. The trial, which is receiving support from WHO, is the latest in a series of trials that are ongoing in Mali, the United Kingdom, and the United States.

About the vaccine
The vaccine is based on a genetically modified chimpanzee adenovirus ("ChAd-Ebola"; Chimpanzee-Adenovirus chAD3-ZEBOV). The trial will test the safety of the vaccine and its capacity to induce an immune response. Results from the CHUV trial will – together with the results of other centres involved – provide the basis for planning subsequent trials involving several thousand participants, and for choosing vaccine dose-level for efficacy trials.

Developed by the US National Institute of Allergy and Infectious Diseases (NIAID) and pharmaceutical company GlaxoSmithKline, the vaccine consists of a virus that is rendered harmless and used as genetic carrier for one Ebola protein. The application, submitted at the end of September 2014, was handled as a priority, given the dimensions of the Ebola epidemic in West Africa.

Vaccine trials
The trial is one of two in Switzerland coordinated by WHO. A second vaccine, rVSV-ZEBOV, is to be tested at the Geneva University Hospitals, concurrent to the Lausanne trial.“These are dosing and safety trials being held in advance of Phase II and III trials currently scheduled for late 2014-early 2015,” says Marie-Paule Kieny, Assistant Director-General for Health Systems and Innovation at WHO. “If shown to be safe and effective, either of the vaccines could be scaled up for production during the first quarter of next year, with millions of doses produced for wide distribution in high-risk countries.” Trials in Lausanne will begin this week, with first results expected in December 2014.

Blood from Ebola survivors tested as short term treatment option.

Friday, 24 October 2014  Full Text

An international research consortium which includes the London School of Hygiene & Tropical Medicine and is led by the Institute of Tropical Medicine in Antwerp (ITM) will assess whether treatment with antibodies in the blood of Ebola survivors could help infected patients to fight off the disease. If proven effective, this straightforward intervention could be scaled up in the short term and provide an urgently needed treatment option for patients in West Africa. The researchers have received € 2.9 million of European Union (EU) funding to evaluate the safety and efficacy of treatment with blood and plasma made from the blood of recovered Ebola patients.

A World Health Organization (WHO) expert meeting in September recommended convalescent blood therapies as one of the most promising strategies meriting urgent evaluation as treatment of Ebola disease. As a result of the current outbreak, there are also substantial numbers of survivors to prepare Ebola plasma. Professor Peter Smith and Tansy Edwards, co-principal investigators from the London School of Hygiene & Tropical Medicine, said: “We look forward to working as part of this consortium to contribute to Ebola control efforts. It's essential that we find out whether blood and plasma therapy can be an effective and safe approach in treating patients with the Ebola virus, and if it can reduce the number of deaths in the present outbreak.”

ITM’s Johan van Griensven, the project’s coordinating investigator, added: “Blood and plasma therapy are medical interventions with a long history, safely used for other infectious diseases. Ebola survivors contributing to curb the epidemic by donating blood could reduce fear of the disease and improve their acceptance in the communities.” Blood and plasma from recovered Ebola patients has been used in a limited number of patients previously. For example, during the 1995 Ebola outbreak in Kikwit, in the Democratic Republic of the Congo (DRC), seven out of eight patients receiving convalescent whole blood survived. However, whether this was due to the transfusions or to other factors is unclear. There is an urgent need to evaluate this therapy in carefully designed studies according to the highest ethical and scientific standards.

EU Research, Innovation and Science Commissioner Máire Geoghegan-Quinn said in the funding announcement that it is urgent to step up medical research on Ebola. According to Geoghegan-Quinn the selected projects “enlist the best academic researchers and industry to take the fight to this deadly disease.” The Wellcome Trust will provide additional support, enabling unparalleled international collaboration across the public, private and not-for-profit sectors to tackle the Ebola emergency. Jeremy Farrar, Director of the Wellcome Trust, said: “The Wellcome Trust is delighted to work in partnership with the European Commission to support and help fast-track this critical work. Convalescent serum offers the best potential treatment for Ebola in the short term that could be scaled up if proven effective. Global collaboration of this nature, including clinical researchers and multiple partners from across Europe and West Africa, is both unprecedented and essential if we are to bring the current outbreak under control.”

The € 2.9 million grant from the EU will fund the Institute of Tropical Medicine in Antwerp, University of Liverpool, London School of Hygiene & Tropical Medicine, University of Oxford, Aix-Marseille University, the French Blood Transfusion Service (Etablissement Français du Sang), Institute Pasteur, and the French National Institute of Health and Medical Research.
The consortium also includes the National Blood Transfusion Centre in Conakry (Guinea), the Institut National de Recherche Biomédicale in Kinshasha (DRC), and the Belgian Red Cross-Flanders. The project, which will start in Guinea in November 2014, is supported and guided by the WHO and the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC).

Ebola situation assessment - 23 October 2014

Introduction
A high-level emergency meeting, convened by WHO at the request of several governments and representatives of the pharmaceutical industry, was held on 23 October to look at the many complex policy issues that surround eventual access to experimental Ebola vaccines. Ways to ensure the fair distribution and financing of these vaccines were discussed in an atmosphere characterized by a high sense of urgency. This sense of urgency was conveyed in many ways – from plans for the different phases of clinical trials to be performed concurrently rather than consecutively, to suggested partnerships for expediting clinical trials, to proposals for getting all development partners moving in tandem and at the same accelerated pace.

Photo Credit: (WHO/M. Missioneiro)
The 1st batch of experimental vaccines, VSV-EBOV, arrived in October 2014 in Geneva, Switzerland, and were stored at the Geneva University Hospital

More than 90 participants, including some of the world’s leading scientists, came, on short notice, from national and university research institutions, also in Africa, government health agencies, ministries of health and foreign affairs, national security councils, and several offices of Prime Ministers and Presidents. Also represented were national and regional drug regulatory authorities, the MSF (Doctors Without Borders) medical charity, funding agencies and foundations, the GAVI alliance for childhood immunization, and development banks, including the African Development Bank, the European Investment Bank, and the World Bank Group.

Main conclusions reached
Impact of vaccines on further evolution of the epidemic
The meeting concluded that vaccines will have a significant impact on the further evolution of the epidemic in any scenario, from best-case to worst-case.
Financing of vaccine development, clinical trials, and vaccination campaigns
The meeting concluded that funding issues should not be allowed to dictate the vaccine agenda. The funds will be found.
Liability
The meeting concluded that neither affected countries nor industry should be left alone to bear the burden should lawsuits arise following possible adverse reactions to an Ebola vaccine. To respond to this potential problem, a proposal was made to establish a “club” of donors, in collaboration with the World Bank.
The timing and quantity of vaccine supplies
The meeting concluded that the timing and quantity of vaccine doses should not constrain the design of clinical trials. Industry confirmed that enough vaccine doses would be available.
GlaxoSmithKline’s monthly production capacity for purified bulk vaccine was expected to rise from the current figure of 24,000 doses to 230,000 by April 2015, if they can be filled for release. NewLink’s bulk vaccine manufacturing capacity for the Canadian vaccine was noted to vary, according to the dose selected, from 52,000 doses to 5.2 million doses anticipated for the first quarter of 2015.
Design of protocols for phase 2 and phase 3 clinical trials
The meeting concluded that randomized controlled clinical trials were the gold standard in terms of yielding reliable scientific data for the analysis and interpretation of efficacy. A stepped-wedge design could also yield useful and meaningful data during the special circumstances of the current epidemic. The 1st batch of experimental vaccines, VSV-EBOV, arrived in October 2014 in Geneva, Switzerland, and were stored at the Geneva University Hospital.
Priority uses of vaccine when supplies are limited
The meeting concluded that health care workers, including medical staff, laboratory staff, burial teams, and facility cleaners, should have first call on vaccine doses while supplies remain limited. Vaccination of health care workers in the three countries was judged feasible during the first quarter of 2015.
Regulatory requirements
The meeting concluded that the licensure and authorization requirements of regulatory authorities should be streamlined and harmonized, enabling the rapid introduction of vaccines for clinical trials and general distribution, yet with no compromise of scientific standards. In order to deliver the number of doses on the schedules proposed by the manufacturers, regulators must work closely with the manufacturers to find ways to overcome a number of regulatory hurdles.
Urgent measures to improve readiness for clinical trials and vaccines
The meeting concluded that two preparatory measures should be given the most urgent priority: community engagement and social mobilization to prepare populations to understand and accept clinical trials and vaccination campaigns, and the building of basic public health infrastructures, especially given the considerable logistical challenges facing health services in Guinea, Liberia, and Sierra Leone.
Coordination and alignment among multiple partners
The meeting concluded that a mechanism or framework must be urgently established, relying on WHO’s convening and coordination powers, to get all partners working in tandem, according to a single agreed plan and aligned with industry’s “critical paths” analysis.
Determination to finish the job
The meeting concluded that all efforts to develop, test, and approve Ebola vaccines must be followed through to completion at the current accelerated pace, even if dramatic changes in the epidemic’s transmission dynamics meant that vaccines were no longer needed.

• Read full meeting report: WHO high-level meeting on Ebola vaccines access and financing.pdf, 563 Kb

Aid group has set the gold standard on Ebola safety

Ebola's evolutionary roots are more ancient than previously thought, study finds
The family of viruses housing Ebola and Marburg is ancient, and the two viruses last shared a common ancestor millions of years ago, scientists say

BUFFALO, N.Y. — A new study is helping to rewrite Ebola's family history.
The research shows that filoviruses — a family to which Ebola and its similarly lethal relative, Marburg, belong — are at least 16-23 million years old. Filoviruses likely existed in the Miocene Epoch, and at that time, the evolutionary lines leading to Ebola and Marburg had already diverged, the study concludes. The research was published in the journal PeerJ in September. It adds to scientists' developing knowledge about known filoviruses, which experts once believed came into being some 10,000 years ago, coinciding with the rise of agriculture. The new study pushes back the family's age to the time when great apes arose. "Filoviruses are far more ancient than previously thought," says lead researcher Derek Taylor, PhD, a University at Buffalo professor of biological sciences. "These things have been interacting with mammals for a long time, several million years."

According to the PeerJ article, knowing more about Ebola and Marburg's comparative evolution could "affect design of vaccines and programs that identify emerging pathogens." The research does not address the age of the modern-day Ebolavirus. Instead, it shows that Ebola and Marburg are each members of ancient evolutionary lines, and that these two viruses last shared a common ancestor sometime prior to 16-23 million years ago.

