Date of Award

1-1-2020

Document Type

Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Amy K. Bei

Abstract

Malaria is still responsible for over 405,000 deaths and 228 million cases of disease globally each year, with the large majority of these cases being caused by the Plasmodium falciparum parasite subspecies1. The RTS,S P. falciparum malaria vaccine, the only malaria vaccine ever licensed, is currently being rolled out in three African countries as part of a pilot implementation program and targets a major circumsporozoite protein (PfCSP). After three doses and a seven-year follow up, the vaccine showed a 7% efficacy on average with a -56.8% efficacy for patients in regions with above average exposure to P. falciparum2. While the creation and licensure of this vaccine are significant accomplishments, the need for a highly effective malaria vaccine remains as important as ever. A major obstacle in the creation of a highly effective vaccine is the extensive genetic diversity displayed in P. falciparum. The P. falciparum reticulocyte binding homolog-5 (PfRh5) ligand used by the merozoite form of the parasite to invade human erythrocytes has been shown to be one of the very few components that is essential for the parasite’s survival and not susceptible to functional change in the event of genetic diversity. We sought to further investigate this phenomenon by obtaining samples from infected patients in the heavily endemic region of Kédougou, Senegal. 31 ex-vivo invasion assays were performed with field samples and 95 patient samples were sequenced for the PfRh5 locus. All 95 patients were shown to be infected with an average of 4.9 (±2.8) different parasite isolates. The invasion assays analyzed thus far showed no significant phenotypic changes that allowed that parasite to successfully invade with the PfRh5 invasion pathway blocked by anti-Basigin (????-BSG) monoclonal antibodies (mAb). PfRh5 NGS sequencing analysis showed over 70% prevalence of a known non-synonymous SNP, C203Y, that has no functional impact. A novel SNP of as yet unknown impact was discovered in one patient sample: D269N. This study shows that in the face of a highly diverse parasite population, PfRh5 remains highly conserved and functionally essential, supporting continued research into its viability as a malaria vaccine target.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 05/27/2021

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