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

Biology Biology
Genomics Genomics
Immunology Immunology
Infectious Disease Infectious Disease
Medicine Medicine
Alex K. Shalek Alex K. Shalek
Sam Kazer Sam Kazer

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


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.