ΔA146Ply-HA stem protein immunization protects mice against influenza A virus infection and co-infection with Streptococcus pneumoniae

Abstract

Influenza virus (IV) is a common pathogen affecting the upper respiratory tract, that causes various diseases. Secondary bacterial pneumonia is a common complication and a major cause of death in influenza patients. Streptococcus pneumoniae (S. pneumoniae) is the predominant co-infected bacteria in the pandemic, which colonizes healthy people but can cause diseases in immunocompromised individuals. Vaccination is a crucial strategy for avoiding infection, however, no universal influenza vaccine (UIV) that is resistant to multiple influenza viruses is available. Despite its limited immunogenicity, the hemagglutinin (HA) stem is a candidate peptide for UIV. ΔA146Ply (pneumolysin with a single deletion of A146) not only retains the Toll-like receptor 4 agonist effect but also is a potential vaccine adjuvant and a candidate protein for the S. pneumoniae vaccine. We constructed the fusion protein ΔA146Ply-HA stem and studied its immunoprotective effect in mice infection models. The results showed that intramuscular immunization of ΔA146Ply-HA stem without adjuvant could induce specific antibodies against HA stem and specific CD4+ T and CD8+ T cellular immunity in BALB/c and C57BL/6 mice, which could improve the survival rate of mice infected with IAV and co-infected with S. pneumoniae, but the protective effect on BALB/c mice was better than that on C57BL/6 mice. ΔA146Ply-HA stem serum antibody could protect BALB/c and C57BL/6 mice from IAV, and recognized HA polypeptides of H3N2, H5N1, H7N9, and H9N2 viruses. Moreover, ΔA146Ply-HA stem intramuscular immunization had a high safety profile with no obvious toxic side effects. The results indicated that coupling ΔA146Ply with influenza protein as a vaccine was a safe and effective strategy against the IV and secondary S. pneumoniae infection.