Intranasal Inactivated Influenza Vaccines: a Reasonable Approach to Improve the Efficacy of Influenza Vaccine?

Influenza is a contagious, acute respiratory disease caused by the influenza virus. The mucosal lining in the host respiratory tract is not only the site of virus infection, but also the site of defense; it is at this site that the host immune response targets the virus and protects against reinfection. One of the most effective methods to prevent influenza is to induce specific antibody (Ab) responses in the respiratory tract by vaccination. Two types of influenza vaccines, intranasal live attenuated influenza virus (LAIV) vaccines and parenteral (injectable) inactivated vaccines, are currently used worldwide. These vaccines are approved by the European Medicines Agency (EMA) and the US Food and Drug Administration. Live attenuated vaccines induce both secretory IgA (S-IgA) and serum IgG antibodies (Abs), whereas parenteral vaccines induce only serum IgG Abs. However, intranasal administration of inactivated vaccines together with an appropriate adjuvant induces both S-IgA and IgG Abs. Several preclinical studies on adjuvant-combined, nasal-inactivated vaccines revealed that nasal S-IgA Abs, a major immune component in the upper respiratory tract, reacted with homologous virus hemagglutinin (HA) and were highly cross-reactive with viral HA variants, resulting in protection and cross-protection against infection by both homologous and variant viruses, respectively. Serum-derived IgG Abs, which are present mainly in the lower respiratory tract, are less cross-reactive and cross-protective. In addition, our own clinical trials have shown that nasal-inactivated whole virus vaccines, including a built-in adjuvant (single-stranded RNA), induced serum hemagglutination inhibition (HI) Ab titers that fulfilled the EMA criteria for vaccine efficacy. The nasal-inactivated whole virus vaccines also induced high levels of nasal HI and neutralizing Ab titers, although we have not yet evaluated the nasal HI titers due to the lack of official criteria to establish efficacy based on this parameter. Data suggest that adjuvant-combined nasal-inactivated vaccines have advantages over the current injectable vaccine because the former induce both S-IgA and serum IgG Abs. In addition, nasal-inactivated vaccines seem to be superior to the LAIV vaccines, because non-infectious preparations could be used in high-risk groups. Thus, the development of intranasal inactivated vaccines is recommended, because such vaccines are expected to improve the efficacy of influenza vaccines.