Safety and immunogenicity of an investigational 4-componentStaphylococcus aureusvaccine with or without AS03_Badjuvant: 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 a-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 mg or 10/10/30/30 mg 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 C /CD8C 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 CD4C 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.

Safety and immunogenicity of a recombinant Staphylococcus aureus α-toxoid and a recombinant Panton-Valentine leukocidin subunit, in healthy adults

“…Results from the 4 component staphylococcal vaccine that utilized mutant a-toxoid in combination with ClfA, also showed a robust antibody response to both antigens, although the investigators did not incorporate a monovalent a-toxoid arm in the study design. 18 We observed a higher incidence of reactogenicity events in subjects receiving the rLukS-PV antigen (alone or in the bivalent formulation) compared to the subjects receiving rAT alone. Neutralizing antibody titers for rLukS-PV were lower than the titers observed for rAT antibodies, and a weaker correlation was observed between rLukS-PV IgG concentration and inhibition of PVL-induced lysis.…”

“…A robust increase in the GMT of a-toxin neutralizing antibodies was observed following the initial dose of the 4 component staphylococcal vaccine (mutant a-toxoid, ClfA, CPS5, CPS8), followed by a lack of response to dose 2 and 3. 18 The peak antibody levels observed after the second dose of StapVAX TM , a CPS5/CPS8 conjugate vaccine, were lower than the levels achieved following the initial vaccination. 36 These findings were attributed to the fact that adult humans were previously primed for these antigens as evident by presence of specific pre-existing antibodies, and therefore one immunization is considered a booster immunization.…”

“…10 or 30 mg) in combination with CPS5 and 8 conjugated to tetanus toxoid), also showed a clinically acceptable safety profile with a low incidence of grade 3 reactogenicity events and no SAEs related to vaccine administration. 18 Although a large proportion (>70%) of subjects were seropositive for a-toxin and PVL-neutralizing antibodies at baseline, the titer of pre-existing antibodies was low. These antibodies were likely in response to carriage of S. aureus strains (very few patients had a history of SSTI in our cohort) expressing PVL, a-toxin or other cross reactive leukocidins.…”

“…8 With the growing burden of S. aureus disease, increasing antibiotic resistance, and limited efficacy of decolonization protocols, 9,10 there is substantial interest in development of a S. aureus vaccine for use in high risk populations. Although an effective S. aureus vaccine remains elusive, [13][14][15][16][17][18] there is general consensus on a multi-antigen approach to vaccine development, which targets T and B cell responses to S. aureus cell surface components, virulence factors and toxins. 19 a-toxin and Panton-Valentine leukocidin (PVL) are 2 toxins of interest for a toxoid based approach that have shown efficacy in animal models.…”

Antibodies toStaphylococcus aureuscapsular polysaccharides 5 and 8 perform similarlyin vitrobut are functionally distinctin vivo

“…25,[39][40][41] Despite their failure in clinical trials when used alone in hemodialysis patients, 42,43 CP5 and CP8 conjugate vaccines are thought to be important components in a multivalent staphylococcal vaccine. 1,25,38,44 Because diverse S. aureus clinical isolates (both methicillin-sensitive and -resistant) produce surface-associated CP5 or CP8, 14,15,37 we considered that mAbs to CP5 or CP8 with opsonic activity might be included in a mAb cocktail to prevent or reduce staphylococcal bacteremia. S. aureus USA300, which is highly prevalent in the United States, does not produce a capsule and thus would not be a target for mAbs against CP5 or CP8.…”