Multivalent Epigraph Hemagglutinin Vaccine Protects against Influenza B Virus in Mice

Influenza B virus is a respiratory pathogen that contributes to seasonal epidemics, accounts for approximately 25% of global influenza infections, and can induce severe disease in young children. While vaccination is the most commonly used method of preventing influenza infections, current vaccines only induce strain-specific responses and have suboptimal efficacy when mismatched from circulating strains. Further, two influenza B virus lineages have been described, B/Yamagatalike and B/Victoria-like, and the limited cross-reactivity between the two lineages provides an additional barrier in developing a universal influenza B virus vaccine. Here, we report a novel multivalent vaccine using computationally designed Epigraph hemagglutinin proteins targeting both the B/Yamagata-like and B/Victoria-like lineages. When compared to the quadrivalent commercial vaccine, the Epigraph vaccine demonstrated increased breadth of neutralizing antibody and T cell responses. After lethal heterologous influenza B virus challenge, mice immunized with the Epigraph vaccine were completely protected against both weight loss and mortality. The superior cross-reactive immunity conferred by the Epigraph vaccine immunogens supports their continued investigation as a universal influenza B virus vaccine

Immunogen Design for Influenza Virus Vaccines

Annually, influenza virus infects over 5% of the world population and remains a pressing issue for global health. Current seasonal vaccines provide strain-specific immunity, and the vaccinated population remains vulnerable to 40-90% of circulating strains each year. Novel vaccines which produce robust cross-reactive immunity are needed to protect against the diverse influenza population. Here we test several computationally optimized immunogens targeting the influenza hemagglutinin (HA) glycoprotein. Our lab developed a consensus, mosaic, and trivalent epigraph vaccine targeting human H1 influenza and expressed these immunogens in a recombinant adenoviral vector for analysis in mice. The consensus HA utilized the most common amino acid at each location in the HA protein. The vaccine induced strain-specific immunity and limited cross-protection. The mosaic HA immunogen utilized in silico recombination to include the most 9-mer potential B and T cell epitopes (PBTE) coverage. Mosaic vaccination produced stronger humoral immunity and protection compared to seasonal vaccines and wild type HA. Epigraph immunogens use a graph-based approach to include the highest PBTE coverage. The epigraph vaccine induced strong humoral immunity but low cellular immunity even against matched strains. Importantly, epigraph vaccination completely protected mice against three divergent influenza challenges. We also investigated the effect of multivalency on vaccine immunogenicity using epigraph HA immunogens targeting IBV. Trivalent HA vaccines were designed for each IBV lineage, Yamagata and Victoria. Only the first epigraph immunogen induced strong humoral immunity while all three immunogens induced cellular immunity in a strain-specific manner. There were no significant immunogenic changes when immunogens were delivered alone or in a trivalent vaccine. Furthermore, combining two trivalent vaccines into one hexavalent vaccine resulted in similar immunogenicity. Our data suggests that mosaic and epigraph strategies should be further investigated for their cross-reactive potential. We found that multivalent epigraph vaccine can maintain the vaccine efficacy of each individual immunogen. Together, our results suggest that a multivalent computationally optimized vaccine may be able to significantly improve the cross-reactivity of influenza vaccines

Multivalent Epigraph Hemagglutinin Vaccine Protects against Influenza B Virus in Mice

Influenza B virus is a respiratory pathogen that contributes to seasonal epidemics, accounts for approximately 25% of global influenza infections, and can induce severe disease in young children. While vaccination is the most commonly used method of preventing influenza infections, current vaccines only induce strain-specific responses and have suboptimal efficacy when mismatched from circulating strains. Further, two influenza B virus lineages have been described, B/Yamagata-like and B/Victoria-like, and the limited cross-reactivity between the two lineages provides an additional barrier in developing a universal influenza B virus vaccine. Here, we report a novel multivalent vaccine using computationally designed Epigraph hemagglutinin proteins targeting both the B/Yamagata-like and B/Victoria-like lineages. When compared to the quadrivalent commercial vaccine, the Epigraph vaccine demonstrated increased breadth of neutralizing antibody and T cell responses. After lethal heterologous influenza B virus challenge, mice immunized with the Epigraph vaccine were completely protected against both weight loss and mortality. The superior cross-reactive immunity conferred by the Epigraph vaccine immunogens supports their continued investigation as a universal influenza B virus vaccine