Vaccination is the best way to prevent influenza virus
infections, but the diversity of antigenically distinct isolates is a persistent challenge for
vaccine development. In order to conquer the antigenic variability and improve
influenza virus vaccine efficacy, our research group has developed computationally optimized broadly reactive
antigens (COBRAs) in the form of recombinant
hemagglutinins (rHAs) to elicit broader immune responses. However, previous COBRA H1N1
vaccines do not elicit immune responses that neutralize H1N1 virus strains in circulation during the recent years. In order to update our COBRA
vaccine, two new candidate COBRA HA
vaccines, Y2 and Y4, were generated using a new seasonal-based COBRA methodology derived from H1N1 isolates that circulated during 2013-2019. In this study, the effectiveness of COBRA Y2 and Y4
vaccines were evaluated in mice, and the elicited immune responses were compared to those generated by historical H1 COBRA HA and wild-type H1N1 HA
vaccines. Mice vaccinated with the next generation COBRA HA
vaccines effectively protected against morbidity and mortality after
infection with H1N1 influenza viruses. The
antibodies elicited by the COBRA HA
vaccines were highly cross-reactive with
influenza A (H1N1) pdm09-like viruses isolated from 2009 to 2021, especially with the most recent circulating viruses from 2019 to 2021. Furthermore, viral loads in lungs of mice vaccinated with Y2 and Y4 were dramatically reduced to low or undetectable levels, resulting in minimal
lung injury compared to wild-type HA
vaccines following H1N1 influenza virus
infection.