Influenza preimmunity increases vaccination efficacy by influencing antibody longevity, neutralization activity, and epitope specificity

Influenza virus infections are a recurrent public health problem causing millions of hospitalizations each year despite vaccination efforts. The well-known yearly cycling of influenza viruses is the result of the reciprocal and coevolutionary relationship between the host and virus. Together, from the frequent infections and yearly vaccinations humans build a complex immune history over their lifetimes. Despite the prominence of immune history, vaccines are rarely evaluated in the imprinted (preimmune) host. We developed a ferret model for this purpose where ferrets were imprinted with a sublethal dose of the historical seasonal H1N1 strain A/USSR/90/1977 (USSR/77). A +60 day recovery period was given to build immune memory prior to vaccination with a split virion QIV vaccine. To evaluate protection, the ferrets 2 were challenged with a 2009 H1N1 pandemic virus matching the vaccine antigens. The preimmunevaccinated ferrets did not experience significant disease during challenge while the naive-vaccinated group were the most severe. Hemagglutination inhibition (HAI) assays showed that preimmune ferrets had a faster and longer antibody response post vaccination for all vaccine antigens compared to minimal HAI responses in the naive-vaccinated group. To investigate the immune mechanisms leading to disease protection in the preimmune ferrets, we performed microneutralization and isotype ELISA assays. Microneutralization suggested preimmune ferrets developed antibodies that were more functional for virus neutralization. Antibody isotype profiling indicated that virus specific antibodies in the preimmunevaccinated ferrets was dominated by the IgG isotype suggesting B cell maturity and possible plasticity in a pre-existing B cell. Surprisingly, the naive-vaccinated ferrets developed a more severe disease with less virus neutralization suggesting improper immunological processing of vaccine antigens. Together, these results showed the preimmune host had greater responses to vaccination, and the predominant IgG virus specific antibodies suggested a flexible long-lived B cell response. These results are important and should be considered for vaccine design.