Mechanisms that promote the evolution of cross-reactive antibodies upon vaccination with designed influenza immunogens

Leerang Yang; Timothy M. Caradonna; Aaron G. Schmidt; Arup K. Chakraborty

Cell Reports (Mar 2023)

Mechanisms that promote the evolution of cross-reactive antibodies upon vaccination with designed influenza immunogens

Leerang Yang,
Timothy M. Caradonna,
Aaron G. Schmidt,
Arup K. Chakraborty

Affiliations

Leerang Yang: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Timothy M. Caradonna: Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
Aaron G. Schmidt: Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
Arup K. Chakraborty: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 3
p. 112160

Abstract

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Summary: Immunogens that elicit broadly neutralizing antibodies targeting the conserved receptor-binding site (RBS) on influenza hemagglutinin may serve as candidates for a universal influenza vaccine. Here, we develop a computational model to interrogate antibody evolution by affinity maturation after immunization with two types of immunogens: a heterotrimeric “chimera” hemagglutinin that is enriched for the RBS epitope relative to other B cell epitopes and a cocktail composed of three non-epitope-enriched homotrimers of the monomers that comprise the chimera. Experiments in mice find that the chimera outperforms the cocktail for eliciting RBS-directed antibodies. We show that this result follows from an interplay between how B cells engage these antigens and interact with diverse helper T cells and requires T cell-mediated selection of germinal center B cells to be a stringent constraint. Our results shed light on antibody evolution and highlight how immunogen design and T cells modulate vaccination outcomes.

CP: Immunology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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