title: Immunization with cross-conserved H1N1 influenza CD4+ T-cell epitopes lowers viral burden in HLA DR3 transgenic mice.
abstract: The emergence of the pandemic H1N1 strain of influenza in 2009 was associated with a unique w-shaped age-related susceptibility curve, with higher incidence of morbidity and mortality among young persons and lower incidence among older persons, also observed during the 1918 influenza pandemic. Pre-existing H1N1 antibodies were not cross-reactive with the prior seasonal vaccine, forcing influenza experts to scramble to develop a new vaccine specific for the pandemic virus. We hypothesized that response to T-cell epitopes that are cross-conserved between pandemic H1N1 and the 2008 seasonal influenza vaccine strains might have contributed to partial protection from clinical illness among older adults, despite the lack of cross-reactive humoral immunity. Using immunoinformatics tools, we previously identified hemagglutinin and neuraminidase epitopes that were highly conserved between seasonal and pandemic H1N1. Here, we validated predicted CD4(+) T-cell epitopes for their ability to bind HLA and to stimulate interferon-γ production in peripheral blood mononuclear cells from a cohort of donors presenting with influenza-like illness during the 2009 pandemic and a separate cohort immunized with trivalent influenza vaccine in 2011. A limited-epitope heterologous DNA-prime/peptide-boost vaccine composed of these sequences stimulated immune responses and lowered lung viral loads in HLA DR3 transgenic mice challenged with pandemic 2009 H1N1 influenza. Cross-priming with conserved influenza T-cell epitopes such as these may be critically important to T cell-mediated protection against pandemic H1N1 in the absence of cross-protective antibodies.
authors.affiliation: EpiVax, Inc.; Providence, RI USA; Institute for Immunology and Informatics; University of Rhode Island; Providence, RI USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Moise
authors.affiliation: EpiVax, Inc.; Providence, RI USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Tassone
authors.affiliation: EpiVax, Inc.; Providence, RI USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Latimer
authors.affiliation: EpiVax, Inc.; Providence, RI USA.
authors.forename: Frances
authors.initials: F
authors.lastname: Terry
authors.affiliation: EpiVax, Inc.; Providence, RI USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Levitz
authors.affiliation: Brown University Warren Alpert Medical School; Providence, RI USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Haran
authors.affiliation: Vaccine & Gene Therapy Institute of Florida; Port Saint Lucie, FL USA.
authors.forename: Ted M
authors.initials: TM
authors.lastname: Ross
authors.affiliation: EpiVax, Inc.; Providence, RI USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Boyle
authors.affiliation: EpiVax, Inc.; Providence, RI USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Martin
authors.affiliation: EpiVax, Inc.; Providence, RI USA; Institute for Immunology and Informatics; University of Rhode Island; Providence, RI USA.
authors.forename: Anne S
authors.initials: AS
authors.lastname: De Groot
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015803:HLA-DR3 Antigen / Q000276:immunology*; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D019562:Viral Load
chemical_list: D018984:Epitopes, T-Lymphocyte; D015803:HLA-DR3 Antigen; D007252:Influenza Vaccines
keywords: T-cell epitope; immunoinformatics; influenza; pandemic; vaccine
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