Clues in 'fossil genes'
Taylor and co-author Jeremy Bruenn, PhD, UB professor of biological sciences, research viral "fossil genes" — chunks of genetic material that animals and other organisms acquire from viruses during infection. In the new study, the authors report finding remnants of filovirus-like genes in various rodents. One fossil gene, called VP35, appeared in the same spot in the genomes of four different rodent species: two hamsters and two voles. This meant the material was likely acquired in or before the Miocene Epoch, prior to when these rodents evolved into distinct species some 16-23 million years ago.

In other words: It appears that the known filovirus family is at least as old as the common ancestor of hamsters and voles."These rodents have billions of base pairs in their genomes, so the odds of a viral gene inserting itself at the same position in different species at different times are very small," Taylor says. "It's likely that the insertion was present in the common ancestor of these rodents." The genetic material in the VP35 fossil was more closely related to Ebola than to Marburg, indicating that the lines leading to these viruses had already begun diverging from each other in the Miocene.

The new study builds on Taylor's previous work with Bruenn and other biologists, which used viral fossil genes to estimate that the entire family of filoviruses was more than 10 million years old. However, those studies used fossil genes only distantly related to Ebola and Marburg, which prevented the researchers from drawing conclusions about the age of these two viral lines. The current PeerJ publication fills this viral "fossil gap," enabling the scientists to explore Ebola's historical relationship with Marburg.

Possible relevance to disease prevention
The first Ebola outbreak in humans occurred in 1976, and scientists still know little about the virus' history. The same dearth of information applies to Marburg, which was recognized in humans in 1967 and implicated in the death of a Ugandan health worker this month. Understanding the virus' ancient past could aid in disease prevention, Taylor says. He notes that if a researcher were trying to create a single vaccine effective against both Ebola and Marburg, it could be helpful to know that their evolutionary lineages diverged so long ago.
Knowing more about filoviruses in general could provide insight into which host species might serve as "reservoirs" that harbor undiscovered pathogens related to Ebola and Marburg, Taylor says. "When they first started looking for reservoirs for Ebola, they were crashing through the rainforest, looking at everything — mammals, insects, other organisms," Taylor says. "The more we know about the evolution of filovirus-host interactions, the more we can learn about who the players might be in the system."

###

Collaborators
Taylor and Bruenn's co-authors on the PeerJ study include UB students Matthew Ballinger, Laura Hanzly and Jack Zhan, all in the UB Department of Biological Sciences.

Aid group has set the gold standard on Ebola safety

by Robyn Dixon

The decontamination ritual, performed dozens of times a day here at the Ebola treatment unit run by Doctors Without Borders, resembles a slow dance. Two European medical workers emerge from the high-infection zone and raise their arms, turning slowly in the rain of heavily chlorinated water directed by men with sprayers. "Take off your mask. Wash your hands." A colleague supervises each of the workers, calling out more than 20 steps as the exhausted women slowly remove their lethally contaminated protective suits, masks, goggles, boots and two sets of gloves. They wash their hands eight times during the process, starting with their gloves on. Their lives could depend on doing it all without a single mistake.

Dizzy in the thick tropical heat, one of the women sways, but recovers. She and her companion are dripping with perspiration, their hair sopping, as they wriggle out of the yellow PPE — personal protective equipment — suits. "You want people, no matter how tired they are, no matter how fuzzy-headed, to be doing things correctly," said Armand Sprecher, head of public health for Doctors Without Borders, the international medical aid group also known by its French initials, MSF. How did an aid group working out of white tents in West Africa become the gold standard in Ebola treatment, when hospitals in Dallas and Madrid have struggled to protect the workers they've deployed to treat Ebola patients? Western hospitals, with access to advanced technology like zero-pressure rooms, confront conditions far less trying than the business of treating thousands of desperately sick Africans in tent isolation wards. Here, the line delineating severe contamination danger is not a heavy door, but orange plastic fencing on gravel-covered ground.

Staff members at the Dallas hospital where Liberian Thomas Eric Duncan died recently of Ebola have complained that the protection gear was flimsy and workers lacked proper training, allegations that mirrored those from a hospital in Madrid also treating an Ebola patient. At the heart of the intense training of staffers working with the MSF in West Africa are the slow, careful procedures of donning the protective gear and, especially, removing it. When putting on the suit, gloves, boots, hood mask, goggles and apron, each nurse, doctor or sprayer has someone spotting them, making sure they don't leave a tiny gap in their gear. Taking it off, they are again observed and guided by a fellow staff member. The MSF has two decades of experience treating Ebola, more than any other organization. The group cut its teeth working on outbreaks of the virus in places such as the Democratic Republic of Congo, when the virus was limited to rural villages. It has also handled outbreaks in Uganda, Sudan, Gabon, Guinea and the Republic of Congo.

Ebola training by Doctors Without Borders

It was easier to isolate cases in villages and to inform communities of the risks of contact. The MSF was better prepared than most to deal with the current outbreak in Guinea, Sierra Leone and Liberia. But as the virus leaped across borders into crowded urban settings, the organization warned that it was slipping out of control. The MSF didn't have an Ebola casualty until the current outbreak, which the organization says has stretched its experience and expertise to the limit. The humanitarian group's safety procedures have been adopted by other organizations working on Ebola in West Africa, including the California-based International Medical Corps, which runs a treatment facility in Bong County, Liberia.

But the MSF record isn't flawless: Two foreign staff members have been infected, including a French nurse who was working at the front gate of the unit in Monrovia, one of the most contaminated areas of the site because of the large numbers of extremely ill patients who arrive there seeking admission, often vomiting or bleeding. The MSF reviewed its procedures afterward, and nurses at the gate began wearing thick plastic face shields when meeting patients. A Norwegian staff member was recently infected in Sierra Leone, a case being investigated. Commenting on that incident, director of operations Brice de le Vingne said there was always a risk involved in dealing with Ebola, despite the strict protocols. In addition, 19 local MSF staff members contracted Ebola, 12 of whom died. But the organization believes that "the vast majority" were infected in the community, not at the treatment center, a spokeswoman said. Medical workers often come under intense pressure from friends, family and community members to help sick people. When other humanitarian groups hesitated to send workers to West Africa after the Ebola outbreak was identified in March, the MSF scaled up dramatically. It was among the few. The infection of three American staff members from the charity Samaritan's Purse in West Africa apparently deterred other groups from involvement.

A smell like a public swimming pool drifts across the MSF compound in Monrovia. Ebola, contagious and potentially deadly when it touches human skin, is quite easily killed with chlorinated water. The virus can be picked up by contact with the bodily fluids of a symptomatic person, or from a surface an infected person touched, or from clothing or bedding. People with backpacks filled with strongly chlorinated water walk around the MSF compound spraying the high-risk areas where patients are treated, the orange plastic barriers around those areas and the gravel in and near the isolation ward. Everyone who enters or leaves the compound has their boots sprayed. Hand-washing tubs filled with chlorinated water stand on every corner. Inside the isolation zone, staff in PPE suits burn every contaminated item, from the clothing of patients to the used suits and gloves. Nothing sharp that could pierce a suit, like a knife for patients to cut food, is allowed inside the facility.

American nurse Monia Sayah, who has worked on Ebola response here and in Congo, said in a recent interview that she never felt afraid when caring for Ebola patients in West Africa. "I feel like if we follow the procedure, I feel very safe. We have very strict infection-control measures. When we use personal protective equipment, we use a set of behaviors," she said. "We have a rule: We don't shake hands, we don't hug." Sayah said her biggest fear was a needle stick injury. But she feels that it would be easier to pick up the virus outside the isolation ward, while visiting a market or interacting with people outside, for example, a view echoed by Sprecher. "Out in the world, you don't know where the virus is," he said. "You get into a cab, you don't know if somebody with Ebola had vomited on the seat."

The MSF puts the safety of staff first, above even patient welfare. Until recently, it didn't offer intravenous drips to patients in the Monrovia facility because of the risk to workers. A spokeswoman in Monrovia said that the facility has begun offering IVs, but only to patients unable to drink fluids. Workers heading to West Africa are trained at a facility in Brussels, training that is duplicated for local staff in Africa. After receiving lessons on how to avoid infection when dealing with patients and how to don and remove protective gear, workers spend time in a simulated Ebola treatment unit learning how to handle the kinds of situations they'll face in the horrors of a real facility. The group has more than 3,000 staff members in West Africa, including 240 foreign workers, operating six treatment units with 549 isolation beds. It has treated more than 2,400 patients, out of the total 8,997 cases, with a survival rate of 37.5%, higher than the overall average of 30% that was cited Tuesday by the World Health Organization.

The MSF has shipped in more than 670 tons of equipment, much of it chlorine and protective gear. By the end of the year, it will have spent $60 million fighting Ebola. Its health workers spend a maximum of a month working in isolation wards and then are rotated out. They work in shifts of only an hour at a time, because of the intense stress and heat involved. At other facilities in the region, particularly under-resourced government facilities, the safety record has been poor: About 427 doctors and nurses have been infected, mainly in government facilities, and 236 of them have died, a catastrophic loss in West Africa, where doctors are scarce. There were so many infections in government facilities that dozens of workers fled this year and treatment collapsed in many areas. The number of casualties has continued to climb steadily in recent weeks. In Liberia this week, staff confidence in government Ebola facilities wobbled again when some doctors and nurses went on strike over inadequate hazard pay. One government staff member, Eric K. Jacobs, told the Liberian news website Front Page Africa that he had seen a colleague infected with Ebola after a patient attacked him and tore his suit with his fingernails. "Many of our colleagues are dying; they are getting infected with the virus," Alphonso Williams, a hygienist at a government facility, told the site. "This work is not a normal hospital. This work we do here is something that is between life and death for us."

Dixon, who is based in South Africa, reported recently from Liberia. Times staff writer Alan Zarembo in Los Angeles contributed to this report.

NIH grants license agreement for candidate Ebola vaccines

Ebola vaccines based on established rabies vaccines may protect against both diseases

WHAT: The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, today announced a new license agreement aimed at advancing dual-purpose candidate vaccines to protect against rabies and Ebola viruses. The vaccines were created by scientists at NIAID and Thomas Jefferson University (TJU) in Philadelphia and are being further developed through a partnership with the German pharmaceutical company IDT Biologika. The candidate vaccines now have been licensed to Exxell BIO of Saint Paul, Minnesota, which aims to advance the products through clinical testing and commercialization. The experimental vaccines—based on rabies virus vaccines currently used in people and in animals—contain either a killed or a live, attenuated (weakened) rabies virus engineered to produce an Ebola protein. The killed, or inactivated, vaccine is being developed to prevent rabies and Ebola infection in people, while the live, attenuated vaccine is intended for use in African wildlife to help prevent Ebola virus transmission from animals to people. Studies conducted by NIAID and TJU researchers have shown that the vaccines are safe and induce rabies- and Ebola-specific immune responses in monkeys. The vaccines also protected the monkeys from infection with the Zaire strain of Ebola, which currently is spreading among people in West Africa. To date, the 2014 Ebola outbreak has caused approximately 8,400 illnesses, including more than 4,000 deaths. In partnership with TJU, IDT Biologika and Exxell BIO, NIAID researchers plan to use the licensed technology to develop rabies-based vaccines to protect at-risk populations from the Zaire and Sudan strains of Ebola virus and the closely related Marburg virus. NIAID also is conducting and supporting numerous other research efforts to develop Ebola vaccines and treatments.

