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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Clonal selection drives protective memory B cell responses in controlled human malaria infection
Science Immunology, Volume 3, No. 20, Article eaap8029, Year 2018
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Description
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 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-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. Copyright © 2018 The Authors.
Authors & Co-Authors
Murugan, Rajagopal
Germany, Heidelberg
German Cancer Research Center
Triller, Gianna
Germany, Heidelberg
German Cancer Research Center
Kreschel, Cornelia
Germany, Berlin
Max Planck Institute for Infection Biology
Costa, Giulia
Germany, Berlin
Max Planck Institute for Infection Biology
Busse, Christian E.
Germany, Heidelberg
German Cancer Research Center
Chakravarty, Sumana
United States, Rockville
Sanaria Inc.
Kim Lee Sim, Betty
United States, Rockville
Sanaria Inc.
Hoffman, Stephen L.
United States, Rockville
Sanaria Inc.
Levashina, Elena A.
Germany, Berlin
Max Planck Institute for Infection Biology
Kremsner, Peter G.
Germany, Tubingen
Eberhard Karls Universität Tübingen
Mordmüller, Benjamin G.
Germany, Tubingen
Eberhard Karls Universität Tübingen
Höfer, Thomas
Germany, Heidelberg
German Cancer Research Center
Wardemann, Hedda
Germany, Heidelberg
German Cancer Research Center
Statistics
Citations: 96
Authors: 13
Affiliations: 5
Identifiers
Doi:
10.1126/sciimmunol.aap8029
ISSN:
24709468
Research Areas
Genetics And Genomics
Infectious Diseases
Maternal And Child Health