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Antibody Feedback Limits the Expansion of B Cell Responses to Malaria Vaccination but Drives Diversification of the Humoral Response

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2020

Cell Host Microbe. 2020 Jul 16;S1931-3128(20)30397-8. doi: 10.1016/j.chom.2020.07.001.

Antibody Feedback Limits the Expansion of B Cell Responses to Malaria Vaccination but Drives Diversification of the Humoral Response

HA McNamara;AH Idris;HJ Sutton;R Vistein;BJ Flynn;Y Cai;BKL Sim;SL Hoffman;M Bonsignori;RA Seder;IA Cockburn

Department of Immunology and Infectious Disease, John Curtin School of Medical Research, the Australian National University, Canberra, ACT 2601, Australia. Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Duke Human Vaccine Institute, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Sanaria Inc., Rockville, MD 20850, USA. Department of Immunology and Infectious Disease, John Curtin School of Medical Research, the Australian National University, Canberra, ACT 2601, Australia.

Service type: Knock-in mice

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. Keywords: B cells; Ig-knockin mice; Plasmodium falciparum; antibody; antibody feedback; malaria; vaccines.

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