Aggregation by peptide conjugation rescues poor immunogenicity of the HA stem

PLoS One. 2020 Nov 2;15(11):e0241649. doi: 10.1371/journal.pone.0241649. eCollection 2020.

Abstract

Influenza virus infection is a global public health threat. Current seasonal influenza vaccines are efficacious only when vaccine strains are matched with circulating strains. There is a critical need for developing "universal" vaccines that protect against all influenza viruses. HA stem is a promising target for developing broad-spectrum influenza vaccines due to its relatively conserved feature. However, HA stem is weakly immunogenic when administered alone in a soluble form. Several approaches have been employed to improve the immunogenicity of HA stem, including conjugation of HA stem with a highly immunogenic carrier protein or displaying HA stem on a nanoparticle scaffold. Converting a weakly immunologic protein into a multimer through aggregation can significantly enhance its immunogenicity, with some multimeric protein aggregates previously shown to be more immunogenic than their soluble counterparts in animal models. Here, we show that a chemically coupling a peptide derived from the head domain of PR8 HA (P35) with the poorly immunogenic HA stem protein results in aggregation of the HA stem which significantly increases stem-specific B cell responses following vaccination. Importantly, vaccination with this conjugate in the absence of adjuvant still induced robust B cell responses against stem in vivo. Improving HA stem immunogenicity by aggregation provides an alternative avenue to conjugation with exotic carrier proteins or nanoparticle formulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • Cells, Cultured
  • Female
  • Hemagglutinin Glycoproteins, Influenza Virus / chemistry
  • Hemagglutinin Glycoproteins, Influenza Virus / immunology*
  • Immunoconjugates / chemistry
  • Immunoconjugates / immunology
  • Immunogenicity, Vaccine*
  • Influenza Vaccines / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Peptide Fragments / chemistry
  • Peptide Fragments / immunology

Substances

  • Hemagglutinin Glycoproteins, Influenza Virus
  • Immunoconjugates
  • Influenza Vaccines
  • Peptide Fragments

Grants and funding

This work was supported by NHMRC grants APP1149990 and GNT112909. WJ is supported by a Melbourne International Research Scholarship and Melbourne International Fee Remission Scholarship. JAJ, AKW and SJK are supported by NHMRC fellowships.