Potent CD8+ T-cell immunogenicity in humans of a novel heterosubtypic influenza A vaccine, MVA-NP+M1

The Jenner Institute, Oxford University, Oxford, United Kingdom.
Clinical Infectious Diseases (Impact Factor: 8.89). 01/2011; 52(1):1-7. DOI: 10.1093/cid/ciq015
Source: PubMed


Influenza A viruses cause occasional pandemics and frequent epidemics. Licensed influenza vaccines that induce high antibody titers to the highly polymorphic viral surface antigen hemagglutinin must be re-formulated and readministered annually. A vaccine providing protective immunity to the highly conserved internal antigens could provide longer-lasting protection against multiple influenza subtypes.
We prepared a Modified Vaccinia virus Ankara (MVA) vector encoding nucleoprotein and matrix protein 1 (MVA-NP+M1) and conducted a phase I clinical trial in healthy adults.
The vaccine was generally safe and well tolerated, with significantly fewer local side effects after intramuscular rather than intradermal administration. Systemic side effects increased at the higher dose in both frequency and severity, with 5 out of 8 volunteers experiencing severe nausea/vomiting, malaise, or rigors. Ex vivo T-cell responses to NP and M1 measured by IFN-γ ELISPOT assay were significantly increased after vaccination (prevaccination median of 123 spot-forming units/million peripheral blood mononuclear cells, postvaccination peak response median 339, 443, and 1443 in low-dose intradermal, low-dose intramuscular, and high-dose intramuscular groups, respectively), and the majority of the antigen-specific T cells were CD8(+).
We conclude that the vaccine was both safe and remarkably immunogenic, leading to frequencies of responding T cells that appear to be much higher than those induced by any other influenza vaccination approach. Further studies will be required to find the optimum dose and to assess whether the increased T-cell response to conserved influenza proteins results in protection from influenza disease.

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Available from: Katharine A Collins
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    • "Recombinant Fowlpox virus (rFPV) vectors expressing NP and M1 transgenes from avian influenza A/Turkey/Turkey/1/2005 (H5N1) or GFP were the kind gift of Dr. Mike Skinner (Imperial College). Modified Vaccinia Ankara (MVA) virus expressing a fusion protein of nucleoprotein and matrix protein 1 (MVA-NpM1) from influenza A/Panama/2007/ 99 (H3N2) was supplied by the Vector Core Facility at the Jenner Institute (Oxford, UK) (Berthoud et al., 2011). "
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    • "Nucleoprotein (NP) is a highly conserved internal antigen of the influenza A virus (Altmuller et al., 1989; Shu et al., 1993) and is the major target antigen for cytotoxic T lymphocyte (CTL) responses (Jameson et al., 1998, 1999; McMichael et al., 1983, 1986). At this time, several vaccines based on the NP antigen alone or in combination with other influenza A virus antigens have been developed including peptide vaccines (Adar et al., 2009; Atsmon et al., 2012; Gao et al., 2013; Jeon et al., 2002; Savard et al., 2012), DNA-based vaccines (Kheiri et al., 2012; Lalor et al., 2008; Luo et al., 2012; Price et al., 2009, 2010; Xu et al., 2011), virus vectorbased vaccines (Price et al., 2009, 2010; Antrobus et al., 2012, 2014; Barefoot et al., 2009; Berthoud et al., 2011; Brewoo et al., 2013; Hessel et al., 2014; Kim et al., 2013; Lambe et al., 2013; Li et al., 2013; Lillie et al., 2012; Moraes et al., 2011; Mullarkey et al., 2013; Rohde et al., 2013; Sipo et al., 2011; Vitelli et al., 2013), recombinant attenuated Salmonella vaccines (RASVs) (Ashraf et al., 2011) or protein subunit vaccines (Luo et al., 2012; Haynes et al., 2012; MacLeod et al., 2013). The efficacy of these vaccines has been evaluated in animal models. "
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