# Understanding and overcoming Plasmodium-specific immune evasion mechanisms

> **NIH NIH F32** · UNIVERSITY OF WASHINGTON · 2024 · $76,756

## Abstract

Project Summary/Abstract
Infection with Plasmodium parasites leads to over 240 million cases of malaria and 700 thousand deaths
annually, the majority of which are children under the age of five. Vector control has reduced transmission of
Plasmodium, though a protective vaccine is required to reduce disease burden further. Currently deployed
vaccines focus on the liver stage circumsporozoite protein (CSP) and offer moderate protection in Plasmodium-
naïve individuals. However, vaccine efficacy and durability severely decline in individuals who have previously
been infected with Plasmodium. Understanding how Plasmodium infection influences the pre-vaccine CSP-
specific memory B cell pool is essential to identify why our current vaccinations are ineffective in endemic areas.
Previous research has demonstrated that antibody responses towards two domains of CSP, the
immunodominant repeat region (RR) and the non-dominant C terminus (CT), may be protective against infection.
In contrast, other data suggest that the highly repetitive sequence of the RR may instead be a mechanism of
immune evasion. The high avidity of this region may drive short-lived humoral responses or concentrate
responses to the RR rather than perhaps more functional regions of CSP. We generated unique tetramers that
allow us to isolate and track RR and CT-specific B cell responses during infection and/or immunization. In a
murine model, we found that Plasmodium infection preferentially expands B cells specific to the RR at the
expense of CT-specific B cells. In contrast, vaccination alone expands B cell populations specific to both
domains. We hypothesize that Plasmodium infection induces a predominantly RR-specific pre-vaccine memory
B cell pool that, due the high avidity of the region, will differentiate into short-lived plasmablasts upon a
subsequent vaccination rather than reseeding memory pools. In this proposal, we will characterize the CSP-
specific memory B cell pool generated during infection or immunization in a murine model and relevant human
clinical trial samples. We will also identify the impact of previous infection on the response to a subsequent
vaccination. Lastly, we will use novel, modified vaccination strategies to improve vaccine efficacy and durability
in previously infected models. Understanding how to induce a larger breadth of B cell responses or induce longer
lived RR-specific cells is important to improve vaccine efficacy in individuals previously infected with
Plasmodium.

## Key facts

- **NIH application ID:** 10898484
- **Project number:** 1F32AI178963-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Courtney McDougal
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $76,756
- **Award type:** 1
- **Project period:** 2024-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898484

## Citation

> US National Institutes of Health, RePORTER application 10898484, Understanding and overcoming Plasmodium-specific immune evasion mechanisms (1F32AI178963-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10898484. Licensed CC0.

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