WHO: NIAID Director Anthony S. Fauci, M.D., and Joseph Blaney, Ph.D., M.B.A., a staff scientist in NIAID's Division of Intramural Research, are available to discuss development of the vaccines.

### CONTACT: To schedule interviews, please contact Hillary Hoffman, (301) 402-1663, hillary.hoffman@nih.gov.

NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov/.

Ebola outbreak: 1st human trials of Canadian vaccine start in U.S.

Health Minister Rona Ambrose says VSV-EBOV vaccine 'very promising and hopeful' in Ebola fight, risk here low

The first human clinical trials of a Canadian-developed Ebola vaccine, VSV-EBOV, begin in Maryland today to assess the vaccine's safety and determine the appropriate dosage to fight the virus that has killed more than 4,000 people, largely in West Africa, Health Minister Rona Ambrose has announced. "We are able to share some very promising and hopeful news in the fight against Ebola," Ambrose said from Calgary.  She made the announcement at a joint news conference with chief public health officer Dr. Gregory Taylor, who spoke from Toronto. Both stressed no individuals in Canada have ever been diagnosed with Ebola, and the risk of contracting the disease remains low in this country. One person in Belleville, Ont., is in isolation with Ebola-like symptoms, though the hospital described the case as "extremely low risk." Another person who had been in isolation in Ottawa since Sunday tested negative for the virus on Monday, health officials said.

The vaccine, which was developed by scientists at the Public Health Agency of Canada's National Microbiology Laboratory in Winnipeg, will be tested on 20 healthy volunteers at the Walter Reed Army Institute of Research in Silver Spring, Md. Studies in primates have shown the vaccine prevents infections, if given before exposure, and increases survival chances among those who get it quickly after exposure. The results from the Phase 1 human trials will be completed by December, Ambrose said, although no specific date was given. The World Health Organization is 'very well aware that fear of infection has spread around the world much faster than the virus,' WHO director general Margaret Chan said.  She said the vaccine has been shown to be "100 per cent effective" in preventing the spread of the Ebola virus when tested on animals. "This provides hope because if the Canadian vaccine is shown to be safe and effective [in humans], it will stop this devastating outbreak," Ambrose said. The Canadian government owns the intellectual property rights to the vaccine but has licensed the rights to a small U.S. biotech company called NewLink Genetics through its wholly owned subsidiary, BioProtection Systems, the public agency said. The U.S. Defence Threat Reduction Agency, which is part of the U.S. Defence Department, is working with BioProtection Systems to further develop the product for use in humans. Canada has supplied 20 vials of the experimental vaccine for use in the trial.

Other Phase 1 clinical trials possible

The public health agency said other Phase 1 clinical trials are being considered for Canada, Europe and Africa. Taylor said if the results are successful, the next stage would be to test it in a larger human sample, including those directly handling Ebola cases in West Africa. "The health-care workers on the ground are the most likely target to do the next step," which could begin by the end of the year or early 2015, he said. "Clearly if those studies show that it's effective in health-care workers, the world would go into mass production." Canada announced in August that it would donate up to 1,000 doses of the vaccine to the World Health Organization as part of its contribution to the international effort to fight the virus, which has mainly affected Liberia, Sierra Leone and Guinea, but the vaccine has yet to be shipped from the Winnipeg lab. The public health agency blamed the delay on the WHO, but an article in the journal Science suggested a fight over intellectual property rights to the vaccine may be behind the delay. The article, published on the journal's website earlier this month, suggested NewLink Genetics was "worried about losing control over the development of the vaccine." The doses are expected to finally be shipped later this week, according to Marie-Paule Kieny, WHO assistant director general for health systems and innovation at the WHO.

Ebola 'most severe' modern health emergency

The WHO on Monday called the Ebola outbreak "the most severe, acute health emergency seen in modern times," and a day after a Texas health-care worker tested positive for Ebola — the first known case of the disease being contracted or transmitted in the U.S. The preliminary test found the Texas worker was wearing full protective gear while caring for a hospitalized patient who later died from the virus, health officials said Sunday. Dr. Tom Frieden, head of the Centers for Disease Control and Prevention, said the diagnosis shows there was a clear breach of safety protocol and all those who treated Thomas Eric Duncan are now considered potentially exposed. "We don't know what occurred in the care of the index patient, the original patient, in Dallas, but at some point there was a breach in protocol, and that breach in protocol resulted in this infection," Frieden told a news conference. The worker wore a gown, gloves, mask and shield while she cared for Duncan during his second visit to Texas Health Presbyterian Hospital, said Dr. Daniel Varga of Texas Health Resources, which runs the hospital. Frieden said the worker has not been able to identify a specific breach of protocol that might have led to her being infected.

Curbing economic disruptions

Earlier Monday, the WHO also said economic disruptions can be curbed if people are adequately informed to prevent irrational moves to dodge infection from Ebola. WHO director general Margaret Chan, citing World Bank figures, said 90 per cent of economic costs of any outbreak "come from irrational and disorganized efforts of the public to avoid infection." Staffers of the global health organization "are very well aware that fear of infection has spread around the world much faster than the virus," Chan said in a statement read out to a regional health conference in Manila.  "We are seeing, right now, how this virus can disrupt economies and societies around the world," she said, but added that adequately educating the public was a "good defence strategy" and would allow governments to prevent economic disruptions. The Ebola epidemic has killed more than 4,000 people, mostly in the West African countries of Liberia, Sierra Leone and Guinea, according to WHO figures published last week. Chan did not specify those steps, but praised the Philippines for holding an anti-Ebola summit last week that was joined by government health officials and private-sector representatives, warning that the Southeast Asian country was vulnerable due to the large number of Filipinos working abroad. While bracing for Ebola, health officials should continue to focus on major health threats, including non-communicable diseases, she said. Philippine Health Secretary Enrique Ona said authorities will ask more than 1,700 Filipinos working in Liberia, Sierra Leone and Guinea to observe themselves for at least 21 days for Ebola symptoms in those countries first if they plan to return home. Once home, they should observe themselves for another 21 days and then report the result of their self-screening to health authorities to be doubly sure they have not been infected, he said, adding that hospitals which would deal with any Ebola patients have already been identified in the Philippines.

Canadian Ebola vaccine safety trials move ahead, NewLink Genetics says

Vaccine vials donated by Canada all in pool for use in clinical studies, company says

By Helen Branswell,

The Canadian Press Posted: Oct 08, 2014 2:36 PM ET With talk turning to the idea that Ebola vaccines and drugs may be needed to quell the West African outbreak, the tiny U.S. company that holds the licence for a Canadian-made vaccine says it is working as fast as it can to get that option tested and ready for use. NewLink Genetics says at least five clinical trials involving the vaccine, known as VSV-EBOV, will soon be under way in the United States, Germany, Switzerland and in an unnamed African country which is not battling Ebola. As well, the Canadian government has said it wants to conduct a trial in this country. Vaccine for these studies will be provided by the Canadian government, said a spokesperson for NewLink, which is based in Ames, Iowa. Brian Wiley, the company's vice-president of business development, said both the vaccine Canada donated to the World Health Organization and the remaining vials Canada was keeping back for clinical studies will be used for human studies. Canada had roughly 1,500 vials of vaccine made for clinical trials before this Ebola crisis began. It offered 800 to 1,000 vials to the WHO and said the rest would be used for clinical trials. Each vial contains at least two doses of the vaccine and perhaps more depending on how much is needed for each injection. "I believe all of those are now being put into the pool of available use for all the various clinical studies," Wiley said in an interview with The Canadian Press. "Some of those [studies] are going to be using the doses donated [to the WHO] by Canada, some of those will be using the doses set aside for us. So there is more than enough supply there.

Canada recently said it wants to retain some supply for emergency use here. Dr. Gregory Taylor, the new head of the Public Health Agency of Canada, said last week that the idea would be to put some vaccine in hospitals designated to treat Ebola patients, if any arrive. That way if a health-care worker looking after an Ebola patient had a risky exposure, he or she could be offered the vaccine. Studies in primates have shown this vaccine works in primates both to prevent infection when given before exposure and increase survival chances when given quickly after exposure. While it was initially thought some of the donated vaccine might be used to protect health-care workers involved in the Ebola response, the current thinking is that this and other experimental vaccines need to be tested for both safety and effectiveness before they can be used in the field. The VSV-EBOV trials, two of which will be held in the United States, will test the experimental vaccine at different doses and in different population groups. The aim of these early trials is to see if the vaccine is safe for human use and how much vaccine is needed to generate what is hoped to be a protective response in people. Later studies will be done to determine if the vaccine actually works.

Warp speed for vaccine world

While some experts had hoped for a more rapid roll out if the vaccine is shown to be safe in humans, sources have suggested the U.S. government wants to know the vaccine is effective before it and others spend what could amount to hundreds of millions of dollars. The U.S. government paid for most of the research on both of the leading experimental Ebola vaccines. Its Biomedical Advanced Research and Development Authority which funds development of drugs and vaccines for pathogens that are deemed to pose a threat to the U.S. is currently helping NewLink manoeuvre the legal and bureaucratic hurdles involved in testing a new vaccine. "They have been very co-operative with us," Dr. Robin Robinson, who runs the BARDA, said in a recent interview. The authority, a division of the U.S. department of health and human services, is also helping the company find vaccine manufacturers that could scale up to make what might turn out to be hundreds of thousands of doses of the vaccine if the vaccine works. NewLink, which is developing cancer vaccines, does not have its own production facility. Wiley understands that there is frustration at the time it is taking to launch the clinical trials but he suggested the work is moving at what amounts to warp speed for the vaccine world. "There's a lot of impatience.… And it's difficult for people to understand on the outside looking in just how many things have to be done to move a drug through the process in the right way," he said. "It might seem like a long time to some but we really have done this in an extremely accelerated fashion."

