Safety and immunogenicity of an investigational 4-component Staphylococcus aureus vaccine with or without AS03B adjuvant: Results of a randomized phase I trial

• Published in: Human vaccines & immunotherapeutics Vol. 11; no. 3; pp. 620 - 631
• Main Authors: Levy, Jack, Licini, Laurent, Haelterman, Edwige, Moris, Philippe, Lestrate, Pascal, Damaso, Silvia, Van Belle, Pascale, Boutriau, Dominique
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 2015
• Subjects: According-to-Protocol; CIs; adjuvant; Adjuvants, Immunologic - administration & dosage; Adolescent; Adult; adverse events; AT; AEs; alpha-Tocopherol - administration & dosage; Antibodies, Bacterial - blood; capsular polysaccharides types 5 and 8; GMC; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; clumping factor A; CPS5 and 8; Confidence Intervals; ClfA; Drug Combinations; Drug-Related Side Effects and Adverse Reactions - epidemiology; Drug-Related Side Effects and Adverse Reactions - pathology; Female; geometric mean concentration; GMT; geometric mean titer; ICS; Healthy Volunteers; Humans; immunogenicity; interferon; IL; interleukin; LNR; intracellular cytokine staining; IFN; laboratory normal range; MRSA; Male; methicillin-resistant S. aureus; OPA; opsonophagocytic assay; pIMDs; Panton-Valentine leucocidin; rEPA; Placebos - administration & dosage; Polysorbates - administration & dosage; potential immune-mediated diseases: PVL; recombinant exoprotein A from Pseudomonas aeruginosa; SAEs; Research Paper; safety; serious adverse events; TT; Single-Blind Method; Squalene - administration & dosage; Staphylococcal Infections - immunology; Staphylococcal Infections - prevention & control; Staphylococcal Vaccines - adverse effects; Staphylococcal Vaccines - immunology; Staphylococcus aureus; tetanus toxoid; vaccine; Young Adult; α-toxin; ATP; serious adverse events; TT; geometric mean concentration; GMT; intracellular cytokine staining; IFN; recombinant exoprotein A from Pseudomonas aeruginosa; SAEs; AEs; methicillin-resistant S. aureus; OPA; capsular polysaccharides types 5 and 8; GMC; opsonophagocytic assay; pIMDs; adjuvant; safety; interferon; IL; Panton-Valentine leucocidin; rEPA; adverse events; AT; α-toxin; ATP; tetanus toxoid; Staphylococcus aureus; According–to-Protocol; CIs; Confidence Intervals; ClfA; potential immune-mediated diseases: PVL; immunogenicity; interleukin; LNR; vaccine; laboratory normal range; MRSA; geometric mean titer; ICS; clumping factor A; CPS5 and 8
• ISSN: 2164-5515; 2164-554X; 2164-554X
• DOI: 10.1080/21645515.2015.1011021

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 AS03 B 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 AS03 B 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.