# The Development and Function of Plasmodium-specific memory B cells

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $596,609

## Abstract

Memory B cells and long-lived plasma cells are responsible for producing neutralizing
antibodies that can effectively eliminate a pathogen. Understanding the function of these cells in
response to infection and how they can be induced and maintained by vaccination is therefore
critical to eradicating diseases that are global health burdens. Malaria, caused by Plasmodium
spp, is a major global health burden that is in urgent need of a vaccine. Over fifty years ago it
was shown that transfer of human immune serum can neutralize Plasmodium parasites during
the blood stage of infection. Little is known however about the Plasmodium-specific B cells that
produce these antibodies due to the difficulties of studying low frequency antigen-specific B
cells. Additionally, it is not understood how recently described populations of heterogeneous
memory B cell (MBC) subsets induced by protein immunization form or function in response to
infection. To clarify functional roles for distinct MBC subsets during malaria infection, tetramers
were generated that identify Plasmodium-specific MBCs in both humans and mice.
Multiparameter flow cytometry and single-cell B cell receptor sequencing revealed that long-
lived murine Plasmodium-specific MBCs consisted of three populations: somatically
hypermutated, classically defined IgG+ (IgG+), a previously unrecognized population of
somatically hypermutated IgM+ (IgMhighIgDlow) MBCs and an unmutated IgD+ (IgMlowIgDhigh) MBC
population. Surprisingly, Plasmodium-specific IgM+ antibody dominated the early response to a
secondary infection. Further analyses revealed that upon rechallenge, IgM+ MBCs rapidly form
two antibody-secreting populations: T cell-independent plasma cells and T-dependent IgM+ and
IgG+ plasmablasts. IgM+ MBCs are therefore rapid, plastic, first responders to Plasmodium
rechallenge and should be targeted by vaccine strategies. We are now poised to further
characterize these and other Plasmodium-specific B cell populations to determine their unique
contributions to protection against malaria in both humans and relevant murine models. The
central hypothesis of this application is that the development of functionally heterogeneous yet
synergistic populations of memory B cells will be required for vaccine-mediated protection to
Plasmodium. The goals of this proposal are to identify the molecular and cellular mechanisms
that lead to the formation of these distinct MBC subsets and to determine how these cells
contribute to protection against malaria in mice and humans. This innovative approach could
provide the information required to develop the first effective vaccine against malaria.

## Key facts

- **NIH application ID:** 10062845
- **Project number:** 5R01AI118803-05
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** MARION PEPPER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $596,609
- **Award type:** 5
- **Project period:** 2016-12-16 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062845

## Citation

> US National Institutes of Health, RePORTER application 10062845, The Development and Function of Plasmodium-specific memory B cells (5R01AI118803-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10062845. Licensed CC0.

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