1. Antibody Feedback Limits the Expansion of B Cell Responses to Malaria Vaccination but Drives Diversification of the Humoral Response.
- Author
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McNamara HA, Idris AH, Sutton HJ, Vistein R, Flynn BJ, Cai Y, Wiehe K, Lyke KE, Chatterjee D, Kc N, Chakravarty S, Lee Sim BK, Hoffman SL, Bonsignori M, Seder RA, and Cockburn IA
- Subjects
- Animals, Antibodies, Protozoan genetics, Antibody Formation immunology, Epitopes immunology, Feedback, Humans, Immunization, Immunoglobulin G, Immunoglobulin M, Malaria immunology, Mice, Mice, Inbred C57BL, Mutation, Plasmodium falciparum immunology, Sporozoites immunology, Vaccines, Attenuated, Antibodies, Protozoan immunology, B-Lymphocytes immunology, Malaria Vaccines immunology, Vaccination
- Abstract
Generating sufficient antibody to block infection is a key challenge for vaccines against malaria. Here, we show that antibody titers to a key target, the repeat region of the Plasmodium falciparum circumsporozoite protein (PfCSP), plateaued after two immunizations in a clinical trial of the radiation-attenuated sporozoite vaccine. To understand the mechanisms limiting vaccine responsiveness, we developed immunoglobulin (Ig)-knockin mice with elevated numbers of PfCSP-binding B cells. We determined that recall responses were inhibited by antibody feedback, potentially via epitope masking of the immunodominant PfCSP repeat region. Importantly, the amount of antibody that prevents boosting is below the amount of antibody required for protection. Finally, while antibody feedback limited responses to the PfCSP repeat region in vaccinated volunteers, potentially protective subdominant responses to PfCSP C-terminal regions expanded with subsequent boosts. These data suggest that antibody feedback drives the diversification of immune responses and that vaccination for malaria will require targeting multiple antigens., Competing Interests: Declaration of Interests S.C., N.K., B.K.L.S., and S.L.H. are salaried employees of Sanaria Inc., the developer and owner of PfSPZ Vaccine and the investigational new drug (IND) application sponsor of the clinical trials. S.L.H. and B.K.L.S. have a financial interest in Sanaria Inc. All other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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