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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.

Original publication

DOI

10.1016/j.ymthe.2022.01.011

Type

Journal article

Journal

Molecular therapy : the journal of the American Society of Gene Therapy

Publication Date

05/2022

Volume

30

Pages

2024 - 2047

Addresses

Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.

Keywords

Animals, Mice, Inbred BALB C, Humans, Mice, Adenoviridae, Influenza A virus, Orthomyxoviridae Infections, Hemagglutinin Glycoproteins, Influenza Virus, Influenza Vaccines, Hemagglutinins, Antibodies, Viral, Influenza, Human, Influenza A Virus, H5N1 Subtype, Influenza A Virus, H1N1 Subtype