Mosaic H5 Hemagglutinin Provides Broad Humoral and Cellular Immune Responses against Influenza Viruses

Abstract

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...

CD4 T cells in protection from influenza virus: Viral antigen specificity and functional potential

“…[74][75][76][77]175,176 For those healthy adults with a very limited repertoire of CD4 T cells that cross-react with avian HA proteins, prepandemic priming with H5 or H7 proteins or peptides might be a very useful strategy. 147,148,[177][178][179] By populating humans with avian HA-epitope-specific CD4 T memory cells that can be recalled, these hosts are more likely to produce neutralizing HA-specific antibody responses and/or to more vigorously respond to avian influenza derived vaccines, if avian influenza viruses gain the ability to transmit across human populations. [180][181][182][183][184][185]…”

Influenza H1 Mosaic Hemagglutinin Vaccine Induces Broad Immunity and Protection in Mice

“…Mosaic immunogens have been explored over the past decade as a vaccination strategy to protect against viruses with high population diversity, such as influenza H5 and HIV [24,25,34]. By maximizing the PBTE coverage across the population, mosaic immunogens are designed to induce stronger immune responses [22].…”

“…In this study, a mosaic HA vaccine was designed to contain the most potential B and T cell epitopes (PBTE) across a spectrum of human H1 influenza viruses using the mosaic vaccine designer tool which predicts the sequence containing the most linear PBTE [22]. This mosaic strategy has shown promise for multiple pathogens including H5 influenza, Dengue, and HIV [23][24][25][26]. However, this is the first published study that applies the mosaic vaccine immunogen approach to human H1 influenza virus.…”

Polyvalent vaccine approaches to combat HIV‐1 diversity

“…A listing of all human HIV vaccine trials is maintained by the AIDS Vaccine Advocacy Coalition, AVAC, at http://www.avac.org. Mosaic vaccines have also shown promise against other highly variable pathogens, including Hepatitis C, 44 Ebola, 45 Influenza, 46 Chlamydia, 47 and foot-and-mouth disease (W. Fischer and E. Rieder, personal communication).…”