Abstract
Conserved epitopes on the influenza hemagglutinin (HA) stem are an attractive target for universal vaccine strategies as they elicit broadly neutralizing antibodies. Such antibody responses to stem-specific epitopes have been extensively characterized for HA subtypes H1 and H5 in humans. H2N2 influenza virus circulated 50 years ago and represents a pandemic threat due to the lack of widespread immunity, but, unlike H1 and H5, the H2 HA stem contains Phe45HA2 predicted to sterically clash with HA stem-binding antibodies characterized to date. To understand the effect of Phe45HA2, we compared the HA stem-specific B cell response in post hoc analyses of two phase 1 clinical trials, one testing vaccination with an H2 ferritin nanoparticle immunogen (NCT03186781) and one with an inactivated H5N1 vaccine (NCT01086657). In H2-naive individuals, the magnitude of the B cell response was equivalent, but H2-elicited HA stem-binding B cells displayed greater cross-reactivity than those elicited by H5. However, in individuals with childhood H2 exposure, H5-elicited HA stem-binding B cells also displayed high cross-reactivity, suggesting recall of memory B cells formed 50 years ago. Overall, we propose that a one-residue difference on an HA immunogen can alter establishment and expansion of broadly neutralizing memory B cells. These data have implications for stem-based universal influenza vaccination strategies.
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Data availability
Cryo-EM maps and fitted coordinates were deposited in the Electron Microscopy Data Bank with accession codes 23098 and 23816 and in the Protein Data Bank with IDs 7L0L and 7MFG. Immunoglobulin sequences are available in GenBank under accession numbers OK669229–OK670607. Source data for Figs. 2–6 and Supplementary Figs. 1–4 and 6 are included as supplementary files. Any additional data are available upon reasonable request from the corresponding authors. Source data are provided with this paper.
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Acknowledgements
We thank D. Ambrozak for help with flow cytometry sorting. Support for this work was provided by the Intramural Research Programs of the Vaccine Research Center and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Some of this work was performed at the Simons Electron Microscopy Center and the National Resource for Automated Molecular Microscopy, located at the New York Structural Biology Center, supported by grants from the Simons Foundation (SF349247) and the National Institute of General Medical Sciences (GM103310), with additional support from NYSTAR and the New York State Assembly Majority. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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Conceptualization, S.F.A.; methodology, S.F.A. and A.C.; formal analysis, S.F.A., R.R., C.-H.S. and J.C.B.; investigation, S.F.A., J.E.R., J.G., R.A.G., C.S., F.C., L.Y.C., A.C., D.R.H., A.S.O., A.N. and T.Z.; resources, K.V.H., G.L.C. and J.E.L.; writing—original draft, S.F.A.; writing—review and editing, S.F.A., J.C.B., K.V.H., M.K., J.R.M., P.D.K. and A.B.M.; visualization, S.F.A. and J.G.; supervision, S.F.A., G.L.C., J.R.M., B.S.G., M.K., J.E.L., P.D.K. and A.B.M.; funding acquisition, A.B.M.
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J.C.B., B.S.G., J.R.M., M.K. and P.D.K. are named inventors of US patents 9,441,019, 10,137,190 and 10,363,301 on influenza hemagglutinin nanoparticle vaccines and stabilized hemagglutinin stem trimers and of several pending applications on related technologies filed by the Department of Health and Human Services (National Institutes of Health).
Peer review information Nature Medicine thanks the anonymous reviewers for their contribution to the peer review of this work. Alison Farrell was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Andrews, S.F., Raab, J.E., Gorman, J. et al. A single residue in influenza virus H2 hemagglutinin enhances the breadth of the B cell response elicited by H2 vaccination. Nat Med 28, 373–382 (2022). https://doi.org/10.1038/s41591-021-01636-8
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DOI: https://doi.org/10.1038/s41591-021-01636-8
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