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.
Highlights
Vaccination has been a common strategy for preventing seasonal influenza worldwide over the last several decades [1]
In order to investigate potential of the αGal HyperAcuteTM technology on influenza vaccines, we developed strategies to conjugate αGal epitope on vaccine candidates, including recombinant proteins, virus-like particles (VLP) and inactivated virus
After successful demonstration of the enhanced humoral immunity generated by αGal-modification of H5N1 recombinant hemagglutinin (rHA) vaccines, we further investigated αGal HyperAcuteTM Technology on another highly pathogenic influenza strain H7N9, which caused 602 cases of human infection with 227 deaths reported from Mar 2013 to Feb 2015 [40,41,42,43]
Summary
Vaccination has been a common strategy for preventing seasonal influenza worldwide over the last several decades [1]. Current seasonal influenza vaccines include live-attenuated influenza vaccines (LAIV) such as FluMist, trivalent inactivated influenza vaccines (TIV) e.g. Fluzone, and the newly approved recombinant vaccine Flublok. Current seasonal influenza vaccines include live-attenuated influenza vaccines (LAIV) such as FluMist, trivalent inactivated influenza vaccines (TIV) e.g. Fluzone, and the newly approved recombinant vaccine Flublok1 ΑGal HyperAcute technology and recombinant avian influenza vaccines decision to publish, or preparation of the manuscript. 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
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