His comments suggest the company may have concerns that moving too quickly could jeopardize the future of the vaccine. "Our primary goal is to do this in the most accelerated, most ethical way possible to ensure the likelihood of success," Wiley said. "If you do something wrong out of the gate and the [vaccine] is used at the wrong dose, or in the wrong patients or the wrong situation and you cause harm, the setback … can be disastrous. And so it's really important that we do the right trials, that we do it in the right patient population and that we take the proper steps to evaluate and monitor those patients." The need for speed and the apparent slowness of this process have led some observers to privately question whether a company of the size and experience of NewLink has the capacity to see this project through to a successful conclusion. The other leading Ebola vaccine candidate, created in the laboratories of the U.S. National Institutes of Allergy and Infectious Diseases, has been licensed to pharma giant GlaxoSmithKline (now known as GSK). The first clinical trial with that vaccine, called cAd3, began in early September. Wiley said NewLink's top priority is moving the Ebola vaccine forward. And he insisted the company has the help it needs to do the job. "The resources that are being offered to us, should we need them, are more than enough to … get the job done and get the job done in a timeline that will be very accelerated to say the least."

Contact: Phil Sahm
phil.sahm@hsc.utah.edu
801-581-2517
University of Utah Health Sciences

A universal Ebola drug target

New study reports design, characterization of universally conserved drug target for current, future strains of virus

(SALT LAKE CITY)—University of Utah biochemists have reported a new drug discovery tool against the Ebola virus. According to a study published in this week's online edition of Protein Science, they have produced a molecule, known as a peptide mimic, that displays a functionally critical region of the virus that is universally conserved in all known species of Ebola. This new tool can be used as a drug target in the discovery of anti-Ebola agents that are effective against all known strains and likely future strains.

The University of Utah (U of U) work, which was funded by the National Institutes of Health, was conducted by a large collaborative team led by Debra Eckert, Ph.D., (research assistant professor of biochemistry) and Michael Kay, M.D., Ph.D., (professor of biochemistry). Key contributions to this work were provided by Dr. John Dye's laboratory at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), the lab of Christopher P. Hill, D.Phil., professor and co-chair of the U of U Department of Biochemistry, and a group led by Brett Welch, Ph.D. at Navigen, Inc., a Salt Lake City pharmaceutical discovery and development company. (Navigen has licensed exclusive rights to the technology from the U of U and is currently screening for drugs against the target.)

The Utah scientists designed peptide mimics of a highly conserved region in the Ebola protein that controls entry of the virus into the human host cell, initiating infection. Importantly, the researchers were able to demonstrate this peptide target is suitable for use in high-throughput drug screens. These kinds of screens allow rapid identification of potential new drugs from billions of possible candidates.

Current experimental drugs generally target only one of Ebola's five species. "The current growing epidemic demonstrates the need for effective broad-range Ebola virus therapies," says Dr. Tracy R. Clinton, lead author on the study. "Importantly, viral sequence information from the epidemic reveals rapid changes in the viral genome, while our target sequence remains the same. Therefore, our target will enable the discovery of drugs with the potential to treat any future epidemic, even if new Ebola virus strains emerge."

Ebola is a lethal virus that causes severe hemorrhagic fever with a 50 percent to 90 percent mortality rate. There are five known species of the virus. Outbreaks have been occurring with increasing frequency in recent years, and an unprecedented and rapidly expanding Ebola outbreak is currently spreading through several countries in West Africa with devastating consequences. The development of an effective anti-Ebola agent to protect against natural outbreaks and potential bioterror exposures is an urgent global health need. There are no approved anti-Ebola agents, but a number of promising experimental drugs are being aggressively advanced to clinical trials to address the current crisis.

Dr. Eckert notes, "Although the current push of clinical trials will hopefully lead to an effective treatment for the Zaire species causing the present epidemic, the same treatments are unlikely to be effective against future outbreaks of a different or new Ebola species. Development of a broadly acting therapy is an important long-term goal that would allow cost-effective stockpiling of a universal Ebola treatment."

Of particular interest, this target was shown to be suitable for the discovery of mirror-image peptide inhibitors (D-peptides), which are promising drug candidates. Unlike natural peptides, they are not digested by enzymes in the blood. D-peptides are also much simpler and less expensive to produce compared to the current most promising approach, antibodies. The Utah group has previously developed highly potent and broadly acting D-peptide inhibitors of HIV entry, currently in preclinical studies, and is now adapting this approach to Ebola using the mimics developed in this study. In collaboration with Navigen, several promising lead D-peptide inhibitors have already been identified. U of U and Navigen are now seeking additional funding to optimize these inhibitors and advance them into clinical trials in humans.

Ebola situation assessment - 6 October 2014

The Ebola virus is transmitted among humans through close and direct physical contact with infected bodily fluids, the most infectious being blood, faeces and vomit. The Ebola virus has also been detected in breast milk, urine and semen. In a convalescent male, the virus can persist in semen for at least 70 days; one study suggests persistence for more than 90 days. Saliva and tears may also carry some risk. However, the studies implicating these additional bodily fluids were extremely limited in sample size and the science is inconclusive. In studies of saliva, the virus was found most frequently in patients at a severe stage of illness. The whole live virus has never been isolated from sweat. The Ebola virus can also be transmitted indirectly, by contact with previously contaminated surfaces and objects. The risk of transmission from these surfaces is low and can be reduced even further by appropriate cleaning and disinfection procedures.

Not an airborne virus

Ebola virus disease is not an airborne infection. Airborne spread among humans implies inhalation of an infectious dose of virus from a suspended cloud of small dried droplets.This mode of transmission has not been observed during extensive studies of the Ebola virus over several decades. Common sense and observation tell us that spread of the virus via coughing or sneezing is rare, if it happens at all. Epidemiological data emerging from the outbreak are not consistent with the pattern of spread seen with airborne viruses, like those that cause measles and chickenpox, or the airborne bacterium that causes tuberculosis. Theoretically, wet and bigger droplets from a heavily infected individual, who has respiratory symptoms caused by other conditions or who vomits violently, could transmit the virus – over a short distance – to another nearby person. This could happen when virus-laden heavy droplets are directly propelled, by coughing or sneezing (which does not mean airborne transmission) onto the mucus membranes or skin with cuts or abrasions of another person. WHO is not aware of any studies that actually document this mode of transmission. On the contrary, good quality studies from previous Ebola outbreaks show that all cases were infected by direct close contact with symptomatic patients.

No evidence that viral diseases change their mode of transmission

Moreover, scientists are unaware of any virus that has dramatically changed its mode of transmission. For example, the H5N1 avian influenza virus, which has caused sporadic human cases since 1997, is now endemic in chickens and ducks in large parts of Asia. That virus has probably circulated through many billions of birds for at least two decades. Its mode of transmission remains basically unchanged. Speculation that Ebola virus disease might mutate into a form that could easily spread among humans through the air is just that: speculation, unsubstantiated by any evidence. This kind of speculation is unfounded but understandable as health officials race to catch up with this fast-moving and rapidly evolving outbreak. To stop this outbreak, more needs to be done to implement – on a much larger scale – well-known protective and preventive measures. Abundant evidence has documented their effectiveness.

A Liberian doctor is using HIV drugs to treat Ebola victims. The NIH is intrigued.

By Elahe Izadi October 2 Article link.

Well before the Ebola virus was brought to the U.S. by a man traveling from Liberia, it was wreaking havoc in the West African country, where nearly 2,000 people have died during the worst Ebola outbreak in history. Now, some doctors in that country are trying new ways of treating Ebola-infected patients. Gorbee Logan, a doctor in rural Liberia, has given at least 15 Ebola patients lamivudine, which is considered a long-term and effective drug to treat HIV patients. All but two of them survived, Logan told CNN last week. Since that interview, Logan has been in contact with Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, about the treatment. "I can't say it's a good idea or bad idea," Fauci told The Post this week. "It's one of those things where you're in a situation where you have no therapy, so you look for things that might be available." Fauci said National Institutes of Health researchers have tested lamivudine's reaction to Ebola in test tubes. There was no response; but Fauci said researchers will adjust some levels and try it again "to see if there's even slight activity against Ebola." If there is, he said, NIH would consider going to the trial stage.

Logan first tried another HIV drug on an Ebola patient, but it didn't seem to work, he told CNN. Then, he gave lamivudine to a health-care worker who'd become sick. The patient improved within a couple of days, CNN reported. It makes sense to consider lamivudine as a potential Ebola treatment: It belongs to a group of drugs known as nucleoside analogs, which interfere with the replication processes of certain viruses, Fauci explained. Other nucleoside analog drugs are in the pre-clinical stage of testing with animals, Fauci said. But there is a potential upshot with lamivudine that could make it stand out from the others, if it does actually work. "It's already an approved drug that can be distributed," Fauci said. "But that's a big, majestic leap." Logan told FrontPageAfrica that his method works only if Ebola patients come in soon after becoming symptomatic. He said desperation pushed him to treat Ebola patients using several different medications. Lamivudine can cause liver damage, he acknowledged. For the drug to be considered an effective Ebola treatment, studies involving many more patients and controls would need to be conducted to make sure it's safe to treat Ebola patients with lamivudine -- and that people are getting better from the drug and not from other factors. But Fauci said crises such as the Ebola epidemic lead doctors to try what they can to help patients. "Whenever you have a disease where people are frustrated with no treatment, there's always the thought of what do we already have approved that we can use," Fauci said. Logan's frustration is clear. "Our people are dying and you're taking about studies?" he said to CNN. "It's a matter of doing all that I can do as a doctor to save some people's lives." Elahe Izadi is a general assignment national reporter for The Washington Post.

WHO consultation on Ebola vaccines

http://www.who.int/mediacentre/news/ebola/01-october-2014/en/

From 29–30 September, WHO organized an expert consultation to assess the status of work to test and eventually license two candidate Ebola vaccines. More than 70 experts, including many from affected and neighbouring countries in West Africa, attended the event. The expertise represented among participants ranged from the virology of emerging infections, to regulatory requirements that must be met, to medical ethics, public health, and infectious diseases. Heads of clinical research and other executives from the pharmaceutical industry also presented their views. Some participants came with more than 3 decades of experience working in Africa on other infectious diseases. Experts on the use of innovative, cutting-edge trial designs also shared their most recent work. The overarching objective was to take stock of the many efforts currently under way to rapidly evaluate Ebola vaccines for safety and efficacy. The next step is to make these vaccines available as soon as possible – and in sufficient quantities – to protect critical frontline workers and to make a difference in the epidemic’s future evolution. All agreed on the ultimate goal: to have a fully tested and licensed product that can be scaled up for use in mass vaccination campaigns.

