Antibiotic Resistance, Vaccines & Diagnostics
Iron Uptake Systems:
We are investigating iron uptake systems in Staphylococcus aureus, a significant opportunistic Gram positive pathogen with a high prevalence of multiple drug resistance such as MRSA. Though generally seen as a problem of the developed world, a recent article in the Lancet infectious Diseases (vol 9, page 130) found “… that its neglected status as a developing world pathogen does not equate with low rates of disease.”
Innate Defence Regulators:
With support from the Grand Challenges in Global Health program, we developed innate defence regulator (IDR) peptides that work by selectively modulating innate immunity (enhancing protective innate immunity while suppressing potentially harmful pro-inflammatory responses). IDRs have demonstrated, both alone and in the presence of suboptimal antimicrobial treatments (mimicking situations of resistance), protection in animal models against invasive S. aureus infections (via IV, IP and SC), local thigh S. aureus infections (via IM), MRSA, VRE, and Salmonella, as well as protection in mice against E. coli, P. aeruginosa, M. tuberculosis, Franciscella, Citrobacter, Pox virus, and cerebral malaria, many with collaborators. These effects can be relatively modest ranging from a 1-4 log change in bacterial load to 75% increase in survival, but are accompanied by a decreased inflammatory response and substantially reduced morbidity. Mechanistic studies in human PBMC and mouse models suggest similar responses of both species.
IDR peptides show efficacy as components of vaccine adjuvants. In collaboration with the Vaccine Infectious Diseases Organization in Saskatoon, we created a formulation of three adjuvant components (CpG oligo, polyphosphazene, and proprietary IDR peptides) that gives (protective) antibody titres (mixed Th1/Th2 response) of 40,000 in a single injection against a model antigen pertussis toxoid; furthermore we have evidence that this works via the mucosal route and in adult and neonatal mice and pigs. Protection exceeds that afforded by the commercial vaccine Quadracel.
Robert Hancock cont’d
To enhance systems biology studies in the areas of host pathogen interactions and innate immunity, we developed InnateDB (www.innatebd.com), a open-source, publicly available database and systems biology analysis platform of the genes, proteins, interactions and signalling responses involved in the human & mouse innate immune responses (2).
InnateDB is becoming an important tool in immunology as evidenced by the >1,500,000 hits per year. While all known human and mouse pathways (>3,000) and molecular interactions (>115,000) are present, the emphasis on innate immunity has been achieved through our contextual review, curation and annotation of >12,000 molecular interactions and pathways involved in innate immunity.
We have demonstrated the usefulness of this tool in systems analyses of host responses to a variety of important pathogens including human clinical datasets: typhoid and malaria in Vietnam, non typhoidal Salmonella infections in AIDS patients in Malawi, helminth infections in children in Ecuador, and mouse models of Cerebral Malaria and M. tuberculosis.
Mapping Outcomes for Mothers (MOM):
A mobile health (mHealth) application for mapping and predicting community specific risk of pregnancy related illness and death. MOM is a mHealth application that uses geographic mapping methods to create an integrated picture of maternal health in the context of local social and physical environments. It is unique because it looks at pregnancy risk in 4 dimensions:
1) social environment
2) physical environment
3) health care system and
4) the woman’s individual characteristics.
The use of geo-spatial mapping is novel: this is the first time it is being used for identifying maternal health risk. By overlaying health with the local social and environmental contexts, MOM identifies the positive and negative influences and how they interact to create risk. It is a point of care diagnostic tool that aids real-time decision making by the frontline health worker. By breaking down a complex phenomenon into its root causes, MOM will ultimately put solutions in the hands of communities.
Development of Fixed Drug Dosing Bands:
The purpose of this project is to simplify assessment and treatment decision making, as well as communication between health providers, thru the development of weight or proxy for weight bands. In Phase I the validity of drug dosing decisions based upon weight bands and proxies were tested and validated using existing data sets from Uganda and Bangladesh. In Phase II these bands will be color coded and tested for accuracy, validity and feasibility under more-or-less ideal conditions (efficacy) within both countries. In Phase III a similar exercise will be carried out, but under actual conditions (effectiveness) in rural health centres. Weight band proxies to be tested include age, height, and long bone measurements (tibia and ulna).
Low-Cost Malaria Diagnostic:
Accurate, sensitive, and cost-effective diagnostic tests are central to the global campaign to control and eradicate malaria. Inaccurate diagnosis not only results in patient mortality and morbidity, but also leads to ineffective use of treatment resources and could potentially accelerate the emergence of drug-resistant strains.
Malaria is caused by a protozoan parasite that invades human red blood cells. Currently, the gold standard detection method is the microscopic examination of Giemsa-stained blood smears to determine the density of infected red blood cells. This detection technique is sensitive and quantitative, but requires expertise and equipment often not available in low-resource regions. Rapid diagnostic tests based on immune-capture of antigens specific to the malaria parasite are a promising low-cost alternative. However, these tests are not as sensitive as microscopy, they do not provide a quantitative measure of parasite density, and they can produce a positive result even when parasites are no longer viable. We are developing a low-cost and portable device for detection of malaria infection that can quantitatively determine parasite density and discriminate viable and non-viable parasites. Such a device could be used to direct treatment until the clearance of all viable parasites, as well as to evaluate the effectiveness of new drugs and vaccines in clinical trials.