V710 protocol 001 represents the first trial for the Merck IsdB S. aureus
vaccine in humans. Preclinical studies in rats and rhesus macaques indicated that V710 had the potential to provide relatively rapid protection against a broad spectrum of S. aureus
). In addition, no safety signals with the vaccine were identified in animal toxicology studies. This initial phase I study was conducted with the expressed purpose to assess the immunogenicity, safety, and tolerability of the adjuvanted liquid formulation of V710 in healthy adults between 18 and 55 years of age.
V710 was immunogenic following a single vaccination with all three dosages evaluated (5 μg, 30 μg, or 90 μg). In a small subset of 36 subjects tested on postvaccination day 3, none developed positive immune responses (as defined by a ≥2-fold increase in IsdB-specific IgG concentrations relative to baseline concentrations). Only a minority of subjects developed positive immune responses by day 7. For the 36 subjects tested on day 10, the majority of subjects given the two higher V710 doses exhibited positive immune responses. Most subjects receiving the higher two doses of V710 had positive immune responses at day 14. Significantly more subjects manifested a positive immune response and achieved higher geometric mean antibody concentrations with the 30- and 90-μg doses than with the 5-μg dose or placebo by postvaccination day 14. Antibody titers in subjects receiving the higher doses of vaccine were comparable to levels achieved in the preclinical studies with rhesus macaques (21
). Subsequent to day 14, immune response rates and antibody concentrations remained relatively stable throughout the course of the study to day 84. V710 generated immune responses in the older cohort of subjects (40 to 55 years of age) that were at least comparable to those noted for the younger cohort of subjects (18 to 39 years of age). Serious adverse events were not encountered, although mild-to-moderate injection-site reactions and constitutional symptoms (primarily headache) were seen in vaccine recipients. Because the placebo did not contain an adjuvant, the observed increase in the frequency of pain at the injection site in the vaccine groups (which was comparable across doses) relative to the placebo group could be a consequence of the adjuvant and/or the protein antigen.
Vaccine strategies to prevent S. aureus
infections may need to be tailored to the specific population at risk. High-risk groups include dialysis and cancer patients with chronic indwelling catheters, recipients of prosthetic valves or joints, and patients recovering from cardiothoracic or other major surgery (3
). The peak risk period for cardiac surgical patients is limited to the intra- and postoperative periods, whereas the risk is indefinitely ongoing for dialysis patients with end-stage renal disease. A vaccine containing S. aureus
type 5 and 8 capsular polysaccharides conjugated to nontoxic recombinant Pseudomonas aeruginosa
exotoxin A (StaphVAX; Nabi Biopharmaceuticals, Arlington, VA) conferred partial short-term protection for approximately 40 weeks against S. aureus
bacteremia in patients undergoing hemodialysis in an initial study (39
); however, a larger subsequent study failed to demonstrate any protection at this same time point (S. Deresinski, presented at the 12th International Symposium on Staphylococci and Staphylococcal Infections, Cairns, Australia, 7 to 10 September 2008 [jeny.ipro.org/attachment.php?attachmentid=4692&d=1276005061]). An appropriately powered efficacy study is under way to confirm that V710 can induce relatively rapid immune responses and provide protection against serious S. aureus
infections following single-dose vaccination in an at-risk population. The antibody concentrations against IsdB necessary for reliable protection from serious infections need to be better established (10
). The role and effectiveness of booster doses in patients at chronic risk for S. aureus
infections remain to be elucidated (11
). The possible impact of vaccination on mucocutaneous colonization has not been examined to date (3
). The contributions of the adjuvant to immunogenicity and tolerability cannot be established from these data.
Our findings imply that adjuvanted V710 could provide meaningful protection within 2 weeks of vaccination for patients anticipated to have a definable finite period of high risk for developing an S. aureus infection in the near term. Antibodies were detected by 7 to 14 days after vaccination in healthy subjects and persisted for at least 84 days. No differences in the safety profiles of the two higher-V710-dose groups were identified, and both the 30-μg and 90-μg dosages of V710 generated generally similar immune response rates and antibody concentrations, affording an opportunity to select a dose for future clinical trials that is well bracketed in terms of safety and immunogenicity.