Two promising candidate vaccines

Given the public health need for safe and effective Ebola interventions, WHO regards the expedited evaluation of all Ebola vaccines with clinical grade material as a high priority. Two candidate vaccines have clinical-grade vials available for phase 1 pre-licensure clinical trials. One (cAd3-ZEBOV) has been developed by GlaxoSmithKline in collaboration with the US National Institute of Allergy and Infectious Diseases. It uses a chimpanzee-derived adenovirus vector with an Ebola virus gene inserted. The second (rVSV-ZEBOV) was developed by the Public Health Agency of Canada in Winnipeg. The license for commercialization of the Canadian vaccine is held by an American company, the NewLink Genetics company, located in Ames, Iowa. The vaccine uses an attenuated or weakened vesicular stomatitis virus, a pathogen found in livestock; one of its genes has been replaced by an Ebola virus gene.

Phase 1 clinical trials

WHO and other partners have helped facilitate expedited evaluation of these two vaccines in order to generate phase 1 safety and immunogenicity data for decision-making. A series of coordinated phase 1 trials is currently under way or will soon be initiated with international consortia at more than 10 sites in Africa, Europe and North America. These studies aim to ensure good communication and harmonization of key design elements to allow for merging of data from different trials of the same candidate products. The trials, which are being conducted in healthy human volunteers, are designed to test safety and immunogenicity and select the appropriate dose. Two phase 1 trials of the cAd3-ZEBOV started in September 2014 in USA and UK, and the first Phase 1 trial of VSV-ZEBOV is due to start early in October in USA. The government of Canada has donated 800 vials of rVSV-ZEBOV to WHO. Once data on dosing from phase 1 trials become available, this donation could translate into about 1500 to 2000 doses of vaccine. Both companies are working to augment their manufacturing capacity. The goal is a very significant increase in scale during the first half of 2015. No delays One shared mindset was readily apparent during the two-day discussions. Nothing must be allowed to slow down the goal of making vaccines accessible to people in affected West African countries. The phrase, “Nothing can be allowed to delay this work”, was heard over and over again. The ambition: to accomplish, within a matter of months, work that normally takes from two to four years, without compromising international standards for safety and efficacy. In other words: to give the African people and their health authorities the best product that the world’s scientists, working collectively, have to offer.

What the experts considered

Against this background, the meeting looked specifically at the objectives and key design elements for moving in an expedited manner to conduct additional clinical trials (phase 2 trial designs) that will generate additional safety data and evidence that the vaccine confers protection. Parallel pathways for emergency use of experimental candidate vaccines with data collection, among frontline health care workers and other critical personnel, were also explored. Apart from the great sense of urgency, the overall spirit of the discussions was characterized by a strong sense of solidarity with the people of West Africa, their governments, and their medical, scientific, and public health communities. Equally strong was the insistence on ensuring that evidence on safety, immunogenicity, and efficacy of the vaccines is collected properly.

Multiple challenges

Multiple potential challenges and uncertainties were put forward and assessed. Issues ranging from barriers to rapid implementation of R&D, to the design of trials and their use to guide eventual widespread vaccination, were discussed together with proposed ways to overcome them. Some of the practical issues discussed included how to address communities’ perceptions regarding vaccines in general, and vaccine studies more specifically, public expectations for vaccine availability for widespread use, and whether there is an adequate infrastructure in place to rapidly and safely evaluate and distribute vaccines. One important technical challenge is the fact that the candidate vaccines must be stored at a temperature of -80°C. Further issues that need to be urgently addressed include identifying staff who can conduct trials meeting international standards, logistical issues (such as cold chain needs for the vaccines), and the resources needed to start the studies quickly. Some of the scientific challenges include how to conduct studies as safely and rapidly as possible to inform decisions about mass production of vaccines and their administration.

Key questions

Discussions focused on the main questions that studies should help address, which part of the research should be conducted in non-affected areas and which part in affected areas, and how such decisions could either help expedite or delay the availability of robust evidence. One overarching conclusion was that the international community, joining the affected countries as a whole, has a responsibility and a role to play in accelerating the evaluation, licensing, and availability of the candidate vaccines – if proven safe and effective. For all these reasons, the actions emerging from the consultation clearly identify a role for each of the main stakeholders.

Randomized controlled trials

Regarding the issue of how to accelerate the assessment and licensure of the vaccines, experts reiterated that, if feasible, randomized controlled trials are the design of choice because they provide the most robust data, in the shortest amount of time, to judge whether a vaccine is safe and induces protection. Trials must be expedited, while preserving ethical and safety standards. Efficacy data of high quality must be gathered. Trials need to be carefully designed so that they concomitantly address the most important questions regarding safety, immunogenicity, and efficacy. While individually randomized controlled trials provide the most robust data, alternative designs should be considered when these trials are not judged feasible. These include cluster-randomized and stepped-wedge designs. As long as the amount of vaccine remains limited, units – such as health or treatment facilities – can be randomized. Regardless of the design chosen, trials should move forward as quickly as possible.

Alternative study designs

Alternative study designs will not delay deployment of vaccine to those who need it. Instead, they will influence the choice of people who receive the vaccine. For some months to come, the critical limiting factor is extremely restricted vaccine supply, and not the need to conduct studies using alternative designs. Descriptions of the so-called “randomized stepped wedge” design attracted lively interest and much discussion. In this design, a “wedge” (like a slice of a pie or a cake) of the study population is selected for step-wise inclusion in the trials. As each “wedge” receives the vaccine, all lessons learned or needed to adjust the study design are then applied to the next group to be included in the study. The selection of study populations can be randomized by units, as described above; the entire study population eventually receives the vaccine if trials demonstrate sufficient efficacy. Such a design makes it possible to roll out vaccinations and evaluate efficacy at the same time. It further has features that meet the explicit objective of fairness. Other designs will be more relevant when large numbers of vaccine doses are available.

Involving countries

Decisions on study designs and target populations must be made with the active participation of experts from the three hardest-hit countries. Consultations with frontline health workers should be undertaken as a matter of urgency to identify the most feasible approaches to evaluate vaccine efficacy and identify factors influencing acceptability of randomized trials. The experts discussed the importance of making sure that the trials are appropriately designed to inform the use of these vaccines in all populations, including children, pregnant women, and immunocompromised populations, including people who are HIV positive. The group also discussed how best to use the doses of experimental vaccine donated by Canada and additional doses that may be available later this year and in 2015. If vaccine doses are used in the short term, vaccines should be deployed to consenting frontline health workers. The decision to initiate such deployment should be informed by data emerging from the phase 1 studies, and will occur with data collection on the deployment itself. Equity is important and therefore vaccine should be made available in an equitable and consensual manner to the affected countries. Maximizing the information gained from the use of these vaccines during this phase is critical.

Information sharing

A cross-cutting issue is the need for data sharing – in real time – among the research, medical, and public health communities, coordinated by WHO. This was considered of paramount importance to inform decisions on future studies and scaling up the production of those experimental vaccines that look most promising. Vaccine development normally takes a long time and is notoriously costly. Even under the best conditions and with the massive efforts of many partners, a significant number of doses will not be available until late in the first quarter of 2015. One important factor for the completion of all the above steps is to secure the funding to ensure the production of the vaccine and to support priority studies. Major international funding partners should promptly pledge or commit the necessary funding so that this critical research is completed without further delay.

The African perspective

The presence of West African researchers, scientists, clinicians, and health officials vastly enriched the discussions, especially concerning the practical dimensions of trial design. These experts further underscored the importance of communicating with communities and engaging their views, and called for qualitative studies to begin immediately. For example, some cultures are deeply distrustful of “Western” medicine and foreign medical staff in general, and of vaccines in particular. Interventions from the three hardest-hit countries, Guinea, Liberia, and Sierra Leone, clearly stated that international assistance is both greatly needed and fully welcomed. Families and entire villages have been shattered. Some communities are on the verge of hopelessness and helplessness. Many do not comprehend what hit them and why, especially as this is the first time that the Ebola virus and Ebola virus disease have been seen in West Africa. Governments are on board. Clinicians are on board. Researchers and their institutes are on board. Statements made by West Africans reminded all participants of what life is really like in these countries. Children do not play in school yards, play pens, fenced back yards, or terraced gardens. They play in the bush. These realities of daily African life need to be kept in mind when high-risk exposures are considered and defined.

Health workers

Participants were further reminded that the definition of “health care workers” in these African countries includes doctors, nurses, and laboratory technicians but also hospital cleaners, ambulance drivers, burial teams, mortuary attendants, and in some instances, traditional healers. As hospitals in many areas are overflowing or closed, the number of treatment beds in all three countries is woefully inadequate, and people frequently do not trust the health care system, more and more patients are being cared for by their loved ones in homes or within the community. These people are also at very high risk of infection and should be considered when priorities for support – in all its forms – are being set. The importance of community engagement cannot be overstated. Operational changes made since the unprecedented resolutions on Ebola virus disease were adopted by an emergency session of the UN Security Council (on 18 September) and by a UN General Assembly high-level session on Ebola (on 25 September) involve a vast ground-swell scaling-up of international support to affected countries. This support includes a much larger number of medical staff working in countries, thanks to generous support from the governments of China, Cuba, and many others.

Lessons learned

Participants also drew heavily on lessons learned, in the African setting, during trials for candidate malaria, HIV/AIDS, cholera, epidemic meningitis, hepatitis B, and other vaccines. As some experts noted, never again can the international community allow what boils down to “market failure” to create such catastrophic suffering for humanity in any country, in any region of the world. The sense of urgency and need for speed, without compromising the integrity of studies or the quality of their data, are fully justified by the dire situation in affected countries and the risk that other countries may soon experience their first imported cases. The Ebola outbreak currently ravaging parts of West Africa is the most severe acute public health emergency in modern times. Never before in recent history has a biosafety level 4 pathogen infected so many people so quickly, over such a wide geographical area, for so long.

Key expected milestones

October 2014:  Mechanisms for evaluating and sharing data in real time must be prepared and agreed upon and the remainder of the phase 1 trials must be started

October–November 2014: Agreed common protocols (including for phase 2 studies) across different sites must be developed

October–November 2014: Preparation of sites in affected countries for phase 2 b should start as soon as possible

November–December 2014: Initial safety data from phase 1 trials will be available

January 2015: GMP (Good Manufacturing Practices) grade vaccine doses will be available for phase 2 as soon as possible

January–February 2015: Phase 2 studies to be approved and initiated in affected and non-affected countries (as appropriate)

As soon as possible after data on efficacy become available: Planning for large-scale vaccination, including systems for vaccine financing, allocation, and use.

