Influenza-specific ex vivo immune responses in ferrets commensurate with number of vaccinations despite decreased protection for repeat vaccines

Abstract There is controversy in the literature whether consecutive year influenza vaccinations lead to decreased vaccine efficacy. Evidence for this effect is strongest in the context of repeated H3N2 vaccinations. As recently reported (NPJ Vaccines 4:28 (2019)), we recreated this phenomenon in the ferret model of influenza. Ferrets exposed to consecutive year vaccinations had significantly increased weight loss, viral shedding and fever after A/Hong Kong/4801/2014 (HK4801) virus challenge than ferrets only exposed to the 2017–2018 vaccine. One possible explanation for this phenomenon is that the repeated vaccination induces non-protective antibodies against influenza virus, which might include low avidity antibodies, non-neutralizing antibodies, and antibodies that otherwise do not elicit a protective immune response. Ferrets that received repeated vaccination had higher avidity antibodies to HK4801 HA at Day 2 and 14 post-infection than did the other two groups. Preliminary data do not support increased levels of HA stem-binding antibodies in repeat vaccinees’ serum. NA and NP are two additional viral proteins expressed on the cell surface, with greater or lesser evidence for their role in protective antibody responses, respectively. Serum reactivity to both proteins correlated with the number of vaccinations. Together, these results do not support a model of increased non-protective antibodies after repeat vaccination. Furthermore, the breadth of the T cell response against H3N2 viruses from different clades was similar between both vaccinated groups. Ongoing studies continue to explore the mechanism for the decreased protection observed in the repeat vaccination group compared with the single year vaccination group.