Christopher Plowe's research focuses on accelerating the translation of genomics into health interventions. To do this, he exploits genomic advances to improve malaria drugs and vaccines that are already well along in clinical development but whose efficacy is threatened by the parasite's genetic diversity.
Identification of Molecular Markers of Artemisinin-Resistant Malaria
Highly effective artemisinin-based antimalarial drugs are used worldwide and have contributed to reductions in the malaria burden in many areas. Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia, and its potential spread threatens to reverse recent gains against malaria and to abort plans for a renewed global eradication campaign. Ongoing efforts to contain artemisinin-resistant malaria are hampered by the lack of tools to gauge the extent and direction of its spread. Presently, only laborious clinical trials can reliably measure resistance. A molecular assay to detect markers of artemisinin resistance would be a highly valuable surveillance tool, but the genetic basis of resistance is unknown. In an effort to identify regions of the genome associated with delayed clearance of malaria parasites after artemisinin treatment, we have conducted genome-wide association studies of P. falciparum. We will identify and prioritize candidate genes in genomic regions identified in our genome-wide association studies. Multiple criteria will be used to prioritize candidate genes for polymorphism discovery. Genotyping assays will be developed to type polymorphisms from high-priority candidate genes that are significantly associated with parasite clearance. These assays can be used to validate candidate markers of artemisinin resistance in completed and ongoing artesunate clinical trials.
Identifying Immunoprotective Epitopes of a Malaria Vaccine Candidate Antigen
This project seeks to understand the human immunological response against, and resulting antigenic diversity of, apical membrane antigen-1 (AMA1), a leading Plasmodium falciparum vaccine antigen, with the ultimate goal of developing an AMA1-based vaccine that provides broad protection against naturally diverse P. falciparum strains. AMA1 is highly polymorphic; antigenic variation is likely a parasite immune escape mechanism that allows repeated infection with different variants in the face of natural immunity. Anti-AMA1 antibodies confer protection against natural infection. Molecular epidemiological and animal studies suggest that some regions of the AMA1 molecule represent “immunogenicity hot spots,” that is, residues within these regions are critical to development of strain-specific protective immunity. In a phase 2 clinical trial of an AMA1 vaccine, we showed allele-specific efficacy against clinical malaria caused by parasites with AMA1 homologous to the vaccine strain with respect to an “immunogenicity hot spot” inferred from our preliminary data, validating the importance of this particular region.
In this project, the student will use molecular cloning and an autotransporter protein expression system to create a library of constructs containing AMA1 fragments. Sera from vaccinees and control subjects will then be evaluated to identify reactive AMA1 fragments that are also associated with clinical protection. Analysis of the antibody responses that are most strongly correlated with protection from malaria will allow us to pinpoint the specific AMA1 amino acid residues that must be considered in designing next-generation, more broadly efficacious AMA1 vaccines.
Assessment of Malaria Immunity in a Malaria-Exposed Elderly Population
Understanding the development of natural protective immunity in malaria-endemic regions has largely focused on children and adults, but not the elderly, who potentially constitute a large reservoir of asymptomatic infections that can sustain parasite populations. Elderly individuals may also comprise a population vulnerable to malaria if natural immunity wanes with senescence. This project will gauge the extent of natural immunity to malaria in an elderly population in Bandiagara, Mali, a region with intense seasonal malaria transmission. We have previously used protein microarrays populated with Plasmodium falciparum antigens to measure malaria immunity in children and adults. In this project, the student will probe such a protein microarray with sera from an elderly Malian population and compare seroreactivity with that from children and adults in the same region. This work will involve probing and scanning of microarrays and extensive data analysis.