? Annual epidemics of influenza A virus are responsible for over 32,000 deaths, 120,000 hospitalizations in the United States alone. Sudden shifts in the antigenic makeup of influenza A virus, usually caused by genome segment reassortment of human and avian influenza virus strains, can lead to worldwide pandemics that have been associated with hundreds of thousands of deaths, the most notorious being the 1918 influenza pandemic estimated to have caused 20 million deaths worldwide. The current influenza vaccine consists of inactivated virus strains expected to circulate in the human population based on strains isolated in the previous calendar year - a process that is time consuming and inherently risky given the propensity of influenza virus to mutate. Generating an influenza vaccine with activity against a variety of virus strains would not only ease the burden of influenza on the current population but also protect individuals from a bioterrorist-initiated release of an influenza A virus strain not currently circulating in the human population. The M2 protein is an attractive candidate for such a vaccine because the amino acid sequence of M2 is nearly identical in all human strains of influenza A virus sequenced to date and antibodies to the influenza A virus M2 protein extracellular domain can protect mice from challenge with a lethal dose of influenza A virus. Antibodies to the M2 protein are not efficiently induced by the current influenza A virus vaccine because M2 is grossly underrepresented in the virus particle. The hepatitis core platform will be used to express the extracellular region of M2 as a hybrid core particle (core-M2e) and its efficacy in inducing an immune response in immunized mice will be assessed by serum antibody ELISA and protection of mice from influenza A virus challenge. Core-M2e will be used by itself or as a supplement to the current influenza vaccine to determine which vaccination approach confers increased protection to influenza A virus strains bearing antigenically distinct HA and NA subtypes. Since the M2 sequence of swine and avian influenza A virus strains differs from that of human strains, we will generate and characterize the ability of core particles containing these sequences to induce protective immunity to influenza A virus strains bearing avian, swine or human M2 sequences. Finally, we will investigate the mechanism by which M2 antibodies confer protection in vivo and characterize the replication and virulence of M2 antibody escape mutants. ? ?
| Wu, Wai-Hong; Pekosz, Andrew (2008) Extending the cytoplasmic tail of the influenza a virus M2 protein leads to reduced virus replication in vivo but not in vitro. J Virol 82:1059-63 |
