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Abstract
Influenza viruses (Orthomyxoviridae) cause acute respiratory diseases in humans that inflict a significant amount of morbidity and mortality every year around the world. Currently, vaccination is the most effective means of preventing seasonal influenza virus infections. However, traditional inactivated wild-type (WT) vaccines often have difficulty preventing illness caused by antigenically drifted strains. This is particularly true for influenza vaccines targeting H3N2 influenza viruses. Methodologies for generating broadly reactive influenza vaccines exist, and offer potential solutions to this problem, but over time the protection offered by these vaccines may wane as influenza viruses naturally evolve to evade host immunity. Thus, developing a method to update broadly reactive vaccine antigens to better protect against antigenically drifted co-circulating viral variants is of great importance. Building upon the computationally optimized broadly reactive antigen (COBRA) methodology for designing influenza hemagglutinin (HA) vaccines, this study describes a next-generation COBRA design methodology that utilizes current seasonal surveillance information, in combination with consensus-based layered sequence building approaches, to produce broadly reactive influenza HA vaccine candidates that can be updated in real time to keep pace with the ever-changing H3N2 viral landscape. Using this next-generation COBRA design methodology, multiple H3 HA vaccine antigens were generated on a seasonal basis from 2002-2019, and tested in influenza naive mice and pre-immune ferrets for their ability to elicit broadly reactive antibodies against historical H3N2 WT vaccine strain isolates as well as antigenically drifted co-circulating H3N2 strains. The H3 COBRA HA antigens were superior to WT HA vaccine antigens at eliciting sero-protective hemagglutination inhibition (HAI) reactive antibodies against historical and antigenically drifted H3N2 viruses from the last 15 years, and also displayed the ability to neutralize infections from newly emerging H3N2 isolates. The lead H3 COBRA HA candidates were then mixed with an H1 COBRA HA antigen, and they were administered together as a bivalent HA vaccine to mice that were pre-immune to both H1N1 and H3N2 influenza viruses. The bivalent mixtures of COBRA H1+H3 antigens outperformed bivalent mixtures of WT H1+H3 HA antigens by eliciting sero-protective HAI antibody titers against all of the H1N1 and H3N2 historical vaccine strain isolates from 2009-2019.