Oral vaccination with inactivated influenza vaccine induces cross-protective immunity

Oral vaccination would provide an easy and safe measure to prevent infectious diseases by facilitating mass immunization. We investigated the feasibility of oral vaccination with inactivated whole influenza virus (A/PR8/34). Oral vaccination of mice induced high levels of serum IgG and IgA antibodies specific to the homologous virus (A/PR8) as well as cross reactive to heterologous (A/California/04/09) and heterosubtypic viruses (A/Philippines/2/82). IgG1 isotype antibodies were found to be induced at significantly higher levels than IgG2a antibodies. These antibodies induced by oral vaccination exhibited hemagglutination inhibition activities. High levels of both IgG and IgA antibodies were induced in vagina and lungs. Mucosal IgA antibodies were also elicited in other sites including saliva, urine, and fecal samples. Orally vaccinated mice were completely protected against challenge with homologous or heterologous viruses, and partially protected against heterosubtypic virus. Importantly, high recall antibody secreting cell (ASC) responses were induced in spleen, indicating the generation of memory B cells by oral vaccination. The present study therefore presents new findings of cross-reactive antibodies at systemic and diverse mucosal sites, recall antibody responses, and cross-protective efficacies by oral vaccination, thus supporting a proof-of-concept that oral delivery of vaccines can be developed as an effective vaccination route.