Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus
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.; Rohrer, Daniel; Lonberg, Nils; Chackerian, Bryce; Graham, Barney S.; Kanekiyo, Masaru; Shalek, Alexander K; Lingwood, Daniel; ... Show more Show less
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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.
DepartmentMassachusetts Institute of Technology. Institute for Medical Engineering and Science; Massachusetts Institute of Technology. Department of Chemistry; David H. Koch Institute for Integrative Cancer Research at MIT; Broad Institute of MIT and Harvard
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
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