Modulating the immunodominance hierarchy of immunoglobulin germline-encoded structural motifs targeting the influenza hemagglutinin stem

Author:

Ataca, Sila

Sangesland, Maya

de Paiva Fróes Rocha, Rebeca

Torrents de la Peña, Alba

Ronsard, Larance

Boyoglu-Barnum, Seyhan

Gillespie, Rebecca A

Tsybovsky,Yaroslav

Stephens,Tyler

Moin, Syed M

Lederhofer, Julia

Creanga, Adrian

Andrews, Sarah F

Barnes, Ralston M

Rohrer, Daniel

Lonberg, Nils

Graham, Barney S

Ward, Andrew B

Lingwood, Daniel

Kanekiyo, Masaru
Author Address

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA., The Scripps Research Institute, La Jolla, CA 92037, USA., Vaccine Research Center Electron Microscopy Unit, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 20701, USA., Bristol-Myers Squibb, Redwood City, CA 94063, USA., Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: kanekiyom@nih.gov.,

Abstract:

Antibodies targeting epitopes through germline-encoded motifs can be found in different individuals. While these public antibodies are often beneficial, they also pose hurdles for subdominant antibodies to emerge. Here, we use transgenic mice that reproduce the human IGHV1-69*01 germline-encoded antibody response to the conserved stem epitope on group 1 hemagglutinin (HA) of influenza A virus to show that this germline-endowed response can be overridden by a subdominant yet cross-group reactive public antibody response. Immunization with a non-cognate group 2 HA stem enriched B cells harboring the IGHD3-9 gene, thereby switching from IGHV1-69- to IGHD3-9-encoded motif-dependent epitope recognition. These IGHD3-9 antibodies bound, neutralized, and conferred cross-group protection in mice against influenza A viruses. A cryoelectron microscopy (cryo-EM) structure of an IGHD3-9 antibody resembled the human broadly neutralizing antibody FI6v3, which uses IGHD3-9. Together, our findings offer insights into vaccine regimens that engage an immunoglobulin repertoire with broader cross-reactivity to influenza A viruses. Published by Elsevier Inc.

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