How a cold call led to a Canadian experimental Ebola treatment

Thomas Geisbert, one of the world’s leading Ebola researchers, is often on the receiving end of pitches from what he calls “snake-oil salesmen” peddling cures for a disease that has long terrified the public, even before this year’s devastating epidemic in West Africa. So the American virologist was skeptical when he got an unsolicited call in late 2004 from Ian MacLachlan, a Canadian biochemist and co-founder of a small British Columbia drug company. Dr. MacLachlan had heard Dr. Geisbert was experimenting with molecules called small interfering RNAs (siRNAs) to silence messengers in the Ebola virus’s genetic code that tell it to replicate, but Dr. Geisbert was not having much luck saving guinea pigs with his approach. The problem, Dr. MacLachlan told him, was his delivery system. “I listened to his pitch,” Dr. Geisbert recalled, “and I said, ‘Look, what have I got to lose?’” He mailed some of his siRNA molecules to Dr. MacLachlan, who packaged them in his company’s lipid nanoparticle delivery system, a minuscule droplet of fat or oil that protects the siRNA molecules as they travel through the bloodstream. “All of a sudden,” Dr. Geisbert said, “100 per cent of the guinea pigs were protected.”

That out-of-the-blue phone call was the genesis of TKM-Ebola, the experimental treatment produced by Burnaby’s Tekmira Pharmaceuticals Corp. that emerged this week from the shadow of another Canadian-developed Ebola therapy, ZMapp. With supplies of ZMapp exhausted, TKM-Ebola has been given to “several” ill patients, the company revealed this week, including an American missionary doctor who was released from an Omaha hospital on Thursday. Now Tekmira – a company that makes a range of therapies using siRNA technology, has 98 employees and a market value of $541-million – is one of at least three drug makers in talks with the international consortium that is trying to speed up delivery of experimental Ebola treatments to the front lines of the outbreak, which has killed nearly 3,000 people and is poised to infect thousands more if the latest bleak forecasts come to pass. TKM-Ebola is part of Canada’s larger contribution to the medical battle against the Ebola virus, a fight in which this country is punching well above its weight. ZMapp was developed largely at Canada’s National Microbiology Laboratory in Winnipeg, the same facility that played an instrumental role in creating a promising vaccine candidate that Ottawa has offered to the World Health Organization for use in West Africa.

Until recently, those two potential experimental tools, along with an American vaccine being developed by GlaxoSmithKline, have generally received more attention than TKM-Ebola, although Tekmira was the only company that had human safety trials of its product under way when the outbreak in Guinea was first reported to the World Health Organization in March. “Tekmira’s [drug] is one drug that has shown some promise, but like all of them, it still has a long way to go,” said Daniel Bausch, a professor at the Tulane University School of Public Health and Tropical Medicine, who is advising the WHO on experimental approaches in this outbreak. “None of them have what we really want, which is full safety testing and full evidence of efficacy.” After Dr. MacLachlan’s call to Dr. Geisbert, now a professor at the University of Texas Medical Branch at Galveston, TKM-Ebola was tested on rhesus macaques at the U.S. Army Medical Research Institute of Infectious Diseases biosafety level 4 containment lab in Maryland. All four macaques challenged with lethal doses of the Ebola virus, then treated for seven days with TKM-Ebola, survived. (In another arm of the study, one of three macaques given four doses, instead of seven, died.) The results, published in The Lancet in 2010, were encouraging enough to persuade the U.S. Department of Defence’s biomedical research arm to sign a $140-million contract with Tekmira.

A phase I clinical trial, designed to test the safety of the treatment in 28 healthy volunteers, began in January, and the U.S. Food and Drug Administration granted the drug fast-track approval in March. But Tekmira announced in July that the trial had hit a road block: The FDA asked the company to halt the trial until it could provide more data to ensure the safety of the healthy volunteers, some of whom were being dosed with as much TKM-Ebola as would be given to a lethally infected patient. The hold was partly lifted in August, allowing Tekmira to offer the drug on an emergency basis to Ebola patients, but the trial itself is still on hiatus. That background was initially all that doctors at the Nebraska Medical Center in Omaha had to rely on when they learned that Rick Sacra, a 51-year-old Massachusetts physician who had contracted Ebola while working for the missionary group SIM USA in Liberia, would be arriving at their biocontainment unit on Sept. 5.  Chris Kratochvil, the associate vice-chancellor for clinical research at the University of Nebraska Medical Center, immediately got on the phone with the FDA, the U.S. Centers for Disease Control and Prevention and Emory University Hospital in Atlanta, the facility that had successfully treated the first two American Ebola patients, both of whom recovered after receiving ZMapp and high-quality supportive care. “What we did very early on was sign a confidentiality agreement with Tekmira which allowed us to access their data that they had available in the development of the drug and the animal studies of the medication,” Dr. Kratochvil said. “That gave us an opportunity to really take a look at what was known about the medication.”

After combing through that data, doctors decided to give TKM-Ebola to Dr. Sacra, who had begun to experience chills and minor fever seven days before landing in Omaha. “When he arrived he was critically ill,” said Philip Smith, medical director of the biocontainment unit at the University of Nebraska Medical Center. “He had low blood pressure, his body chemistries were out of whack and he was only semi-conscious.” Twenty days later, Dr. Sacra left the isolation unit after two blood tests 24 hours apart confirmed he was free of the Ebola virus. He marked his release with a written statement full of thank-yous and exuberant punctuation. “On behalf of my family, and SIM, thank you so much!!! You have made me feel so welcome that I am now an official lifetime [Nebraska Cornhuskers] Fan!!!! Go Big Red!” Teasing out what role TKM-Ebola played in Dr. Sacra’s recovery is virtually impossible. Along with his seven days of intravenous TKM-Ebola treatment, Dr. Sacra received plasma transfusions on days two and three of his treatment from Kent Brantly, an Ebola survivor whose type A blood matched Dr. Sacra’s. Dr. Sacra also received traditional supportive care that is simply not available to patients in Guinea, Liberia and Sierra Leone, where rickety health systems have collapsed under the epidemic’s pressure. Tekmira would not confirm which other patients have received TKM-Ebola so far, citing patient confidentiality. A French nurse infected in Liberia has been approved to receive three experimental drugs, including TKM-Ebola, but the details of her treatment have not been made public. Right now, supplies of the treatment are “limited,” according to Tekmira; a WHO report from early September put the number of available treatment courses at fewer than 30. However, the same report said as many as 900 doses of the drug, which is manufactured synthetically, could be ready by the first quarter of next year. The idea that TKM-Ebola could help more people is exhilarating for Dr. Geisbert, who wondered if a drug he had spent years developing would ever make it into the field. “I wish you could save everybody,” he said. “But I think the fact that you can save anyone is awesome.”

Experimental Therapies: whole blood or plasma from recovered Ebola patients

http://www.who.int/mediacentre/news/ebola/26-september-2014/en/

Background

Ebola virus disease currently has no vaccines or medicines approved by national regulatory authorities for use in humans save for the purpose of compassionate care. To date, the virus has infected 6242 people and killed 2909 of them. These figures, which are far greater than those from all previous Ebola outbreaks combined, are known by WHO to vastly underestimate the true scale of the epidemic. The Ebola epidemic ravaging parts of West Africa is the most severe acute public health emergency seen in modern times. Never before in recorded history has a biosafety level four pathogen infected so many people so quickly, over such a broad geographical area, for so long. On 11 August, a group of experts convened by WHO reached consensus that the use of experimental medicines and vaccines under the exceptional circumstances of the Ebola epidemic is ethically acceptable. Following that advice, WHO convened (from 4–5 September) a consultation on potential Ebola therapies and vaccines. The meeting was attended by more than 200 experts from around the world, including West Africa, though bans and restrictions on international flights to and from that region diminished the numbers significantly. The meeting aimed to identify the most promising candidate vaccines and experimental therapies and map out the next most urgent steps to take. The experts agreed to prioritize convalescent blood and plasma therapies for further investigation. That decision further stimulated already intense interest, with the result that new knowledge is expected to grow fairly quickly. This assessment looks at what is known about the efficacy of convalescent therapies and the potential role they might play in improving clinical care and reducing the unacceptably high number of deaths.

The current evidence base: limited data – from 1976 up to now

Convalescent therapy was first used for a young woman infected with Ebola in the Democratic Republic of Congo (then Zaire) in 1976 – the year the virus first emerged. The woman was treated with plasma from a person who survived infection with the closely-related Marburg virus. She had less clinical bleeding than other Ebola patients, but died within days. During the 1995 Ebola outbreak in Kikwit, Democratic Republic of Congo, whole blood collected from recovered patients was administered to eight patients. Seven of the eight recovered. However, as the study did not include a control group, no firm conclusions could be reached concerning whether the treatment alone was responsible for the favourable clinical outcome or even contributed to this outcome in some way. In the current outbreak, convalescent therapies have been used in a few patients. The numbers are too small to support any conclusions about efficacy. In one well-known case, an American doctor, who became infected while working in Monrovia, Liberia, received whole blood from a recovered patient while still in Monrovia. He likewise fully recovered, though it is not possible to determine whether that recovery can be attributed to convalescent therapy, the administration of the experimental medicine, ZMapp, or the excellent supportive care he received in the United States. In another well-documented case, a foreign medical doctor, who was infected in Sierra Leone, has been improving following outstanding supportive care. He did not receive treatment with any experimental therapy. In yet another case, an American doctor, who became infected while working in Liberia, was subsequently treated in the US. As part of that treatment, he received a transfusion of convalescent plasma from blood donated by the first case mentioned above. The infusion was well-tolerated. Yesterday, he was declared by his attending physicians and the US Centers for Disease Control and Prevention (CDC) to be “virus-free”. He is weak but fully recovered. Again, as he also received the experimental medicine TKM-EBV, together with outstanding supportive care, it is impossible to know which component of care contributed most – or at all – to his recovery. The hospital where he was treated will share clinical lessons learned with doctors working in West Africa.

