title: Potent CD8+ T-cell immunogenicity in humans of a novel heterosubtypic influenza A vaccine, MVA-NP+M1.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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(+).
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Jenner Institute, Oxford University, Oxford, United Kingdom.
authors.forename: Tamara K
authors.initials: TK
authors.lastname: Berthoud
authors.forename: Matthew
authors.initials: M
authors.lastname: Hamill
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Lillie
authors.forename: Lenias
authors.initials: L
authors.lastname: Hwenda
authors.forename: Katharine A
authors.initials: KA
authors.lastname: Collins
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Ewer
authors.forename: Anita
authors.initials: A
authors.lastname: Milicic
authors.forename: Hazel C
authors.initials: HC
authors.lastname: Poyntz
authors.forename: Teresa
authors.initials: T
authors.lastname: Lambe
authors.forename: Helen A
authors.initials: HA
authors.lastname: Fletcher
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Gilbert
mesh_terms: D000293:Adolescent; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004337:Drug Carriers; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D007252:Influenza Vaccines / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D007271:Injections, Intradermal; D007273:Injections, Intramuscular; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019590:Nucleocapsid Proteins; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D022223:Vaccines, Subunit / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics*; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*; D055815:Young Adult
chemical_list: D004337:Drug Carriers; D007252:Influenza Vaccines; C488936:M1 protein, Influenza A virus; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D016601:RNA-Binding Proteins; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; D014758:Viral Core Proteins; D014763:Viral Matrix Proteins; D007371:Interferon-gamma