Eliciting a single amino acid change by vaccination generates antibody protection against group 1 and group 2 influenza A viruses

Rashmi Ray; Faez Amokrane Nait Mohamed; Daniel P Maurer; Jiachen Huang; Berk A Alpay; Larance Ronsard; Zhenfei Xie; Julianna Han; Monica Fernandez-Quintero; Quynh Anh Phan; Rebecca L Ursin; Mya Vu; Kathrin H Kirsch; Thavaleak Prum; Victoria C Rosado; Thalia Bracamonte-Moreno; Vintus Okonkwo; Julia Bals; Caitlin McCarthy; Usha Nair; Masaru Kanekiyo; Andrew B Ward; Aaron G Schmidt; Facundo D Batista; Daniel Lingwood

doi:10.1016/j.immuni.2024.03.022

Eliciting a single amino acid change by vaccination generates antibody protection against group 1 and group 2 influenza A viruses

Immunity. 2024 Apr 18:S1074-7613(24)00143-2. doi: 10.1016/j.immuni.2024.03.022. Online ahead of print.

Authors

Rashmi Ray¹, Faez Amokrane Nait Mohamed², Daniel P Maurer¹, Jiachen Huang³, Berk A Alpay⁴, Larance Ronsard¹, Zhenfei Xie¹, Julianna Han³, Monica Fernandez-Quintero⁵, Quynh Anh Phan¹, Rebecca L Ursin¹, Mya Vu¹, Kathrin H Kirsch¹, Thavaleak Prum¹, Victoria C Rosado¹, Thalia Bracamonte-Moreno¹, Vintus Okonkwo¹, Julia Bals¹, Caitlin McCarthy¹, Usha Nair¹, Masaru Kanekiyo⁶, Andrew B Ward³, Aaron G Schmidt⁷, Facundo D Batista⁸, Daniel Lingwood⁹

Affiliations

¹ The Ragon Institute of Mass General, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA.
² The Ragon Institute of Mass General, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA. Electronic address: fnaitmohamed@mgh.harvard.edu.
³ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁴ Systems, Synthetic, and Quantitative Biology Program, Harvard University, Cambridge, MA 02138, USA; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.
⁵ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of General, Inorganic and Theoretical Chemistry, Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82/III, 6020 Innsbruck, Austria.
⁶ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 40 Convent Drive, Bethesda, MD 20892-3005, USA.
⁷ The Ragon Institute of Mass General, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: aschmidt@crystal.harvard.edu.
⁸ The Ragon Institute of Mass General, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; Department of Biology, The Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: fbatista1@mgh.harvard.edu.
⁹ The Ragon Institute of Mass General, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA. Electronic address: dlingwood@mgh.harvard.edu.

PMID: 38670113
DOI: 10.1016/j.immuni.2024.03.022

Abstract

Broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem of influenza A viruses (IAVs) tend to be effective against either group 1 or group 2 viral diversity. In rarer cases, intergroup protective bnAbs can be generated by human antibody paratopes that accommodate the conserved glycan differences between the group 1 and group 2 stems. We applied germline-engaging nanoparticle immunogens to elicit a class of cross-group bnAbs from physiological precursor frequency within a humanized mouse model. Cross-group protection depended on the presence of the human bnAb precursors within the B cell repertoire, and the vaccine-expanded antibodies enriched for an N55T substitution in the CDRH2 loop, a hallmark of the bnAb class. Structurally, this single mutation introduced a flexible fulcrum to accommodate glycosylation differences and could alone enable cross-group protection. Thus, broad IAV immunity can be expanded from the germline repertoire via minimal antigenic input and an exceptionally simple antibody development pathway.

Keywords: human antibody repertoire; immunogen; influenza virus; somatic hypermutation; universal; vaccine.