As the epidemic worsens, interest in convalescent therapies grows WHO has been encouraged by the growth of interest in convalescent therapies as an already bad epidemic gets worse. In the three hardest-hit countries, Guinea, Liberia, and Sierra Leone, health systems have begun to buckle under the pressure of closed or overflowing hospitals, the difficulties of staffing newly opened treatment centres, and the exceptionally large number of Ebola deaths among health care workers. The number of cases continues to grow exponentially. The number of treatment beds is grossly and visibly inadequate. Good supportive clinical care is becoming increasingly difficult to implement. The need to expand the current very limited arsenal of clinical tools is self-evident. WHO has been approached by several donors, foundations, public health agencies, and development partners seeking guidance and advice. Major questions need to be answered about the safety and efficacy of convalescent therapies, and the feasibility of implementation in countries with shattered health systems and an acute shortage of medical staff. WHO is also being asked to assess whether rapid scaling up of convalescent therapy is feasible to an extent that could begin to reduce the estimated 70.8% case fatality rate seen consistently across the three outbreak sites. Some partners and donors are asking for rough estimates of what needs to be in place to support rapid implementation on the largest possible scale. They have questions about the number of staff needed and their training requirements, safety risks and how to manage them, laboratory capacities and how to enhance them, specific needs for equipment and supplies, and what all of this might cost. As initial supplies of these therapies will inevitably be limited, questions about which groups should have priority access also need to be addressed.WHO is currently holding discussions with health experts in the Democratic Republic of Congo, Guinea, Liberia, Nigeria, and Sierra Leone. These discussions aim to identify practical needs for implementation and potential bottlenecks that could stand in the way. One great appeal of this drive to assess and introduce convalescent therapies is the opportunity to strengthen basic public health infrastructures by helping these countries develop good quality blood services. The list of common and severe health problems that could benefit from safe and well-functioning blood services is long – ranging from malaria, dengue, Lassa fever, and yellow fever to complications of childbirth and injuries following accidents and traffic crashes. The current situation is so dire that, in several areas that include capital cities, many of these common diseases and health conditions are barely being managed at all. Technical guidance for experts Early next week, WHO is issuing new interim guidance on Use of convalescent whole blood or plasma collected from patients recovered from Ebola virus disease for transfusion during outbreaks. The document is addressed to national health authorities and blood transfusion services. A link to the new document will be added here once it is released. WHO media contacts: Fadéla Chaib Telephone: + 41 22 791 3228 Mobile:+ 41 79 475 5556 E-mail: chaibf@who.int

Tekmira Joins International Consortium to Conduct Clinical Trials of Ebola Virus Therapeutics in West Africa

September 23, 2014 Consortium Receives £3.2 Million Funding From Wellcome Trust VANCOUVER, British Columbia, Sept. 23, 2014 (GLOBE NEWSWIRE) --

Tekmira Pharmaceuticals Corporation (Nasdaq:TKMR) (TSX:TKM), a leading developer of RNA interference (RNAi) therapeutics, today reported that it is collaborating with an international consortium to provide an RNAi based investigational therapeutic for expedited clinical studies in West Africa. Led by Dr. Peter Horby of the Centre for Tropical Medicine and Global Health at the University of Oxford and the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), the consortium includes representatives from the World Health Organization (WHO), US Centers for Disease Control, Médecins Sans Frontières - Doctors without Borders (MSF), ISARIC, and Fondation Mérieux, among others.

The Wellcome Trust has announced it has awarded £3.2 million to the consortium to fund this initiative. The award will include funds for the manufacture of investigational therapeutics as well as the establishment of an operational clinical trials platform in two or more Ebola Virus Disease (EVD) treatment centers in West Africa. RNAi has been prioritized as an investigational therapeutic and may be selected for clinical trials at these centers. The objective of the clinical trials is to assess the efficacy and safety of promising therapeutics and vaccines, reliably and safely, in patients with EVD by adopting strict protocols that comply with international standards. It is hoped this initiative will permit the adoption of safe and effective interventions rapidly. The genetic sequence of the Ebola virus variant responsible for the ongoing outbreak in West Africa is now available. Under this program, Tekmira will produce an RNAi based product specifically targeting the viral variant responsible for this outbreak. The ability to rapidly and accurately match the evolving genetic sequences of emerging infectious agents is one of the powerful features of RNAi therapeutics. "We commend the Wellcome Trust for their leadership in providing the necessary funds to launch and expedite this ground breaking initiative. We are gratified that RNAi has been prioritized as a potential investigational therapeutic to assist in the ongoing public health and humanitarian crisis in Africa," said Dr. Murray, Tekmira's President and CEO. "We are an active collaborator in this consortium and through our ongoing dialogue with the WHO, NGOs and governments in various countries; we have been discussing the creation of appropriate clinical and regulatory frameworks for the potential use of investigational therapeutics in Africa. This initiative goes a long way towards achieving this aim. Many complex decisions remain to fully implement this unique clinical trial platform. At this time, there can be no assurances that our product will be selected by the consortium for clinical trials in Africa," said Dr. Murray.

About Wellcome Trust The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending over £600 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. For more information, visit www.wellcome.ac.uk

About RNAi and Tekmira's LNP RNAi therapeutics have the potential to treat a broad number of human diseases by "silencing" disease causing genes. The discoverers of RNAi, a gene silencing mechanism used by all cells, were awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi therapeutics, such as "siRNAs," require delivery technology to be effective systemically. Tekmira believes its LNP technology represents the most widely adopted delivery technology for the systemic delivery of RNAi therapeutics. Tekmira's LNP platform is being utilized in multiple clinical trials by both Tekmira and its partners. Tekmira's LNP technology (formerly referred to as stable nucleic acid-lipid particles or SNALP) encapsulates siRNAs with high efficiency in uniform lipid nanoparticles that are effective in delivering RNAi therapeutics to disease sites in numerous preclinical models. Tekmira's LNP formulations are manufactured by a proprietary method which is robust, scalable and highly reproducible, and LNP-based products have been reviewed by multiple FDA divisions for use in clinical trials. LNP formulations comprise several lipid components that can be adjusted to suit the specific application.

About Tekmira Tekmira Pharmaceuticals Corporation is a biopharmaceutical company focused on advancing novel RNAi therapeutics and providing its leading lipid nanoparticle (LNP) delivery technology to pharmaceutical partners. Tekmira has been working in the field of nucleic acid delivery for over a decade and has broad intellectual property covering LNPs. Further information about Tekmira can be found at www.tekmira.com. Tekmira is based in Vancouver, B.C. Canada.

Forward-Looking Statements and Information This news release contains "forward-looking statements" or "forward-looking information" within the meaning of applicable securities laws (collectively, "forward-looking statements"). Forward-looking statements in this news release include statements about Tekmira's strategy, future operations, clinical trials, prospects and the plans of management; Tekmira's collaboration with an international consortium to provide an RNAi based investigational therapeutic for expedited clinical trials of Ebola virus therapeutics in West Africa; the funding of the consortium from the Wellcome Trust, including funds for the manufacture of investigational therapeutics as well as the establishment of an operational clinical trials platform in two or more EVD treatment centers in West Africa; the prioritization of RNAi as an investigational therapeutic and the potential selection of RNAi for clinical trials in the aforementioned centers; the objective of the clinical trials; the adoption of safe and effective interventions; Tekmira's production of an RNAi based product targeting the viral variant responsible for the current outbreak in West Africa; and the creation of appropriate clinical and regulatory frameworks for the potential use of investigational therapeutics in Africa. With respect to the forward-looking statements contained in this news release, Tekmira has made numerous assumptions regarding, among other things, the effectiveness of RNAi therapeutics in the treatment of Ebola virus and the adequacy of funding from the Wellcome Trust for the anticipated program of the international consortium. While Tekmira considers these assumptions to be reasonable, these assumptions are inherently subject to significant business, economic, competitive, market and social uncertainties and contingencies. Additionally, there are known and unknown risk factors which could cause Tekmira's actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements contained herein. Known risk factors include, among others: RNAi based therapeutics may not prove to be effective in the treatment of Ebola virus as currently anticipated, compared to other therapeutics, or at all; funding provided by the Wellcome Trust may not be adequate for the anticipated program of the international consortium; manufacture of investigational therapeutics or the establishment of operational clinical trial platforms may not occur as currently anticipated, or at all; there can be no assurances that Tekmira's product will be selected by the consortium or be given to patients for treatment; Tekmira may not produce an RNAi based product targeting the viral variant responsible for the current outbreak in West Africa as currently anticipated, or at all; appropriate clinical and regulatory frameworks for the potential use of investigational therapeutics in Africa may never be established, or may not be beneficial to Tekmira's products; the FDA may refuse to approve Tekmira's products, or place restrictions on Tekmira's ability to commercialize its products; anticipated pre-clinical and clinical trials may be more costly or take longer to complete than anticipated, and may never be initiated or completed, or may not generate results that warrant future development of the tested drug candidate; and Tekmira may not receive the necessary regulatory approvals for the clinical development of Tekmira's products. A more complete discussion of the risks and uncertainties facing Tekmira appears in Tekmira's Annual Report on Form 10-K and Tekmira's continuous disclosure filings, which are available at www.sedar.com or www.sec.gov. All forward-looking statements herein are qualified in their entirety by this cautionary statement, and Tekmira disclaims any obligation to revise or update any such forward-looking statements or to publicly announce the result of any revisions to any of the forward-looking statements contained herein to reflect future results, events or developments, except as required by law.

CONTACT: Investors Julie P. Rezler Director, Investor Relations Phone: 604-419-3200 Email: jrezler@tekmira.com Media Please direct all media inquiries to media@tekmira.com

How a Winnipeg lab became an Ebola research powerhouse

National Microbiology Laboratory in Winnipeg behind innovative, experimental ZMapp Ebola drug

By Helen Branswell, The Canadian Press Posted: Sep 21, 2014 12:34 PM CT Last Updated: Sep 22, 2014 4:51 AM CT

Researchers with the National Microbiology Laboratory in Winnipeg say they are optimistic that a tool to combat the Ebola virus may be on the horizon. Winnipeg is half a world away from the countries in Africa where Ebola, and its viral cousin, Marburg, occasionally slip out of their animal reservoir to start infecting and killing people, as Ebola is now doing in West Africa. The current outbreak has infected at least 5,335 people and killed at least 2,622. To date, there has never been a case of either viral hemorrhagic fever infections within Canadian borders. So why then is Canada's national lab an Ebola research powerhouse? Why is a facility on the edge of the Prairies, near North America's longitudinal centre, the site from whence some of the most promising Ebola research emanates? What research? Well, there's ZMapp, the most promising of the current experimental treatments. There's also an Ebola vaccine that may be useful both to prevent infection and stop it in its tracks, if given shortly after exposure. And a mobile diagnostic lab that has changed the way outbreak testing is done. These are enormous contributions to the scientific efforts to prevent or contain Ebola. And the fact that they come from Winnipeg seems to come down to a few good men.

2 key players

If you ask why Winnipeg is such a player in Ebola research, the instant answer comes in the form of two names — Heinz Feldmann, the lab's first special pathogens chief and Gary Kobinger, his successor and the current branch chief. "Both of these guys are absolutely world class. I can't say enough good things about them. They are both superb scientists and in addition to being superb scientists they are great individuals," said Jim LeDuc, director of the Galveston National Laboratory at the University of Texas Medical Branch, which also employs key Ebola researchers. "They have the right attitude. They're collaborative, they're co-operative, they share their information readily and they have a global perspective. And they know exactly what needs to be done. And they're incredibly well respected within the scientific community." But the story doesn't begin with Feldmann and Kobinger. When the federal government decided to build in Winnipeg a new, state-of-the-art laboratory to replace aging Health Canada facilities in Ottawa, it was not immediately clear the complex would contain a Level 4 lab, the high containment space needed to work on the world's most dangerous pathogens. The Ottawa facility had not had one, meaning that any time Canada had to test a specimen that might contain a Level 4 bug, it was forced to ship the sample to the labs of the U.S. Centers for Disease Control in Atlanta, Ga. Dr. Joseph Losos, then director general of Health Canada's Laboratory Centre for Disease Control, gave the go-ahead. The search began for someone to head the special pathogens team.

