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

Second Advisor

Daniel Weinberger

Abstract

Malaria remains a major global health threat as control efforts have stalled in recent years. Recently, theWHO began recommending two vaccines, RTS,S/AS01 and R21, both of which target the pre-erythrocytic stage of malaria. However, these vaccines are only partially protective and do not protect against the blood-stage of malaria where clinical disease begins. Therefore, a more broadly protective vaccine is still needed. Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is a leading candidate for next-generation blood-stage malaria vaccines with the most advanced formulation, RH5.1/Matrix-M, recently entering Phase 2b clinical trials. However, historically, malaria vaccine development has been challenged by the Plasmodium falciparum parasite’s extensive genetic diversity. Therefore, evaluating vaccine efficacy across genetically diverse parasite strains early in the development process is critical to its success. To address this, this study combines ex vivo and in vivo approaches to assess how naturally occurring mutations in PfRH5 may affect vaccine-induced protection. Using ex vivo growth inhibition assays on malaria clinical isolates, we found that PfRH5 vaccine-induced antibodies effectively inhibited parasite invasion across parasite variants. This is the first time the most potent anti-PfRH5 monoclonal antibodies have been tested against genetically diverse strains. While some parasites showed higher inhibition relative to wild-type, no isolate displayed evidence of immune escape, and structural analysis confirmed that none of the identified mutations compromised antibody binding. These findings support the strain-transcendent potential of RH5-based vaccines. To complement these findings, the framework for an in vivo sieve analysis was developed to assess whether specific PfRH5 variants are enriched in breakthrough infections from a Phase 2b trial in Burkina Faso, providing real-world insights into the potential for vaccine-driven immune selection. Together, this multi-method approach offers insight into the impact of PfRH5 genetic diversity on vaccine performance, highlights the most protective epitopes for inclusion in future vaccine designs, and serves as an early detection system for parasite variants that may compromise broad vaccine coverage.

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This is an Open Access Thesis.

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