Men and nonpregnant women aged 18 to 80 years with ESRD who were on chronic hemodialysis via one of a variety of access sites (including native-vessel fistula, synthetic/heterologous graft, or dual-lumen cuffed catheter) and who had a Karnofsky score of ≥50 were eligible. Pertinent exclusion criteria included known or suspected immunologic impairment (beyond ESRD), anticipated renal transplantation within 180 days of study entry, serious S. aureus infection in the previous 12 months, an oral-equivalent temperature of ≥100.4°F (≥38.0°C) in the 48 h before vaccination, previous vaccination with V710, vaccination with a live-virus vaccine within 30 days before the study vaccination or anticipated vaccination with a live-virus vaccine within 60 days following study entry, any other vaccination within 14 days of the study vaccination or anticipated vaccination within 60 days following study entry (except for influenza and hepatitis B vaccines, which were prohibited only from 7 days before to 15 days after each study injection), and systemic corticosteroid (prednisone equivalent dose of ≥20 mg daily) or other immunosuppressive therapy or biological agents within 14 days of the study vaccination or anticipated administration of such medications within 60 days of study entry.
All patients gave written informed consent prior to participation. The study was conducted in accordance with the principles of the Declaration of Helsinki and good clinical practices and was approved by the appropriate institutional review boards and regulatory agencies.
This 1-year, randomized, blinded, placebo-controlled study of adults with ESRD who were on chronic hemodialysis (Merck protocol 005, ClinicalTrials.gov registration number NCT00572910) was conducted at 12 centers in the United States from 25 August 2008 to 28 January 2010. Eligible patients were randomized in a 2:2:2:2:2:1 ratio to 1 of 5 experimental groups to receive at least 1 dose of V710 (groups 1 to 5) or to 1 control group receiving saline placebo only (group 6) (). All patients received their priming doses on day 1 and day 28, with a booster dose (equally divided between V710 and placebo) on day 180. For data presentation in this paper, each group is described by the 3 doses received on days 1, 28, and 180 (for example, 60 μg/60 μg/60 μg represents group 1a, who received 3 60-μg doses of V710).
Patient groups and dosing regimens. AAHSA, amorphous aluminum hydroxyphosphate sulfate adjuvant.
V710 was supplied as a lyophilized product in a glass vial and was reconstituted with either 0.45% saline or amorphous aluminum hydroxyphosphate sulfate adjuvant (AAHSA), depending on the treatment group. Because of the differences in appearance between the lyophilized V710 solution and the saline placebo, an unblinded member of the study site staff prepared and administered vaccine or placebo but had no further involvement with any subsequent study procedure, including safety follow-up. All other individuals involved with the study, including investigators, participants, and the clinical monitors and statisticians employed by the sponsor, remained blinded to treatment group throughout the study. Randomization and allocation were assigned using an interactive voice response system. Numbered packaging was used to implement allocation.
Sera were assayed for IsdB-specific IgG antibodies using the Luminex multianalyte profiling platform. Samples were collected at day 1 (prevaccination), day 28 (prevaccination), and days 56, 84, 180 (prevaccination), 210, 270, and 360 after the initial vaccination. Specimens were drawn before or within the first hour of hemodialysis when hemodialysis coincided with a study visit.
Immunogenicity was evaluated as the geometric mean fold rise (GMFR) over baseline and the geometric mean concentration (GMC) of anti-IsdB IgG. The primary immunogenicity endpoint was ≥2.5 GMFR over baseline in anti-IsdB IgG titers 28 days after the second vaccination (i.e., day 56) in groups receiving 2 doses of 60 or 90 μg of V710 (i.e., groups 1, 3, and 5). The threshold of 2.5 GMFR represents a value exceeding assay and routine biological variability so that a change of this magnitude or greater is a reliable index of immunogenicity (even if not necessarily a marker for clinical protection). The criterion was empirically derived from the observed within-subject variability and maximum longitudinal fluctuations in titers among control subjects in earlier studies (7
Secondary endpoints included (i) ≥2.5 GMFR 28 days after the first vaccination of 60 or 90 μg of V710 (groups 1 and 2 combined, groups 3 and 4 combined, and group 5), (ii) ≥2.0 GMFR 180 days after the first vaccination of 60 or 90 μg of V710 in groups receiving 2 active doses (groups 1, 3, and 5), and (iii) ≥2.5 GMFR 56 days after a single vaccination of 60 μg of V710 (groups 2 and 4).
