Influenza virus infection continues to impose significant global health and economic consequences each year despite large-scale vaccination efforts. Constant antigenic changes along with the threat of pandemic strains necessitate periodic reformulation of traditional influenza vaccines. One approach which could help reduce the disease burden associated with the loss of vaccine efficacy due to antigenic drift and shift is to generate vaccine strategies induce protective immunity against conserved viral proteins. The matrix protein 2 (M2) with its small ectodomain (M2e) has remained remarkably conserved across influenza A virus strains and possess as an ideal target for antibody-mediated protection. The purpose of the research presented here focuses on the development of two novel vaccine approaches with the common goal of exploiting the M2 protein for protection against influenza virus infection. The first approach utilizes novel M2e-specific single-chain minibodies. Passive immunization with M2 minibodies conferred protection against a lethal influenza virus challenge. In addition, M2 minibodies were shown to facilitate activation of Fc-mediated immune functions proposing mechanism(s) of protection involved in immunity. The second approach involves the use of recombinant adenovirus (rAd) vectors used for vaccination with conserved influenza virus proteins able to induce rapid immunity protective against challenge with a pandemic influenza virus strain. rAd vectors encoding the M2 protein from influenza were capable of inducing serum antibody titers able to recognize the M2e sequence of the vaccine antigen as well as the divergent M2e sequence of the pandemic challenge virus. Taken together, the novel vaccine approaches presented here represent potential prophylactic and therapeutic interventions to combat both seasonal and pandemic influenza virus infection.
