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Clonal selection drives protective memory B cell responses in controlled human malaria infection. | LitMetric

AI Article Synopsis

  • Affinity maturation is crucial for creating effective B cell memory responses during infections, as it involves the selection and expansion of B cells that have mutated to produce better antibodies after repeated exposure to an antigen.
  • This study analyzed how affinity maturation compares to clonal selection of naïve B cells in generating strong memory responses against the malaria parasite in humans after multiple vaccinations.
  • The findings suggest that clonal selection tends to be more important than affinity maturation for developing effective memory responses to complex antigens, indicating new strategies for designing vaccines against malaria and similar pathogens.

Article Abstract

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 naïve B cells into the response. Here, we determined the relative impact of affinity maturation versus antigen-mediated clonal selection of naïve B cells to mount potent B cell memory responses in humans after repeated exposure to a complex pathogen, the malaria parasite (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-naïve 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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Source
http://dx.doi.org/10.1126/sciimmunol.aap8029DOI Listing

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