Exploratory endpoints included the kinetics and durability of the immune response assessed by GMFRs and GMCs over time, comparisons between 60- and 90-μg doses of V710, and immunogenicity of 60 μg V710 with and without AAHSA. For a subset of patients in each group, preimmune and 28-day postvaccination sera were tested for opsonophagocytic antibody (16
); bactericidal activity was not assessed.
Safety and tolerability.
Patients were monitored for 30 min after each vaccination for immediate reactions. Patients recorded the following on vaccination report cards after each vaccination: oral temperatures and injection site reactions for 5 days, all systemic and local adverse events (AEs) for 14 days, and concomitant medications and non-study vaccinations for 14 days. Report cards were collected and reviewed by study personnel 14 days after each vaccination. Fever was defined as any oral temperature ≥100.4°F (≥38.0°C); documented or subjective fever within 14 days of vaccination was to be reported as an AE.
Safety parameters included all serious AEs and systemic AEs for 14 days following each vaccination, injection site AEs for 5 days following each vaccination, and body temperatures for 5 days following each vaccination. To provide an overall safety assessment, vaccine-related serious AEs, serious AEs leading to death, and serious AEs involving S. aureus infection were assessed for the entire study duration.
An independent safety evaluation committee reviewed all unblinded safety data once at least 50% of patients had received each of the first, second, and third vaccinations to determine whether enrollment should continue in a given treatment group.
The primary hypothesis was that at least 1 of the 3 groups receiving 2 doses of V710 (i.e., groups 1, 3, and 5) would have a ≥2.5-fold rise from the baseline in anti-IsdB IgG titers (i.e., the lower bound of the 95% confidence interval [CI] of the GMFR would be ≥2.5 times the baseline titers) 28 days after the second vaccination (i.e., day 56). GMFR was analyzed using a linear mixed longitudinal model that included baseline and postbaseline natural-log-transformed antibody titers as response variables. Repeated measures included terms for treatment, time, the interaction of time and treatment, and age (<50 years and ≥50 years). The primary analysis was based on the per-protocol population, defined as subjects who were followed for 56 days postvaccination and did not develop an S. aureus infection during this time frame. Patients who missed vaccinations were not included in serology analysis at time points after the missed vaccinations. For patients who developed S. aureus infection after day 56, serology data collected at a visit right before or any time subsequent to infection onset were also excluded from immunogenicity analyses.
A step-down procedure was used to account for multiple comparisons among treatment groups and endpoints. Group 5 was tested first (1-sided α = 0.025), and if significant, testing proceeded to groups 1 and 3, which were tested using Hochberg's approach. Both groups were first tested using a 1-sided α of 0.025. If both tests were significant or nonsignificant, testing was complete. If only one test was significant, that group was retested at a 1-sided α of 0.0125.
Each of the secondary immunogenicity analyses were controlled individually for type I errors at 0.025 in the same manner as for the primary immunogenicity analysis. No multiplicity adjustments were made for the safety comparisons.
All patients who were vaccinated and who had follow-up safety data were included in the safety summaries. Only descriptive statistics without formal between-group comparisons were computed.
Assuming GMFRs at day 56 of 5.0 in group 1, 5.0 in group 3, and 6.0 in group 5 and a standard deviation of log (fold rise) of 1.0, 34 evaluable patients (i.e., in the per-protocol population) in each of these groups would provide >99% power to detect a GMFR of ≥2.5 at day 56 (1-sided α = 0.025) for group 5 and ~99% power for groups 1 and 3, with a global power of ~97.9%.