Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus.
Sangesland, Maya 1; Ronsard, Larance 1; Kazer, Samuel W. 1,2,3; Bals, Julia 1; Boyoglu-Barnum, Seyhan 4; Yousif, Ashraf S. 1; Barnes, Ralston 5; Feldman, Jared 1; Quirindongo-Crespo, Maricel 5; McTamney, Patrick M. 6; Rohrer, Daniel 5; Lonberg, Nils 5; Chackerian, Bryce 7; Graham, Barney S. 4; Kanekiyo, Masaru 4; Shalek, Alex K. 1,2,3; Lingwood, Daniel 1,8,*
[Article]
Immunity.
51(4):735-749,749e1-749e8, October 15, 2019.
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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.
* Generated mice with user-defined human antibody VH genes and humanized CDRH3 diversity
* IGHV1-69 use enables elicitation of IgG against a "universal" site on influenza
* A single flu immunogen elicited gene-encoded broadly neutralizing antibodies
* The response was achieved when IGHV1-69 B cells were titrated to human frequency
(C) 2019Elsevier, Inc.