Cytotoxic T cell vaccination with PLGA microspheres interferes with influenza A virus replication in the lung and suppresses the infectious disease.

Current influenza virus vaccines aim to elicit antibodies directed toward viral surface glycoproteins, which however are prone to antigenic drift. Cytotoxic T lymphocytes (CTLs) can exhibit heterosubtypic immunity against most influenza A viruses. In our study, we encapsulated the highly conserved, immunodominant, HLA-A*0201 restricted epitope from the influenza virus matrix protein M158-66 together with TLR ligands in biodegradable poly(d,l-lactide-co-glycolide) (PLGA) microspheres. Subcutaneous immunization of transgenic mice expressing chimeric HLA-A*0201 molecules with these microspheres induced a strong and sustained CTL response which sufficed to prevent replication of a recombinant vaccinia virus expressing the influenza A virus (IAV) matrix protein but not the replication of IAV in the lung. However, subcutaneous priming followed by intranasal boosting with M158-66 bearing PLGA microspheres was able to induce vigorous CTL responses both in the lung and spleen of mice which interfered with IAV replication, weight loss, and infection-related death. Taken together, vaccination with well-defined and highly conserved IAV-derived CTL epitopes encapsulated into clinically compatible PLGA microspheres contribute to the control of influenza A virus infections. The promptitude and broad reactivity of the CTL response may help to attenuate pandemic outbreaks of influenza viruses.