Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans

• Type of Material: Article
• Authors: Ali Ellebedy, Emory University; Florian Krammer, Icahn Sch Med Mt Sinai; Gui-Mei Li, Emory University; Matthew S. Miller, Icahn Sch Med Mt Sinai; Christopher Chiu, Emory University; Jens Wrammert, Emory University; Cathy Y. Chang, Emory University; Carl Davis, Emory University; Megan McCausland, Emory University; Rivka Elbein, Emory University; Srilatha Edupuganti, Emory University; Paul Spearman, Emory University; Sarah F. Andrews, University of Chicago; Patrick C. Wilson, University of Chicago; Adolfo Garcia-Sastre, Icahn Sch Med Mt Sinai; Mark Mulligan, Emory University; Aneesh Mehta, Emory University; Peter Palese, Icahn Sch Med Mt Sinai; Rafi Ahmed, Emory University
• Language: English
• Date: 2014-09-09
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2014 National Academy of Sciences. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1414070111
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 111
• Issue: 36
• Start Page: 13133
• End Page: 13138
• Grant/Funding Information: Some of clinical studies were supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award UL1TR000454.; This work was funded in parts by National Institute of Allergy and Infectious Diseases Contracts HHSN266200700006C (to R.A. and P.C.W.) and HHSN26620070010C (to A.G.-S. and P.P.); Contract HHSN272200800005C (to M.J.M.), which supported the H5N1 vaccination trial; Grant 1P01AI097092 (to P.P., P.C.W., and R.A.); Grant 1U19AI109946-01 (to P.P.); the Georgia Research Alliance (M.J.M.); Children’s Healthcare of Atlanta (M.J.M.); the National Center for Advancing Translational Sciences of the National Institutes of Health under Award UL1TR000454 (to M.J.M.); Training Grant T32AI074492 from the National Institute of Allergy and Infectious Diseases (to A.H.E.); Erwin Schrödinger Fellowship J3232 from the Austrian Science Fund (to F.K.); a Canadian Institutes of Health Research Postdoctoral fellowship (to M.S.M.).
• Keywords: IMMUNITY; VIRUS; IMMUNOGENICITY; breadth; ANTIGENIC STRUCTURE; MEMORY B-CELLS; Science & Technology - Other Topics; neutralization; FUSION; Science & Technology; stalk; immunoglobulin; Multidisciplinary Sciences; NEUTRALIZATION

Abstract

The emergence of pandemic influenza viruses poses a major public health threat. Therefore, there is a need for a vaccine that can induce broadly cross-reactive antibodies that protect against seasonal as well as pandemic influenza strains. Human broadly neutralizing antibodies directed against highly conserved epitopes in the stem region of influenza virus HA have been recently characterized. However, it remains unknown what the baseline levels are of antibodies and memory B cells that are directed against these conserved epitopes. More importantly, it is also not known to what extent anti-HA stem B-cell responses get boosted in humans after seasonal influenza vaccination. In this study, we have addressed these two outstanding questions. Our data show that: (i) antibodies and memory B cells directed against the conserved HA stem region are prevalent in humans, but their levels are much lower than B-cell responses directed to variable epitopes in the HA head; (ii) current seasonal influenza vaccines are efficient in inducing B-cell responses to the variable HA head region but they fail to boost responses to the conserved HA stem region; and (iii) in striking contrast, immunization of humans with the avian influenza virus H5N1 induced broadly cross-reactive HA stem-specific antibodies. Taken together, our findings provide a potential vaccination strategy where heterologous influenza immunization could be used for increasing the levels of broadly neutralizing antibodies and for priming the human population to respond quickly to emerging pandemic influenza threats.