Gene Vaccine-mediated Induction of Protective Immunity against Influenza Virus

Abstract

Among emerging and re-emerging infectious diseases, influenza constitutes one of the major threats to the public health of human. Most influenza vaccines target hemagglutinin (HA) in order to protect the host against infection. However, these vaccines are strain-specific due to major antigenic variations of HA. Since it is difficult to predict epidemic and pandemic strains of influenza, the development of effective vaccines against divergent influenza viruses is urgently needed. In this study, I investigated gene vaccine-mediated induction of protective immunity against influenza virus.First of all, I examined the effect of a DNA vaccine expressing a fusion protein of H1N1 HA and extracellular domain of Matrix 2 (M2e) on the immunogenicity and protective efficacy against a lethal challenge of a H5N2 avian influenza virus. Vaccination with the M2e-HA DNA induced a broad immunity in the absence of detectable immune interference. In addition, HA-specific CD8+ T cell responses elicited by M2e-HA DNA vaccination were significantly higher than those by vaccination with HA DNA alone. Following challenge with a heterosubtypic avian influenza virus infection, M2e-HA DNA vaccine conferred complete protection compared with HA or M2e DNA vaccine alone. In combination, these results suggest that a DNA vaccine expressing a fusion protein, M2e-HA, may represent an attractive approach for the development of broad-spectrum influenza vaccines.An ideal broad-spectrum influenza vaccine should have the potential to generate a broad immunity both systemically and at mucosal sites, which are primary sites utilized by influenza virus. However, conventional influenza vaccines have been administered via intramuscular route, thereby resulting in less effective at inducing mucosal immunity. Therefore, I next investigated whether the vaccination route (systemic vs. mucosal) would affect the immunogenicity at both sites and protective efficacy following a lethal challenge with an antigenically distinct avian influenza virus using a replication-defective recombinant adenovirus-based avian influenza virus vaccine (rAdv-AI) expressing the M2e-HA-CD40L and the M1-M2 fusion proteins. Although there were no significant differences in the systemic immune responses observed between the intramuscular prime-intramuscular boost regimen (IM/IM) and the intranasal prime-intramuscular boost regimen (IN/IM), the IN/IM induced more potent CD8+ T cell and antibody responses at mucosal sites than the IM/IM, resulting in complete protection against a lethal challenge of an antigenically distinct avian influenza virus. These findings suggest that the strategies used to induce multi-antigen-targeted mucosal immunity, such as IN/IM delivery of rAdv-AI, may represent a promising approach for the development of an ideal influenza vaccine against divergent influenza viruses.