# Exploring the roles of acquired immunity and functional constraint in sculpting malaria antigenic diversity in a longitudinal cohort

> **NIH NIH R01** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2020 · $617,080

## Abstract

Malaria parasite antigenic diversity is driven by acquired immunity and bounded by functional
constraints. The interplay between these forces, if better understood, could accelerate vaccine
development. The genome of Plasmodium falciparum, the eukaryotic parasite that causes the most
lethal form of human malaria, exhibits a strong signature of evolutionary interaction with human hosts.
While most of the genome exhibits low population diversity, several hundred genes encoding antigenic
proteins harbor very high levels of variation resulting from immune-mediated balancing selection.
Humans do not develop sterilizing immunity to infection with P. falciparum parasites, but develop
naturally acquired immunity (NAI) through recurrent infection that reduces parasite density in the blood,
and thus morbidity and mortality. For natural selection to maintain antigenic variability in parasite
populations, it must confer a fitness advantage, such that parasites harboring certain variants enjoy
enhanced probability of successful transmission to another human host. We recently generated PCR-
based next-generation sequencing data from more than 5000 clinical samples to demonstrate that
vaccination with the RTS,S/AS01 malaria vaccine, a protein subunit vaccine targeting the
circumsporozoite protein (CSP), results in a reduction of subsequent blood-stage infections harboring a
CSP genotype identical to the vaccine strain. This indicates that immunity conferred by the vaccine was
transiently sterilizing in some individuals, but in an allele-specific manner. To explore whether NAI
structures antigenic diversity in a manner similar to the RTS,S vaccine on a much larger set of
antigens, and whether some observed variants impair antigen function, we propose to genetically
profile parasite antigens in blood samples from different age groups, collected deeply within a single
transmission season and longitudinally across transmission seasons in Mali, using whole-genome
sequencing surveys. Using mathematical models, we will elucidate the mechanistic forces structuring
antigenic diversity by generating detailed molecular epidemiological profiles of all malaria infections in
multiple age groups within one transmission season (AIM 1), across multiple transmission seasons
(AIM 2), and we will evaluate the functional constraints on malaria parasite antigen polymorphism
through growth efficiency/inhibition assays (AIM 3). This work will provide a new means of ranking
vaccine targets that is complementary to existing rankings, and inform polyvalent development
strategies for existing vaccine targets known to exhibit allele-specific protection. Our findings will clarify
a fundamental phenomenon relevant to many infectious disease systems and vaccine development
efforts.

## Key facts

- **NIH application ID:** 9991736
- **Project number:** 5R01AI141544-03
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** Daniel E Neafsey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $617,080
- **Award type:** 5
- **Project period:** 2018-09-25 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991736

## Citation

> US National Institutes of Health, RePORTER application 9991736, Exploring the roles of acquired immunity and functional constraint in sculpting malaria antigenic diversity in a longitudinal cohort (5R01AI141544-03). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/9991736. Licensed CC0.

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