Journal
SCIENCE IMMUNOLOGY
Volume 3, Issue 20, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.aap8029
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Funding
- German Research Foundation (DFG) [GRK1121]
- Federal Ministry of Education and Research (BMBF) [PB12204]
- DFG [EXC81]
- German Federal Ministry of Education and Research (BMBF) through the German Center for Infection Research (DZIF)
- NIAID of the NIH under Small Business Innovation Research [5R44AI058375, 5R44AI055229]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R44AI058375, R44AI055229] Funding Source: NIH RePORTER
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Affinity maturation, the clonal selection and expansion of antigen-activated B cells expressing somatically mutated antibody variants that develop during T cell-dependent germinal center reactions, is considered pivotal for efficient development of protective B cell memory responses to infection and vaccination. Repeated antigen exposure promotes affinity maturation but each time also recruits antigen-reactive naive B cells into the response. Here, we determined the relative impact of affinity maturation versus antigen-mediated clonal selection of naive B cells to mount potent B cell memory responses in humans after repeated exposure to a complex pathogen, the malaria parasite Plasmodium falciparum (Pf). Using single-cell immunoglobulin (Ig) gene sequencing and production of recombinant monoclonal antibodies, we analyzed the origin, development, and quality of memory B cell responses to Pf circumsporozoite protein (PfCSP), the major sporozoite surface protein. We show that after repeated immunization of Pf-naive volunteers with infectious Pf sporozoites (PfSPZ Challenge) under chloroquine prophylaxis (PfSPZ-CVac), the clonal selection of potent germline and memory B cell precursors against the central PfCSP NANP repeat outpaces affinity maturation because the majority of Ig gene mutations are affinity-neutral. Mathematical modeling explains how the efficiency of affinity maturation decreases strongly with antigen complexity. Thus, in the absence of long-term exposure, the frequency of antigen-reactive precursors and likelihood of their activation rather than affinity maturation will determine the quality of anti-PfCSP memory B cell responses. These findings have wide implications for the design of vaccination strategies to induce potent B cell memory responses against PfCSP and presumably other structurally complex antigens.
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