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

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 (V) 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 V-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.