Current seasonal inactivated influenza vaccines (S-IIV) provide suboptimal protection against antigenic drift, and repeated annual vaccinations are recommended to sustain antibody levels. We assessed protection from influenza challenge in a mouse model of repeated S-IIV in parallel to a human randomized control trial of vaccine immunogenicity. In a mouse model, we found that the timing of vaccination and antigenic change impacted the quality of immune responses for S-IIV. When mice received two different H3N2 strains (A/Hong Kong/4801/2014 and A/Singapore/INFIMH-16-0019/2016) by staggered timing of vaccination, there was a higher H3-HA antibody and B-cell memory responses than four cumulative vaccinations or when two vaccinations were successive. Interestingly, after challenge with a lethal drifted H3N2 virus (A/Hong Kong/1/1968), mice with staggered vaccination were unable to produce high titers of antibodies specific to the challenge strain compared to other vaccination regimens due to high levels of vaccine specific cross-reactive antibodies. All S-IIV vaccination regimens resulted in protection, in terms of viral loads and survival, from lethal challenge, whilst lung IL-6 and inflammation was lowest in staggered or cumulative vaccination groups, indicating further advantage. Therefore, repeated vaccination may result in higher titer antibody response that can reduce recognition of new viruses but remain protective against infection.