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

• Main Authors: Sangesland, Maya (Author), Ronsard, Larance (Author), Kazer, Samuel Weisgurt (Author), Bals, Julia (Author), Boyoglu-Barnum, Seyhan (Author), Yousif, Ashraf S. (Author), Barnes, Ralston (Author), Feldman, Jared (Author), Quirindongo-Crespo, Maricel (Author), McTamney, Patrick M. (Author), Rohrer, Daniel (Author), Lonberg, Nils (Author), Chackerian, Bryce (Author), Graham, Barney S. (Author), Kanekiyo, Masaru (Author), Shalek, Alexander K (Author), Lingwood, Daniel (Author)
• Other Authors: Massachusetts Institute of Technology. Institute for Medical Engineering & Science (Contributor), Massachusetts Institute of Technology. Department of Chemistry (Contributor), Broad Institute of MIT and Harvard (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor)
• Format: Article
• Language: English
• Published: Elsevier BV, 2020-10-30T17:10:54Z.
• Subjects: Article
• Online Access: Get fulltext

 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.