The Impact of Vaccine Composition and Pre-Existing Immunity on Human Adaptive Immune Responses After Influenza Vaccination

Abstract

Seasonal vaccination is the most effective way to protect against mortality and morbidity caused by the influenza virus, especially among vulnerable populations. Influenza vaccines are targeted towards hemagglutinin (HA), the surface protein of the virus, which undergoes frequent antigenic drift and shift. The antigenic drift of HA leads to yearly vaccine reformulations and re-administrations. Although vaccine formulations are determined by the WHO and CDC, vaccines are manufactured in different ways, using either split, subunit, or recombinant methods of production, and seasonal vaccines are not always effective.

The overall goal of this dissertation was to examine how vaccine formulations and immune history impact the effectiveness of influenza vaccines using both an experimental and population-based approach. Naïve mice were vaccinated with either a split or subunit licensed influenza vaccine and the antibody responses were found to match the protein composition found by western blot. We also investigated human CD4 T cell and antibody responses to different influenza vaccines, and whether baseline immunity and vaccination history relate to vaccine responses.

We analyzed a 5-year cohort of subjects who were vaccinated with one of three licensed vaccine types. Plasma and PBMCs were collected from these subjects at baseline and several time points after vaccination, and CD4 T cell and antibody assays were completed to measure the responses to vaccination. We compared the CD4 T cell and antibody responses between subjects who received different vaccine types. We also compared the vaccine responses in subjects with differing vaccination histories, and those with differing frequencies of pre-existing influenza specific CD4 T cells and antibodies.

The studies revealed first that subjects who were vaccinated with recombinant HA vaccines exhibited more robust CD4 T cell and antibody responses compared to those who received subunit and split vaccines. Second, subjects who were vaccinated in the previous season have higher pre-existing antibodies. Third, subjects who exhibited these high levels of baseline antibodies had lowered antibody and CD4 T cell responses to vaccination, likely contributing to the heterogeneity in vaccination responses. Collectively, these studies revealed vaccine formulation, vaccine history, and pre-existing immunity to influenza proteins can all impact vaccine effectiveness.