title: Safety and immunogenicity of an investigational 4-component Staphylococcus aureus vaccine with or without AS03B adjuvant: Results of a randomized phase I trial.
abstract: We assessed the safety, reactogenicity and immunogenicity of a staphylococcal vaccine combining capsular polysaccharides types 5 and 8 (CPS5/8), conjugated to tetanus toxoid (TT), with mutated detoxified α-toxin (AT) and clumping factor A (ClfA). In this phase I, randomized, placebo-controlled, observer-blind trial (NCT01160172), 88 healthy 18- to 40-year-olds received CPS5-TT/CPS8-TT/AT/ClfA vaccine (5/5/10/10 μg or 10/10/30/30 μg dose, each with or without AS03B adjuvant) or saline, at months 0, 1, 6. Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 d post-vaccination, respectively; potential immune-mediated diseases (pIMDs) and serious AEs (SAEs) were recorded throughout the study. Humoral and antigen-specific CD4(+)/CD8(+) T-cell immunity were assessed from Day (D) 0 to D540 post-vaccination. The most frequently reported solicited local and general AEs were pain (78.6%-100% of subjects), fatigue (36.4%-93.3% of subjects post-dose 1-2) and headache (20%-44.4% of subjects post-dose 3). Overall, 4 SAEs and 2 potential immune-mediated diseases (pIMDs) (none fatal or vaccine-related) were reported. For each antigen, pre-vaccination seropositivity rates were high (85.7%-100%) and geometric mean concentrations (GMCs) in vaccine recipients sharply increased from D0 to D14, then plateaued to study end. Exploratory group comparisons suggested higher GMCs with higher dosage, without AS03B effect. Vaccine-induced antibodies were functional (CPS5 opsonophagocytic assays, and AT/ClfA inhibition assays). AT- and ClfA-specific CD4(+) T-cells with Th0/Th1 cytokine profile were induced at low levels (median <0.05%) by each formulation (intracellular cytokine staining). In conclusion, no safety concerns were identified and each vaccine formulation induced robust humoral immune responses after the first vaccine dose.
authors.affiliation: a Saint-Pierre University Hospital ; Brussels , Belgium.
authors.forename: Jack
authors.initials: J
authors.lastname: Levy
authors.forename: Laurent
authors.initials: L
authors.lastname: Licini
authors.forename: Edwige
authors.initials: E
authors.lastname: Haelterman
authors.forename: Philippe
authors.initials: P
authors.lastname: Moris
authors.forename: Pascal
authors.initials: P
authors.lastname: Lestrate
authors.forename: Silvia
authors.initials: S
authors.lastname: Damaso
authors.forename: Pascale
authors.initials: P
authors.lastname: Van Belle
authors.forename: Dominique
authors.initials: D
authors.lastname: Boutriau
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000293:Adolescent; D000328:Adult; D000907:Antibodies, Bacterial / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004338:Drug Combinations; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D010919:Placebos / Q000008:administration & dosage; D011136:Polysorbates / Q000008:administration & dosage; D016037:Single-Blind Method; D013185:Squalene / Q000008:administration & dosage; D013203:Staphylococcal Infections / Q000276:immunology / Q000517:prevention & control*; D013209:Staphylococcal Vaccines / Q000009:adverse effects* / Q000276:immunology*; D055815:Young Adult; D024502:alpha-Tocopherol / Q000008:administration & dosage
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D004338:Drug Combinations; D010919:Placebos; D011136:Polysorbates; D013209:Staphylococcal Vaccines; D013185:Squalene; C550253:AS03 adjuvant; D024502:alpha-Tocopherol
keywords: AEs; According–to-Protocol; CIs; Confidence Intervals; ClfA; Panton-Valentine leucocidin; rEPA; Staphylococcus aureus; adjuvant; adverse events; AT; capsular polysaccharides types 5 and 8; GMC; clumping factor A; CPS5 and 8; geometric mean concentration; GMT; geometric mean titer; ICS; immunogenicity; interferon; IL; interleukin; LNR; intracellular cytokine staining; IFN; laboratory normal range; MRSA; methicillin-resistant S. aureus; OPA; opsonophagocytic assay; pIMDs; potential immune-mediated diseases: PVL; recombinant exoprotein A from Pseudomonas aeruginosa; SAEs; safety; serious adverse events; TT; tetanus toxoid; vaccine; α-toxin; ATP