Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus
Name
nihms-1539316.pdf
Description
Accepted version
Size
3.73 MB
Format
Adobe PDF
Checksum (MD5)
968e910b207b007dccc4b635d0e2c5a6
Author(s)
Sangesland, Maya
Ronsard, Larance
Kazer, Samuel Weisgurt
Bals, Julia
Boyoglu-Barnum, Seyhan
Yousif, Ashraf S.
Barnes, Ralston
Feldman, Jared
Quirindongo-Crespo, Maricel
McTamney, Patrick M.
Date Issued
October 2019
Journal
Immunity
Publisher
Elsevier BV
Citation
Sangesland, Maya et al. "Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus." Immunity 51, 4 (October 2019): P735-749.e8 © 2019 Elsevier
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Chemistry
Broad Institute of MIT and Harvard
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.immuni.2019.09.001
