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

Abstract

We conducted a randomized, double-blind, placebo-controlled dose-escalation study in healthy adults to evaluate the safety and immunogenicity of recombinant Staphylococcus aureus candidate vaccine antigens, recombinant a-toxoid (rAT) and a sub-unit of Panton-Valentine leukocidin (rLukS-PV). 176 subjects were enrolled and randomized within 1 of 11 treatment cohorts: monovalent rAT or rLukS-PV dosages of 10, 25, 50, and 100 mg; bivalent rAT:rLukS dosages of 10:10, 25:25, and 50:50 mg; and alum or saline placebo. All subjects were assessed at Days 0, 7, 14, 28, and 84. Subjects in the 50:50 mg bivalent cohort received a second injection on Day 84 and were assessed on Days 98 and 112. Incidence and severity of reactogenicity and adverse events (AEs) were compared. Geometric mean serum concentrations (GMC) and neutralizing activity of anti-rAT and anti-rLukS-PV IgG were assessed. Reactogenicity incidence was significantly higher in vaccine than placebo recipients (77% versus 55%, respectively; p D 0.006). However, 77% of reactogenicity events were mild and 19% were moderate in severity. The AE incidence and severity were similar between the cohorts. All monovalent and bivalent rAT dosages resulted in a significant increase in the anti-rAT IgG and anti-rLukS-PV GMCs between day 0 and 28 compared with placebo, and persisted through Day 84. Exploratory subgroup analyses suggested a higher GMC and neutralizing antibody titers for the 50 mg monovalent or bivalent rAT and rLukS-PV dose as compared to the other doses. No booster effect was observed after administration of the second dose. We conclude that the rAT and rLukS-PV vaccine formulations were well-tolerated and had a favorable immunogenicity profile, producing antibody with neutralizing activity through day 84. There was no benefit observed with a booster dose of the vaccine.

Safety and immunogenicity of an investigational 4-componentStaphylococcus aureusvaccine with or without AS03Badjuvant: Results of a randomized phase I trial

“…In other staphylococcal vaccine trials conducted in healthy subjects or end-stage renal disease patients and using vaccines with related antigens, antibody titers also increased with the antigen dose. 54,63,64 We evaluated 5 mg and 10 mg of CPS5 and CPS8, whereas StaphVAX TM contains 100 mg of each CPS type. In a tri-valent vaccine combining staphylococcal CPS types 5 and 8 conjugated to CRM 197 and a mutant form of ClfA, 10, 30 or 100 mg of each CPS were previously evaluated and the dose of 30 mg was selected for further development.…”

“…In one trial testing a recombinant AT and a sub-unit of Panton-Valentine leukocidin (PVL) toxoids, Landrum et al reported statistically significantly higher AT-specific antibody GMC levels in the group receiving 50 mg of AT compared with the other groups who received lower antigen doses. 63 In a tri-valent vaccine, 10, 60 and 200 mg of ClfA were evaluated and the 60 mg dose was selected for further clinical trial evaluation. 64,65 In the current study, we evaluated only 2 escalating doses for the antigen part of our vaccine and we can therefore not conclude on the optimal dosage for the AT and ClfA antigens in our vaccine; it should be noted however that the addition of a 2nd and 3rd dose did not further increase the antibody response.…”

Panton-Valentine leucocidin is the key determinant of Staphylococcus aureus pyomyositis in a bacterial genome-wide association study

“…This property is shared by toxin-driven, vaccine-preventable diseases such as tetanus and diphtheria. Therefore, vaccines that generate neutralising anti-toxin antibodies against PVL 29 may protect human populations against this common tropical disease. They also raise the hypothesis that antibiotics which decrease toxin expression, and have been recommended in some PVL-associated infections, 30 may offer specific clinical benefit in treating pyomyositis.…”

New developments and future challenges in prevention, diagnosis, and treatment of prosthetic joint infection

“…Vaccines targeting cell wall components of Staphylococcus aureus (LTA acid, capsular polysaccharides), cell wall anchored proteins (IsdB), toxins (α‐toxin, Panton‐Valentine leukicidin, SpA) 117–124 …”