The most effective way to prevent influenza virus infection is via vaccination. However, the constant mutation of influenza viruses due to antigenic drift and shift compromises vaccine efficacy. This represents a major challenge to the development of a cross-protective vaccine that can protect against circulating viral antigenic diversity. Using the modified vaccinia Ankara (MVA) virus, we had previously generated a recombinant vaccine against highly pathogenic avian influenza virus (H5N1) based on an in silico mosaic approach. This MVA-H5M construct protected mice against multiple clades of H5N1 and H1N1 viruses. We have now further characterized the immune responses using immunodepletion of T cells and passive serum transfer, and these studies indicate that antibodies are the main contributors in homosubtypic protection (H5N1 clades).
Influenza viruses still pose a serious threat for both humans and animals. Every year, seasonal influenza infects an estimated one billion people around the globe, resulting in 3 to 5 million severe cases (1). Avian influenza viruses, especially highly pathogenic avian influenza (HPAI) H5N1 viruses, have also caused public health concerns and have the potential to cause the next influenza pandemic. The main intervention strategy against both seasonal and pandemic influenza viruses is vaccination.Conventional vaccination methods against influenza viruses include inactivated (whole virus, split, or subunit) and live-attenuated influenza vaccine (LAIV). These vaccines provide protection by inducing a hemagglutinin (HA)-specific neutralizing antibody. The efficacy of inactivated vaccines and LAIVs are strongly affected by antigenic mismatch between circulating and vaccine strains. Inactivated vaccine effectiveness is about 50 to 70% based on age and health condition but can be as low as 30% (2). LAIVs are, in general, more broadly protective than inactivated vaccines and can have up to 93% overall efficacy against matched strains (3). However, LAIVs are still significantly less effective against mismatched strains. In addition, seasonal vaccine strains need to be selected each year to match the circulating strain. Inactivated vaccines from specific strains of H5N1 virus have been generated and stockpiled, in case of a pandemic, but this vaccine is also less effective against heterologous H5N1 strains (4).Several vaccine approaches have attempted to address the high genetic variation of influenza viruses that can occur via antigenic drift and shift. One such strategy is based on choosing immunogens from conserved regions of the HA stalk domain (5, 6) or highly conserved proteins such as the M2 gene (7,8). Alternative approaches have attempted to centralize the virus antigenic sequences by using a consensus algorithm (9). Recently, a novel "mosaic" approach has been introduced in the field of human immunodeficiency virus (HIV) vaccinology and has been shown to provide broader protection against mismatched HIV strains than natural or consensus-derived antigens (10). The algorit...