Date of Award

January 2025

Document Type

Open Access Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Amy K. Bei

Abstract

The development of a highly effective malaria vaccine is of global health priority, given the persistently high malaria burden in Sub-Saharan Africa (SSA) and growing resistance to antimalarial treatment and vector control measures. P. falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as a leading target among blood-stage malaria vaccine candidates due to its essential role in erythrocyte invasion and initial documentation of limited polymorphisms. However, recent studies have revealed greater PfRH5 genetic diversity than previously believed, raising concerns about potential parasite evasion of vaccine-induced immunity. This study utilized deep targeted amplicon next-generation sequencing to characterize PfRH5 genetic variation in 98 clinical P. falciparum isolates from Ghana, Burkina Faso, and Tanzania. A total of 15 non-synonymous single nucleotide polymorphisms (SNPs) were identified, seven of which were novel variants. C203Y was the only allele shared across all sites, whereas most variants were rare and unique to individual isolates. With the exception of Q279K (n=3), all novel SNPs were observed in a single isolate. Generally, SNPs with high prevalence also exhibited high intra-sample variant allele frequencies (VAFs). Ghanaian isolates exhibited the greatest SNP diversity, possibly due to increased urbanicity, more gene flow, and a larger sample size. A novel mutation of a premature stop codon at position 272 is of particular interest and warrants further investigation as it may disrupt PfRH5’s function. Future efforts must adopt a pan-African sequencing approach to capture PfRH5 diversity across SSA comprehensively. Downstream research should prioritize functionally validating novel SNPs — particularly those at high prevalence and frequency — to understand their impacts on erythrocytic invasion and immune evasion. Consequent insights would ensure that PfRH5-based vaccines can elicit broadly neutralizing responses across diverse parasite populations in SSA.

Comments

This is an Open Access Thesis.

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