Addition of αGal HyperAcute™ technology to recombinant avian influenza vaccines induces strong low-dose antibody responses

PLoS One. 2017 Aug 7;12(8):e0182683. doi: 10.1371/journal.pone.0182683. eCollection 2017.

Abstract

Highly pathogenic avian influenza represents a severe public health threat. Over the last decade, the demand for highly efficacious vaccines against avian influenza viruses has grown, especially after the 2013 H7N9 outbreak in China that resulted in over 600 human cases with over 200 deaths. Currently, there are several H5N1 and H7N9 influenza vaccines in clinical trials, all of which employ traditional oil-in-water adjuvants due to the poor immunogenicity of avian influenza virus antigens. In this study, we developed potent recombinant avian influenza vaccine candidates using HyperAcute™ Technology, which takes advantage of naturally-acquired anti-αGal immunity in humans. We successfully generated αGal-positive recombinant protein and virus-like particle vaccine candidates of H5N1 and H7N9 influenza strains using either biological or our novel CarboLink chemical αGal modification techniques. Strikingly, two doses of 100 ng αGal-modified vaccine, with no traditional adjuvant, was able to induce a much stronger humoral response in αGT BALB/c knockout mice (the only experimental system readily available for testing αGal in vivo) than unmodified vaccines even at 10-fold higher dose (1000 ng/dose). Our data strongly suggest that αGal modification significantly enhances the humoral immunogenicity of the recombinant influenza vaccine candidates. Use of αGal HyperAcute™ technology allows significant dose-sparing while retaining desired immunogenicity. Our success in the development of highly potent H5N1 and H7N9 vaccine candidates demonstrated the potential of αGal HyperAcute™ technology for the development of vaccines against other infectious diseases.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Viral / immunology*
  • Epitopes / immunology
  • Female
  • Galactosyltransferases / deficiency
  • Galactosyltransferases / genetics
  • Gene Knockout Techniques
  • Immunity, Humoral / immunology
  • Influenza A Virus, H5N1 Subtype / immunology*
  • Influenza A Virus, H7N9 Subtype / immunology*
  • Influenza Vaccines / chemistry
  • Influenza Vaccines / genetics*
  • Influenza Vaccines / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Vaccines, Synthetic / chemistry
  • Vaccines, Synthetic / genetics*
  • Vaccines, Synthetic / immunology*
  • Vaccines, Virus-Like Particle / genetics
  • Vaccines, Virus-Like Particle / immunology

Substances

  • Antibodies, Viral
  • Epitopes
  • Influenza Vaccines
  • Vaccines, Synthetic
  • Vaccines, Virus-Like Particle
  • Galactosyltransferases
  • alpha 1,3 galactosyltransferase, mouse

Grants and funding

This study was supported by Defense Threat Reduction Agency Award HDTRA1-09-C-0014 to BioProtection Systems Corporation, a wholly-owned subsidiary of NewLink Genetics Corporation." The Defense Threat Reduction Agency (DTRA) provided support in the form of salaries for authors [WAC, JZ, KMH, CBM, SK, EJD, BKM], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. NewLink Genetics Corporation provided salary support for all authors of this manuscript, but the roles in study design, data collection and analysis, decision to publish, or preparation of the manuscript were limited to the authors of this manuscript, and did not extend to others in the organization.