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Abstract
Influenza B viruses (IBVs) can cause severe disease and death much like influenza A viruses (IAVs), and the prevention of influenza virus infection by vaccination is the best way to minimize severe cases. While better than going unvaccinated, current standard of care vaccines are often ineffective. Our lab designed more broadly-reactive influenza B HA antigens using a layered consensus approach termed computationally optimized broadly reactive antigen (COBRA). I evaluated these HA candidates compared to wild-type HA vaccinations in naïve mice and in ferrets pre-immunized to IBV. B-COBRA-2 (BC2) HA elicited neutralizing antibodies with high HAI titers against all IBVs regardless of pre-immunization whereas wild-type IBV HA antigens preferentially boosted titers against viruses from the same lineage. Importantly, this study showed that a single IBV HA developed using the COBRA methodology elicited protective antibodies against current and future drifted IBVs from both lineages. While other groups have demonstrated cross-lineage antibodies directed to the more conserved stem region, this is the first known HA-directed antigen capable of this from what I have seen published. I wanted to further explore the cross-reactive nature of B-COBRA-2 (BC2) through measuring antigen specific memory B cells in mice with different pre-existing immunities. Overall, this study further highlighted the lineage-specificity of immunological imprinting with IBV and demonstrated an increased activation of predominantly IgM+ antigen-specific memory B cells by broadly-reactive influenza HA antigens. Lastly, I wanted to take the success of BC2 HA and modernize it to better cover influenza viruses that have circulated since it was designed. And following the disappearance of the B/YAM lineage in 2020, I particularly wanted to show improved antibody responses towards B/VIC-like strains compared to BC2 HA. Through various point mutations made to the BC2 HA sequence, I designed a new sequence which became dubbed BC17 HA. In naïve mice and pre-immune mice, I demonstrated that BC17 HA elicited not only improved B/VIC responses compared to BC2 HA, but better responses than the B/VIC wild-type comparator.