A single-shot adenoviral vaccine provides hemagglutinin stalk-mediated protection against heterosubtypic influenza challenge in mice

Carly M. Bliss, Alec W. Freyn, Tom G. Caniels, Victor H. Leyva-Grado, Raffael Nachbagauer, Weina Sun, Gene S. Tan, Virginia L. Gillespie, Meagan McMahon, Florian Krammer, Adrian V.S. Hill, Peter Palese, Lynda Coughlan

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish
Pages (from-to)2024-2047
Number of pages24
JournalMolecular Therapy
Volume30
Issue number5
DOIs
StatePublished - 4 May 2022

Keywords

  • adenoviral
  • adenovirus
  • hemagglutinin
  • heterosubtypic
  • immunogenicity
  • influenza
  • stalk
  • stem
  • universal vaccine
  • vaccine
  • vector

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