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

Maya Sangesland; Larance Ronsard; Samuel W Kazer; Julia Bals; Seyhan Boyoglu-Barnum; Ashraf S Yousif; Ralston Barnes; Jared Feldman; Maricel Quirindongo-Crespo; Patrick M McTamney; Daniel Rohrer; Nils Lonberg; Bryce Chackerian; Barney S Graham; Masaru Kanekiyo; Alex K Shalek; Daniel Lingwood

doi:10.1016/j.immuni.2019.09.001

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

Immunity. 2019 Oct 15;51(4):735-749.e8. doi: 10.1016/j.immuni.2019.09.001. Epub 2019 Sep 25.

Authors

Maya Sangesland¹, Larance Ronsard¹, Samuel W Kazer², Julia Bals¹, Seyhan Boyoglu-Barnum³, Ashraf S Yousif¹, Ralston Barnes⁴, Jared Feldman¹, Maricel Quirindongo-Crespo⁴, Patrick M McTamney⁵, Daniel Rohrer⁴, Nils Lonberg⁴, Bryce Chackerian⁶, Barney S Graham³, Masaru Kanekiyo³, Alex K Shalek², Daniel Lingwood⁷

Affiliations

¹ The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA.
² The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Massachusetts Institute of Technology and Harvard University, 415 Main St, Cambridge, MA 02142, USA.
³ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, 40 Convent Drive, Bethesda, MD 20892-3005, USA.
⁴ Bristol-Myers Squibb, 700 Bay Road, Redwood City, CA 94063-2478, USA.
⁵ Medimmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
⁶ Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, 2425 Camino de Salud, Albuquerque, NM 87106, USA.
⁷ The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA. Electronic address: dlingwood@mgh.harvard.edu.

Abstract

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_H) 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_H-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.

Keywords: BCR; conserved site of vulnerability; influenza; innate-like; rational vaccine; universal.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antibodies, Viral / genetics
Antibodies, Viral / metabolism*
Antibody Affinity
B-Lymphocytes / immunology*
Broadly Neutralizing Antibodies / genetics
Broadly Neutralizing Antibodies / metabolism*
Complementarity Determining Regions / genetics
Germ-Line Mutation / genetics
Hemagglutinin Glycoproteins, Influenza Virus / immunology
Humans
Immunity, Humoral
Immunization, Secondary
Immunoglobulin Heavy Chains / genetics
Influenza A virus / physiology*
Influenza Vaccines / immunology*
Influenza, Human / immunology*
Mice
Mice, Transgenic
Nanoparticles
Protein Engineering
Receptors, Antigen, B-Cell / genetics*

Substances

Antibodies, Viral
Broadly Neutralizing Antibodies
Complementarity Determining Regions
Hemagglutinin Glycoproteins, Influenza Virus
Immunoglobulin Heavy Chains
Influenza Vaccines
Receptors, Antigen, B-Cell
hemagglutinin, human influenza A virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding