MVA Vectors Expressing Conserved Influenza Proteins Protect Mice against Lethal Challenge with H5N1, H9N2 and H7N1 Viruses

Abstract

BackgroundThe availability of a universal influenza vaccine able to induce broad cross-reactive immune responses against diverse influenza viruses would provide an alternative to currently available strain-specific vaccines. We evaluated the ability of vectors based on modified vaccinia virus Ankara (MVA) expressing conserved influenza proteins to protect mice against lethal challenge with multiple influenza subtypes.MethodsMice were immunized with MVA vectors expressing H5N1-derived nucleoprotein (NP), the stem region of hemagglutinin (HA), matrix proteins 1 and 2 (M1 and M2), the viral polymerase basic protein 1 (PB1), or the HA stem fused to a quadrivalent matrix protein 2 extracellular domain (M2e). Immunized mice were challenged with lethal doses of H5N1, H7N1 or H9N2 virus and monitored for disease symptoms and weight loss. To investigate the influence of previous exposure to influenza virus on protective immune responses induced by conserved influenza proteins, mice were infected with pandemic H1N1 virus (H1N1pdm09) prior to immunization and subsequently challenged with H5N1 virus. Antibody and T cell responses were assessed by ELISA and flow cytometry, respectively.ResultsMVA vectors expressing NP alone, or co-expressed with other conserved influenza proteins, protected mice against lethal challenge with H5N1, H7N1 or H9N2 virus. Pre-exposure to H1N1pdm09 increased protective efficacy against lethal H5N1 challenge. None of the other conserved influenza proteins provided significant levels of protection against lethal challenge. NP-expressing vectors induced high numbers of influenza-specific CD4+ and CD8+ T cells and high titer influenza-specific antibody responses. Higher influenza-specific CD4+ T cell responses and NP-specific CD8+ T cell responses were associated with increased protective efficacy.ConclusionsMVA vectors expressing influenza NP protect mice against lethal challenge with H5N1, H7N1 and H9N2 viruses by a mechanism involving influenza-specific CD4+ and CD8+ T cell responses.

Modified Vaccinia Virus Ankara Encoding Influenza Virus Hemagglutinin Induces Heterosubtypic Immunity in Macaques

“…A recent study reported that MVA vectors expressing only NP from A/Vietnam/1203/2004 protected mice against H5N1, H9N2, and H7N1 influenza viruses; cross-reactive CD4 ϩ and CD8 ϩ T cells were thought to be the main correlate of protection (42). While MVA alone can induce strong T cell responses in mice, previous studies have suggested that MVA vectors alone, even with multiple booster immunizations, may not be strongly immunogenic for CD8 ϩ T cells in macaques (43,44).…”

Immunogenicity of modified vaccinia virus Ankara expressing the hemagglutinin stalk domain of pandemic (H1N1) 2009 influenza virus

“…Previous studies by Hessel et al [31] could detect the induction of CD8+ T cells but not CD4+ T cells and antibodies by a recombinant MVA expressing the hlHA of VN/04 virus in BALB/c mice that, however, did not survive against high challenge virus doses. In the present study, the cell proliferative response to antigen in vitro and DTH response measured in vivo against soluble recombinant HA protein of CA/09 virus, clearly suggest a functional role of CD4+ T cells in these responses.…”

Universal influenza vaccines: a realistic option?

“…Live vaccines, or viral vectors such as recombinant adenoviruses or pox viruses, may be suitable for this purpose because they facilitate de novo synthesis of the proteins of interest. Indeed, it has been demonstrated that broadly protective immunity could be induced in mice [63] by vaccination with a recombinant replication-deficient poxviral vector (modified vaccinia virus Ankara [MVA]) expressing the influenza virus NP. MVA that drives the expression of NP and M1 protein was also tested in clinical trials and proved to be immunogenic in humans [64][65][66].…”