Safety and immunogenicity of a novel Staphylococcus aureus vaccine: results from the first study of the vaccine dose range in humans

Abstract

Merck V710 is a novel vaccine containing the conserved Staphylococcus aureus iron surface determinant B shown to be protective in animal models. A phase I, multicenter, double-blind study of the dose range was conducted to assess the immunogenicity and safety of an adjuvanted liquid formulation of V710. A total of 124 adults (18 to 55 years of age) were randomized 1:1:1:1 to receive one 0.5-ml intramuscular injection of V710 (5 μg, 30 μg, or 90 μg) or saline placebo. A positive immune response was defined as at least a 2-fold increase in IsdB-specific IgG levels from baseline levels. Local and systemic adverse events were assessed for 5 and 14 days, respectively, following vaccination. Positive immune responses were detected in 12 (67%) of the 18 subjects in the groups receiving 30 and 90 μg V710 tested at day 10. At day 14, a significantly greater proportion of subjects manifested a positive immune response with higher geometric mean concentrations in the V710 30-μg (86%; geometric mean concentration of 116 μg/ml) and 90-μg (87%; geometric mean concentration of 131 μg/ml) dose groups than in the V710 5-μg (29%; geometric mean concentration of 51 μg/ml) or placebo (4%; geometric mean concentration of 23 μg/ml) groups. Immune responses were durable through day 84. Subjects <40 and ≥40 years of age had comparable immune responses. The most common adverse events were injection-site pain, nausea, fatigue, and headache, usually of mild intensity. No immediate reactions or serious adverse events were reported. In this first study of V710 in humans, a single 30-μg or 90-μg dose was more immunogenic than the 5-μg dose or placebo. Immune responses were evident by 10 to 14 days after vaccination in most responders.

Figures

FIG. 1.

Subject accounting and disposition. All enrolled patients were randomized and vaccinated. All vaccinated patients were included in the safety analysis. There were no deaths during the study period. A total of 119 (96%) of the 124 vaccinated subjects completed the trial through postvaccination day 84. Of the five subjects who discontinued the study, three were lost to follow-up (one V710 5-μg recipient and two placebo recipients), one moved (a V710 5-μg recipient), and one joined the Army Reserve (a V710 90-μg recipient). No subject discontinued the study because of an adverse event. Six subjects (three each in the V710 90-μg and placebo groups) were excluded from the per-protocol immunogenicity analysis at day 14 because of serious protocol violations (including high baseline antibody concentration in two subjects, concomitant vaccination[s] in one subject, and missing data for three subjects).

FIG. 2.

Proportion of subjects with a positive immune response (A) and geometric mean concentrations of IsdB-specific IgG (B) over time. All vaccinated patients without serious protocol violations were included in these analyses. No missing data were imputed. Bars at day 14 represent 95% confidence intervals.