Pre-existing strain specific neutralising antibodies abrogates the induction of interferon type I and cytotoxic T cell responses to subsequent homotypic influenza A virus challenge.

Abstract

Current inactivated influenza vaccines target the generation of influenza-specific antibodies to provide homotypic protection. However, little is known about the effects of annual vaccinations on the immune response during a subsequent influenza A virus infection. Here, we investigated the effect of pre-existing influenza-specific neutralising antibodies on innate and adaptive immunity during secondary infections. We report that the presence of pre-existing antibodies abrogates the induction of interferon type I (IFN-I) responses and cytotoxic T cell responses during subsequent influenza A virus infection. Wild-type mice were vaccinated intravenously with gamma-irradiated A/PR8 [H1N1] (γ-A/PR8) and challenged 3 weeks later with live A/PR8, and splenocytes were analysed 24 hours later for IFN-I mediated lymphocyte activation using fluorescent activated cell sorting. Our data clearly show absence of partial systemic lymphocyte activation and IFN-I responses in vaccinated mice. Furthermore, co-administration of A/PR8-specific sera and live A/PR8 virus abrogated the ability of live virus to induce partial lymphocyte activation, IFN-I responses as well as cytotoxic T cell responses. To test the clinical relevance of this observation, mice were mock or vaccinated with γ-A/PR8 and infected 3 weeks later with sub-lethal dose of A/PR8. These animals were then challenged 3 weeks later with lethal dose of A/PC [H3N2]. Our data clearly illustrate the effect of pre-existing antibodies on the ability of sub-lethal infection to generate cytotoxic T cell mediated heterosubtypic protection. I also investigated whether IFN-I responses are required for the generation of cytotoxic T cell responses in the presence of neutralising immune sera. My data show that addition of exogenous Poly I:C to A/PR8 virus pre-treated with A/PR8-specific sera did not rescue the induction of cytotoxic T cell responses. Thus, the presence of neutralising antibodies abrogates the induction of IFN-I and cytotoxic T cell responses during homotypic influenza A virus re-infection.