Enhancing the cross protective efficacy of live attenuated influenza virus vaccine by supplemented vaccination with M2 ectodomain virus-like particles.

Current influenza vaccines including live attenuated influenza virus (LAIV) provide suboptimal protection against drift and potential pandemic strains. We hypothesized that supplementing LAIV with a highly conserved antigenic target M2 ectodomain (M2e) would confer cross-protection by inducing humoral and cellular immune responses to conserved antigenic targets. Intranasal vaccination with LAIV (A/Netherlands/602/09, H1N1) supplemented with tandem repeat M2e containing virus-like particles (M2e5x VLP) induced M2e- and virus-specific antibodies. Upon heterosubtypic virus challenge, M2e5x VLP-supplemented LAIV vaccination of mice induced significantly improved cross protection by preventing weight loss and lowering lung viral titers. Further mechanistic studies on heterosubtypic immunity suggest that T cell responses to M2e and nucleoprotein as well as systemic and mucosal antibodies to M2e and viruses might be contributing to cross protection. Therefore, this study demonstrates a novel vaccination strategy to improve the cross protective efficacy of LAIV by supplementing with a conserved M2e antigenic target.