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Immunity. 2019 Oct 15;51(4):735-749.e8. doi: 10.1016/j.immuni.2019.09.001. Epub 2019 Sep 25.

Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus.

Author information

1
The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA.
2
The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Massachusetts Institute of Technology and Harvard University, 415 Main St, Cambridge, MA 02142, USA.
3
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, 40 Convent Drive, Bethesda, MD 20892-3005, USA.
4
Bristol-Myers Squibb, 700 Bay Road, Redwood City, CA 94063-2478, USA.
5
Medimmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
6
Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, 2425 Camino de Salud, Albuquerque, NM 87106, USA.
7
The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA. Electronic address: dlingwood@mgh.harvard.edu.

Abstract

Antibody paratopes are formed by hypervariable complementarity-determining regions (CDRH3s) and variable gene-encoded CDRs. The latter show biased usage in human broadly neutralizing antibodies (bnAbs) against both HIV and influenza virus, suggesting the existence of gene-endowed targeting solutions that may be amenable to pathway amplification. To test this, we generated transgenic mice with human CDRH3 diversity but simultaneously constrained to individual user-defined human immunoglobulin variable heavy-chain (VH) genes, including IGHV1-69, which shows biased usage in human bnAbs targeting the hemagglutinin stalk of group 1 influenza A viruses. Sequential immunization with a stalk-only hemagglutinin nanoparticle elicited group 1 bnAbs, but only in IGHV1-69 mice. This VH-endowed response required minimal affinity maturation, was elicited alongside pre-existing influenza immunity, and when IGHV1-69 B cells were diluted to match the frequency measured in humans. These results indicate that the human repertoire could, in principle, support germline-encoded bnAb elicitation using a single recombinant hemagglutinin immunogen.

KEYWORDS:

BCR; conserved site of vulnerability; influenza; innate-like; rational vaccine; universal

PMID:
31563464
PMCID:
PMC6801110
[Available on 2020-10-15]
DOI:
10.1016/j.immuni.2019.09.001

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