@article{6327763108da4a1d9e38831e651bcc55,
title = "A single-shot adenoviral vaccine provides hemagglutinin stalk-mediated protection against heterosubtypic influenza challenge in mice",
abstract = "Conventional influenza vaccines fail to confer broad protection against diverse influenza A viruses with pandemic potential. Efforts to develop a universal influenza virus vaccine include refocusing immunity towards the highly conserved stalk domain of the influenza virus surface glycoprotein, hemagglutinin (HA). We constructed a non-replicating adenoviral (Ad) vector, encoding a secreted form of H1 HA, to evaluate HA stalk-focused immunity. The Ad5_H1 vaccine was tested in mice for its ability to elicit broad, cross-reactive protection against homologous, heterologous, and heterosubtypic lethal challenge in a single-shot immunization regimen. Ad5_H1 elicited hemagglutination inhibition (HI+) active antibodies (Abs), which conferred 100% sterilizing protection from homologous H1N1 challenge. Furthermore, Ad5_H1 rapidly induced H1-stalk-specific Abs with Fc-mediated effector function activity, in addition to stimulating both CD4+ and CD8+ stalk-specific T cell responses. This phenotype of immunity provided 100% protection from lethal challenge with a head-mismatched, reassortant influenza virus bearing a chimeric HA, cH6/1, in a stalk-mediated manner. Most importantly, 100% protection from mortality following lethal challenge with a heterosubtypic avian influenza virus, H5N1, was observed following a single immunization with Ad5_H1. In conclusion, Ad-based influenza vaccines can elicit significant breadth of protection in naive animals and could be considered for pandemic preparedness and stockpiling.",
keywords = "adenoviral, adenovirus, hemagglutinin, heterosubtypic, immunogenicity, influenza, stalk, stem, universal vaccine, vaccine, vector",
author = "Bliss, {Carly M.} and Freyn, {Alec W.} and Caniels, {Tom G.} and Leyva-Grado, {Victor H.} and Raffael Nachbagauer and Weina Sun and Tan, {Gene S.} and Gillespie, {Virginia L.} and Meagan McMahon and Florian Krammer and Hill, {Adrian V. S.} and Peter Palese and Lynda Coughlan",
note = "Funding Information: We would like to thank Dr. Alison Turner and Louisa Rose at The Jenner Institute's Viral Vector Core Facility for assistance in generating recombinant adenoviral vectors. We thank Dr. Carole Henry and Dr. Patrick Wilson (University of Chicago) for providing plasmids to express CR9114 and FI6 mAbs. We would like to acknowledge the members of the Flow Cytometry Core and The Center for Comparative Medicine and Surgery (CCMS) at the Icahn School of Medicine at Mount Sinai (ISMMS), in addition to Chen Wang, the Palese laboratory manager at ISMMS. This research project was supported in part by funding from NIH /NIAID 1R21AI146529 (L.C.) and NIH/ NIAID CEIRS HHSN272201400008C (L.C., P.P., and F.K.) and the CEIRS Training Program ( HHSN272201400008C ). The work was also partially funded by NIAID grant P01 AI097092-07 (P.P.), NIAID grant R01 AI145870-03 (P.P.), and the NIAID Collaborative Influenza Vaccine Innovation Centers (CIVIC) contract 75N93019C00051 (P.P., F.K., and W.S.). L.C. was funded by the HC Roscoe Grant 2016 from the British Medical Association (BMA) Foundation for Medical Research, and the US Graduate Women in Science (GWIS) 2017 Nell Mondy and Monique Braude Fellowship. Figures were created with BioRender— biorender.com . Work was performed at Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA. Funding Information: We would like to thank Dr. Alison Turner and Louisa Rose at The Jenner Institute's Viral Vector Core Facility for assistance in generating recombinant adenoviral vectors. We thank Dr. Carole Henry and Dr. Patrick Wilson (University of Chicago) for providing plasmids to express CR9114 and FI6 mAbs. We would like to acknowledge the members of the Flow Cytometry Core and The Center for Comparative Medicine and Surgery (CCMS) at the Icahn School of Medicine at Mount Sinai (ISMMS), in addition to Chen Wang, the Palese laboratory manager at ISMMS. This research project was supported in part by funding from NIH/NIAID 1R21AI146529 (L.C.) and NIH/NIAID CEIRS HHSN272201400008C (L.C. P.P. and F.K.) and the CEIRS Training Program (HHSN272201400008C). The work was also partially funded by NIAID grant P01 AI097092-07 (P.P.), NIAID grant R01 AI145870-03 (P.P.), and the NIAID Collaborative Influenza Vaccine Innovation Centers (CIVIC) contract 75N93019C00051 (P.P. F.K. and W.S.). L.C. was funded by the HC Roscoe Grant 2016 from the British Medical Association (BMA) Foundation for Medical Research, and the US Graduate Women in Science (GWIS) 2017 Nell Mondy and Monique Braude Fellowship. Figures were created with BioRender?biorender.com. Work was performed at Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA. Conceptualization, L.C.; methodology, C.M.B. A.W.F. R.N. W.S. M.M. and L.C.; validation, C.M.B. and L.C.; formal analysis, A.W.F. C.M.B. V.L.G. and L.C.; investigation, C.M.B. A.W.F. W.S. T.G.C. V.L.G. V.H.L.-G. and L.C.; resources, R.N. G.S.T. M.M. F.K. A.V.S.H. P.P. and L.C.; writing ? original draft, C.M.B. and L.C.; writing ? review and editing, all authors contributed to review and editing of the final draft; visualization, C.M.B. and L.C.; supervision, L.C.; funding acquisition, P.P. and L.C. The Icahn School of Medicine has submitted patents covering a universal influenza virus vaccine (P.P. W.S. and F.K.). A.V.S.H. is named as an inventor on a patent covering use of adenoviral vectored vaccines and is a co-founder of, consultant to, and shareholder in Vaccitech plc, which is developing adenoviral vectored vaccines. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = may,
day = "4",
doi = "https://doi.org/10.1016/j.ymthe.2022.01.011",
language = "English",
volume = "30",
pages = "2024--2047",
journal = "Molecular therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "5",
}