'It's bitterly cold out there'

Lab leaders keenly wanted Heinz Feldmann, a young German researcher who had recently spent time at the CDC. "We knew we wanted Heinz. We thought he was a good fit for the lab, which he absolutely was," Artsob, who is now retired, recalls. The lab flew Feldmann to Winnipeg to meet NML leaders. He liked what he saw, even though the first trip occurred in December. "When I came home I told my wife... 'It's bitterly cold out there.' But she said 'That's fine,' and that's how I got to Winnipeg," Feldmann says. He liked the idea of starting his own lab, building up his own program, rather than taking over an existing one. As well, he'd been impressed by how supportive the environment appeared to be. And he was drawn to the mandate: Do science, but also do public health. "I had the feeling that the leadership would be basically willing to put it in the people's hands, in our hands, to build this program up under the condition that we have to fulfill the public health portion of it," said Feldmann, who left Winnipeg in 2008 to become chief scientist for Level 4 laboratories at the U.S. National Institute of Health's Rocky Mountain Laboratories in Hamilton, Mont. Under Feldmann, the Winnipeg lab created Ebola and Marburg vaccines that are widely thought to be highly promising. Between 800 and 1,000 vials of the Ebola vaccine, called VSV-EBOV, have been donated to the World Health Organization and will be used in this outbreak, if preliminary trials show it is safe in humans. The team also created a mobile laboratory, a low-tech but safe lab-in-a-suitcase that has revolutionized how testing is done in the remote locations where Ebola and Marburg outbreaks typically occur. "Once they [WHO] deployed us the first time I think they realized that the on site thing was giving some advantage," Feldmann said. The Winnipeg mobile lab has been deployed by the WHO during most subsequent Ebola and Marburg outbreaks. And many other countries have copied the model. A number of other mobile labs are in the Ebola zone helping with the current epidemic.

'Set your people free'

Also instrumental in Winnipeg's success was Plummer, a seasoned HIV scientist with years in the field who returned to Canada to take over as head of the new lab in 2001. "I think that Frank's motto is: Set your people free. And I think basically he created the environment here," said Kobinger, the rising star in Ebola research. Another thing about Plummer: He was always keen to bring top Canadian scientists home. Gary Kobinger — born in Europe but raised in Quebec — was working on an Ebola vaccine at the University of Pennsylvania. He approached Feldmann about collaborating, and ended up splitting his time between Philadelphia and the Level 4 labs of Winnipeg. "Heinz basically introduced Gary to me saying 'He's a really good guy, it would be great if we could find a job for him," Plummer says. "So I hired him and it was one of the smartest things I ever did." When Feldmann was lured away to the U.S., Kobinger became his successor. "I think with Gary they found the perfect person to run that project," Feldmann says.

Antibody cocktail

Kobinger has continued work on the Ebola vaccine. But it is with something known as monoclonal antibodies where he's made a major mark. Our immune systems produce a soup of antibodies to protect against various invaders. But scientists try to figure out which specific ones target a given pathogen, then grow up lots of that individual antibody. Those are called monoclonals. Kobinger and his team produced a cocktail of three Ebola monoclonals that looked promising against the virus in animal testing. Scientists at the U.S. Army Medical Research Institute of Infectious Diseases in Frederick, Md., were also working on a monoclonal cocktail of three antibodies. There was no overlap between the two. Kobinger decided to try to optimize the cocktails, testing various combinations to see which was best. The result: ZMapp, which is made up of two of Winnipeg's monoclonals and one made by the U.S. team. A recently published study showed the antibody cocktail protected 100 per cent of Ebola-infected primates, even when treatment was only begun five days after infection. Plummer couldn't be prouder. "People had been trying [to make Ebola monoclonals] for years and couldn't. And we had people who were very good at making monoclonals."

'Canada became a player'

Winnipeg's success comes down to excellent scientists given free rein to do world class work. But serendipity plays a role in science too. "Out of small things and maybe being lucky — I'm sure being lucky — and maybe certain people making the right decisions, Canada became a player in the game. And I think that was the concept," Feldmann said. Kobinger admits he occasionally meets people who want to know the secret of the Winnipeg lab's success. "They're trying to understand if it's because we have more resources. I guarantee you, no," he says with a chuckle. "In relation to many labs in the U.S., definitely we have less." It comes down to people, an institutional philosophy and support. Plummer sums it up. "My strategy, and I think it still is the department's strategy, is to keep the scientific opportunity as rich as possible."

Fast Tracking Treatments

The Economist Sept 13, 2014 Exerpt:

Stepping up the pace

The scale of the present outbreak, together with the fear and suffering it is causing, has resulted in a burst of scientific activity to find new treatments and vaccines. Some of these medicines look promising. But to contain the spread of Ebola, scientists and health officials will have to bypass many of the existing rules that govern the delivery of new drugs, and develop potential remedies with unprecedented speed. This strategy is being endorsed widely. In August experts from the WHO concluded that, provided certain conditions are met, it would be ethical to offer unproven, experimental treatments or methods to prevent infection. Ebola experts gathered by the WHO in Geneva on September 4th-5th repeated this, and said the delivery of new medicines was now essential. A number of groups are pushing ahead with human trials of vaccines that have shown promise in animal tests. Last week the first phase 1 clinical trials started in America for a vaccine developed by the US National Institutes of Health (NIH) and GlaxoSmithKline (GSK).

In parallel, a British group is planning tests using volunteers in the UK, the Gambia and Mali. Phase 1 trials are used to test whether a drug is safe in healthy individuals, after which a series of further trials establish whether it works. But in this case, vaccines are expected to be offered directly to health-care workers in infected areas once the initial tests are complete. The effects of the vaccine would then be monitored in the field. The NIH/GSK vaccine is based on a benign virus which causes a cold in chimpanzees (an adenovirus). It is able to infect cells and deliver fragments of genetic material from two variations of Ebola (one of which is the Zaire strain responsible for the current outbreak). When Ebola proteins are expressed by infected cells, an immune response is triggered. A version using a single strain of Ebola is also being tested. On September 7th, Nature Medicine reported that immediate and lasting immunity to Ebola could be stimulated in monkeys if a dual jab is used.

The first jab primes the immune system with an adenovirus-based vaccine; the second boosts it with a modifiedvaccinia virus (the active component of the vaccine that eradicated smallpox). Johnson & Johnson, a big American health-care company, has accelerated laboratory testing of a combined vaccine, which could begin clinical trials next year. Another candidate vaccine was developed many years ago by the Public Health Agency of Canada. It was recently licensed by NewLink Genetics of Ames, Iowa, which has approval to start phase 1 trials. This jab is based on a vesicular stomatitis virus (VSV), a livestock infection that resembles foot-and-mouth disease. VSV has been used previously to develop vaccines. The new vaccine, VSV-EBOV, is a live, replicating virus that infects cells and carries Ebola viral proteins into the host. Again, this stimulates an immune response. Importantly, VSV-EBOV also works in monkeys after they have been infected. The reason Ebola is so deadly is that the virus is good at tamping down the innate immune response to viral infection, says Jonathan Ball, a professor of molecular virology at the University of Nottingham in Britain. Thus Ebola replicates unchecked before the immune system can adapt and mount a tailored response. Some people recover naturally. They are able to summon defences more speedily, and before their bodies are overcome with symptoms such as organ failure and haemorrhaging.

Production under way

The results of the safety trials will start to arrive in November, and vaccines may be provided immediately to health-care workers who agree to be injected—some vaccine production is already under way. Experts hope they will be safe, as the viral “platforms” on which they are based have already been tested in humans. But these vaccines will not be available to restrain the epidemic over the next few months—a time that many think will be critical in containing the disease. The experts at the WHO’s Geneva meeting were most optimistic about two related methods of treatment: whole blood transfusion and purified blood plasma, known as convalescent serum. The idea is to take blood containing Ebola antibodies from survivors and give this to existing patients where, according to theory, the antibodies will then fight the virus. There are no data yet on the efficacy of this treatment on a large scale, but transfusions were used in previous Ebola outbreaks, and have been used for over 100 years on a small scale to combat other infectious diseases.

Jeremy Farrar, director of the Wellcome Trust, a large British health charity, agrees with this approach. He adds that such blood products can be safely provided, and are accepted widely in the affected countries. There are other possibilities, too. Mapp Biopharmaceutical, a San Diego drug company, is developing a cocktail of monoclonal antibodies, made by genetic engineering. These appear to protect against the Ebola virus. In tests, all 18 monkeys given ZMapp, as the treatment is called, were protected even five days after infection. Four infected people have received it, and two have recovered. But doctors do not know if ZMapp helped. Because the drug is difficult to make, supplies are exhausted for now. Another approach to fighting Ebola is to constrain viral replication. Tekmira Pharmaceuticals, a Canadian firm, is working on TKM-EBOLA, a drug that silences the cellular messages that allow viral proteins to be made. Human trials were halted earlier this year because the drug caused flu-like symptoms—but America’s Food and Drug Administration has recently agreed that it can now be tried on Ebola patients. Other antivirals, such as Favipiravir, an influenza treatment, might also help.

But more data from animal tests are needed. Some researchers propose going “off-label” with the unapproved use of existing drugs for other purposes. Interferon drugs have an antiviral effect and statins might help treat the complications of Ebola, such as organ failure. Experts at the WHO worry about the potential for harm with statins. But it is possible that some doctors, lacking alternatives, might try them. The arrival of new medicines will encourage health-care workers who have given up their posts to return to attend the sick. It would also help address the fear and panic that is proving so disastrous in the infected countries. But there are other difficulties. One is highlighted in a forthcoming working paper for the National Bureau of Economic Research, which finds that some Indian drugmakers are taking advantage of the lack of regulatory oversight to send their lowest-quality antibiotics to Africa. The biggest problem remains containment, especially in the months before new medicines arrive. Virologists, such as Dr Ball at Nottingham, worry that increasing human-to-human transmission is giving Ebola the opportunity to become more transmissible. Each time the virus replicates, new mutations appear. It has accumulated and hung on to some mutations, like “cherries on a one-armed bandit”, he says. Nobody knows what would happen if Ebola hit the jackpot with a strain that is even better-adapted to humans. But the outcome could be grim, for Africa and the rest of the world.