title: Coupling sensitive in vitro and in silico techniques to assess cross-reactive CD4(+) T cells against the swine-origin H1N1 influenza virus.
abstract: The outbreak of the novel swine-origin H1N1 influenza in the spring of 2009 took epidemiologists, immunologists, and vaccinologists by surprise and galvanized a massive worldwide effort to produce millions of vaccine doses to protect against this single virus strain. Of particular concern was the apparent lack of pre-existing antibody capable of eliciting cross-protective immunity against this novel virus, which fueled fears this strain would trigger a particularly far-reaching and lethal pandemic. Given that disease caused by the swine-origin virus was far less severe than expected, we hypothesized cellular immunity to cross-conserved T cell epitopes might have played a significant role in protecting against the pandemic H1N1 in the absence of cross-reactive humoral immunity. In a published study, we used an immunoinformatics approach to predict a number of CD4(+) T cell epitopes are conserved between the 2008-2009 seasonal H1N1 vaccine strain and pandemic H1N1 (A/California/04/2009) hemagglutinin proteins. Here, we provide results from biological studies using PBMCs from human donors not exposed to the pandemic virus to demonstrate that pre-existing CD4(+) T cells can elicit cross-reactive effector responses against the pandemic H1N1 virus. As well, we show our computational tools were 80-90% accurate in predicting CD4(+) T cell epitopes and their HLA-DRB1-dependent response profiles in donors that were chosen at random for HLA haplotype. Combined, these results confirm the power of coupling immunoinformatics to define broadly reactive CD4(+) T cell epitopes with highly sensitive in vitro biological assays to verify these in silico predictions as a means to understand human cellular immunity, including cross-protective responses, and to define CD4(+) T cell epitopes for potential vaccination efforts against future influenza viruses and other pathogens.
authors.affiliation: sanofi pasteur, VaxDesign Campus, Orlando, FL 32826, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Schanen
authors.forename: Anne S
authors.initials: AS
authors.lastname: De Groot
authors.forename: L
authors.initials: L
authors.lastname: Moise
authors.forename: Matt
authors.initials: M
authors.lastname: Ardito
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McClaine
authors.forename: William
authors.initials: W
authors.lastname: Martin
authors.forename: Vaughan
authors.initials: V
authors.lastname: Wittman
authors.forename: William L
authors.initials: WL
authors.lastname: Warren
authors.forename: Donald R
authors.initials: DR
authors.lastname: Drake
mesh_terms: D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D019295:Computational Biology / Q000379:methods; D056738:Cross Protection; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D008875:Middle Aged
chemical_list: D018984:Epitopes, T-Lymphocyte