title: An adjuvanted polyprotein HIV-1 vaccine induces polyfunctional cross-reactive CD4+ T cell responses in seronegative volunteers.
abstract: BACKGROUND
  This phase I/II partially blinded, randomized, dose-ranging study assessed the safety and immunogenicity of a novel human immunodeficiency virus type 1 (HIV-1) vaccine candidate consisting of a recombinant fusion protein (F4) containing 4 HIV-1 clade B antigens (Gag p24, Pol reverse transcriptase, Nef, and Gag p17) adjuvanted with AS01 in HIV-seronegative volunteers. Methods. Two doses of the recombinant F4 protein (10, 30, or 90 μg/dose), adjuvanted with AS01 or reconstituted with water for injection, were administered 1 month apart to 180 healthy volunteers aged 18-40 years. F4-specific CD4(+) T cell responses were measured using intracellular cytokine staining after in vitro stimulation by overlapping peptide pools covering the 4 individual antigens. Results. Reactogenicity was higher during the 7-day period after each vaccine dose in the adjuvanted than in the nonadjuvanted groups. In the adjuvanted groups, the overall immune response rate was high after the second vaccine dose, with highest responder rates seen in the 10-μg F4/AS01 group (100% to 3 HIV-1 antigens and 80% to all 4 HIV-1 antigens). High and long-lasting CD4(+) T cell frequencies were observed (up to a median value of 1.2% F4-specific CD4(+) T cells at day 44), with strongest responses directed against reverse transcriptase. Antigen-specific CD4(+) T cells exhibited a polyfunctional phenotype, expressing at least CD40 ligand and interleukin 2, often in combination with tumor necrosis factor α and/or interferon γ. Vaccine-induced CD4(+) T cell responses were broadly cross-reactive to all 4 antigens derived from HIV-1 clades A and C. Conclusions. These results support further clinical investigation of this HIV-1 vaccine candidate both in a prophylactic setting (alone, in conjunction with an envelope-based antigen or in combination with other vaccine approaches in a heterologous prime-boost regimen) and as a potentially disease-modifying therapeutic vaccine in HIV-1-infected subjects.
  
  
  BACKGROUND
  NCT00434512.
authors.affiliation: Center for Vaccinology, Ghent University and Hospital, Ghent. Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Van Braeckel
authors.forename: Patricia
authors.initials: P
authors.lastname: Bourguignon
authors.forename: Marguerite
authors.initials: M
authors.lastname: Koutsoukos
authors.forename: Frédéric
authors.initials: F
authors.lastname: Clement
authors.forename: Michel
authors.initials: M
authors.lastname: Janssens
authors.forename: Isabelle
authors.initials: I
authors.lastname: Carletti
authors.forename: Alix
authors.initials: A
authors.lastname: Collard
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Demoitié
authors.forename: Gerald
authors.initials: G
authors.lastname: Voss
authors.forename: Geert
authors.initials: G
authors.lastname: Leroux-Roels
authors.forename: Lisa
authors.initials: L
authors.lastname: McNally
mesh_terms: D016915:AIDS Vaccines / Q000009:adverse effects / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000009:adverse effects; D000293:Adolescent; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D018023:HIV Seronegativity / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007117:Immunization, Secondary / Q000379:methods; D008297:Male; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014611:Vaccination / Q000379:methods; D022223:Vaccines, Subunit / Q000009:adverse effects / Q000276:immunology; D014614:Vaccines, Synthetic / Q000276:immunology; D055815:Young Adult
chemical_list: D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D016207:Cytokines; D011993:Recombinant Fusion Proteins; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic