The Use of Recombinant Hemagglutinin Proteins in the Study of Vaccination Against Emergent Influenza Viruses

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Microbiology and Immunology, 2011.The current model for influenza vaccine design and production is not adequate to respond against emergent strains with high rates of mortality. Recent evidence has established recombinant hemagglutinin protein (rHA) based vaccines as an alternative to subunit influenza vaccination. Here, we test the hypothesis that the structure of rHAs must closely match the native viral HA displayed on the surface of the virion, or infected cells, in order to elicit optimal stimulation and/or recognition of the HA-specific antibody response. We observed that organized rHA oligomeric structures consistently elicited higher hemagglutinin inhibition titers (HAI) and were better recognized by virus immune sera. These results informed the design of a sequential vaccination strategy against H5N1 avian influenza using drifted variant rHAs. Using this vaccination strategy we sought to test the hypothesis that pre-vaccination establishes a baseline HA-specific immunity, that even in the context of a poorly matched strain, is beneficial over the lack of pre-existing immunity. Protection upon viral challenge was observed in drift variant H5 HA vaccine recipients. Furthermore, this protection was primarily mediated through HA-specific antibodies, even when the antibody mediated neutralizing activity was undetectable. We did not observed detrimental effects to infection when vaccinated mice were challenged with a virus containing a mismatch H5 HA. This suggests that original antigenic sin (OAS) does not play a role in rHA vaccination. These findings suggest that prevaccination against H5 influenza has the potential to prime immunity against emerging drifted H5 strains, and could also lower the dose requirements of vaccination in the event of a pandemic