A recombinant H7N9 influenza vaccine with the H7 hemagglutinin transmembrane domain replaced by the H3 domain induces increased cross-reactive antibodies and improved interclade protection in mice

Antiviral Res. 2017 Jul:143:97-105. doi: 10.1016/j.antiviral.2017.03.029. Epub 2017 Apr 10.

Abstract

Influenza A H7N9 virus is the latest emerging pandemic threat, and has rapidly diverged into three clades, demanding a H7N9 virus vaccine with broadened protection against unmatched strains. Hemagglutinin (HA)-based structural design approaches for stabilizing HA proteins have provided excitingly promising results. However, none of the HA-based structural design approaches has been applied to a recombinant replicative influenza virus. Here we report that our HA-based structural design approach is a first in the field to generate a recombinant replicative H7N9 virus (H7N9-53TM) showing broadened protection. The H7N9-53TM contains a replaced H3 HA transmembrane domain (TM) in its HA protein. In mice, the inactivated H7N9-53TM vaccine induced significantly higher HI titers, HA-specific IgG titers, and IFN-γ production than the corresponding H7N9-53WT inactivated virus vaccine containing wild-type HA. More excitingly, mice immunized with the H7N9-53TM showed full protection against homologous (H7N9-53) and interclade (H7N9-MCX) challenges with minimal weight loss, no detectable lung viral loads, and no apparent pulmonary lesions and inflammation, while mice immunized with the H7N9-53WT showed partial protection (only 60% against H7N9-MCX) with severe weight loss, detectable lung viral loads, and severe pulmonary lesions and inflammation. In summary, this study presents a better vaccine candidate (H7N9-53TM) against H7N9 pandemics. Furthermore, our HA-based structural design approach would be conceivably applicable to other subtype influenza viruses, especially the viruses from emerging pandemic and epidemic influenza viruses such as H5N1 and H1N1.

Keywords: Cross-protection; H7N9; Hemagglutinin; Influenza A virus; Transmembrane domain; Trimerization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Viral / blood
  • Antibodies, Viral / immunology
  • Chickens
  • Cross Protection / immunology
  • Cross Reactions / immunology*
  • Disease Models, Animal
  • Dogs
  • Female
  • HEK293 Cells
  • Hemagglutinin Glycoproteins, Influenza Virus / genetics*
  • Hemagglutinin Glycoproteins, Influenza Virus / immunology*
  • Humans
  • Immunoglobulin G / blood
  • Inflammation
  • Influenza A Virus, H1N1 Subtype / immunology
  • Influenza A Virus, H5N1 Subtype / immunology
  • Influenza A Virus, H7N9 Subtype / genetics
  • Influenza A Virus, H7N9 Subtype / growth & development
  • Influenza A Virus, H7N9 Subtype / immunology*
  • Influenza A Virus, H7N9 Subtype / pathogenicity
  • Influenza Vaccines / immunology*
  • Interferon-gamma / blood
  • Lung / pathology
  • Lung / virology
  • Madin Darby Canine Kidney Cells
  • Mice
  • Mice, Inbred BALB C
  • Orthomyxoviridae Infections / prevention & control*
  • Phylogeny
  • Protein Domains / genetics
  • Protein Domains / immunology
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Survival Rate
  • Vaccination
  • Vaccines, Inactivated / immunology
  • Vaccines, Synthetic / genetics*
  • Vaccines, Synthetic / immunology*
  • Viral Load / drug effects
  • Weight Loss

Substances

  • Antibodies, Viral
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Immunoglobulin G
  • Influenza Vaccines
  • Recombinant Proteins
  • Vaccines, Inactivated
  • Vaccines, Synthetic
  • hemagglutinin, avian influenza A virus
  • Interferon-gamma