Current inactivated influenza vaccines target the generation of influenza-specific antibodies to provide homotypic protection. We investigated the effect of pre-existing influenza-specific neutralising antibodies on innate and adaptive immunity during secondary infections. Our data show that the presence of neutralising antibodies abrogates the induction of interferon type I (IFN-I) responses and cytotoxic T (Tc) cell responses during subsequent influenza A virus infection. Wild-type mice were vaccinated intravenously with gamma-irradiated A/PR8 [H1N1] (-A/PR8) and challenged 3 weeks later with live A/PR8. Serum IFN-I responses and IFN-I mediated lymphocyte activation were tested 24 hours post-challenge, while Tc cell responses were tested at day 7 post challenge. Our data clearly show absence of partial systemic lymphocyte activation, IFN-I, and Tc cell responses in vaccinated mice. To test the clinical relevance of this observation, mice were mock or vaccinated with ɣ-A/PR8 and infected 3 weeks later with sub-lethal dose of A/PR8. These animals were then challenged 3 weeks later with a 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 Tc mediated heterosubtypic protection. Therefore, vaccinated individuals that lack cross-reactive Tc cell responses may be at increased risk to sever infection with newly emerging influenza A viruses.