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Abstract
Highly pathogenic avian influenza (HPAI) H5 and H7 viruses are well-known for the severe disease outcomes and high mortality rates they can cause in both birds and humans. H2N2 influenza viruses caused the 1957 Asian flu pandemic and most adults today have little to no pre-existing immunity to H2 viruses. Therefore, H2 influenza viruses have the potential to cause a new pandemic. The overall objective of this dissertation is to develop and characterize the protective efficacy and immune responses elicited by multivalent COBRA hemagglutinin (HA) and neuraminidase (NA) vaccines against these pre-pandemic viruses.The effect of seasonal influenza virus-induced immunity has on pre-pandemic influenza vaccination was explored. Formulated with AddaVaxTM, a trivalent pre-pandemic COBRA HA vaccine consisting of H2, H5, H7 recombinant antigens was evaluated in both immunologically naïve and pre-immune DBA2/J mice. COBRA HA vaccinated mice with H1/H3 pre-immunity were protected from the lethal H2/H5 challenge, whereas mock vaccinated mice, with or without pre-immunity, were not protected from morbidity or mortality. Mice vaccinated twice with the trivalent COBRA HA vaccine had similar antibody responses, regardless of their pre-immune backgrounds.
A pentavalent vaccine was formulated with the same COBRA H2, H5, and H7 HA proteins in the trivalent vaccine in the previous study, and included the N1 and N2 NA proteins, at lower dose per antigen. The pentavalent COBRA HA/NA vaccinated mice were protected from a lethal H7N9 challenge. Lung pathology and inflammation were observed in the mock vaccinated mice, but not in the COBRA HA/NA vaccinated mice, total Ig and H7-specific antibody-secreting cells (ASCs) were only boosted in the COBRA HA/NA vaccinated mice following challenge.
The same pentavalent pre-pandemic vaccine was able to elicit four-month long protection against a clade 2.3.4.4 H5 viral challenge. All vaccinated mice survived with fast viral lung clearance and no lung pathology.
COBRA HA/NA vaccinated mice elicited antibodies that recognized a broader number of H2 and H5 strains than wild-type HA/NA vaccinated mice, however, the H7 component did not elicit broadly reactive antibodies against a panel of H7Nx viruses. Therefore, improved updated H7 COBRA HA vaccines need to be developed.