Germline-encoded affinity for cognate antigen enables vaccine amplification of a human broadly neutralizing response against influenza virus

  • Biology
  • Genomics
  • Immunology
  • Infectious Disease
  • Medicine
  • Sam Kazer
  • Alex K. Shalek
  • Sangesland et al.▾
    Sangesland, M., Ronsard, L., Kazer, S.W., Bals, J., Boyoglu-Barnum, S., Yousif, A.S., Barnes, R., Feldman, J., Quirindongo-Crespo, M., McTamney, P.M., Rohrer, D., Lonberg, N., Chackerian, B., Graham, B.S., Kanekiyo, M., Shalek, A.K., Lingwood, D.
  • Immunity , Volume 51
  • October, 2019
Biology
Genomics
Immunology
Infectious Disease
Medicine
Sam Kazer
Alex K. Shalek

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.

Germline-encoded affinity for cognate antigen enables vaccine amplification of a human broadly neutralizing response against influenza virus