Efficacy profile of a bivalent Staphylococcus aureus glycoconjugated vaccine in adults on hemodialysis: Phase III randomized study

Abstract

In a previous study in end-stage renal disease (ESRD) hemodialysis patients, a single dose of Staphylococcus aureus type 5 and 8 capsular polysaccharides (T5/T8) conjugated to nontoxic recombinant Pseudomonas aeruginosa exotoxin A investigational vaccine showed no efficacy against S. aureus bacteremia 1 year post-vaccination, but a trend for efficacy was observed over the first 40 weeks post-vaccination. Vaccine efficacy (VE) of 2 vaccine doses was therefore evaluated. In a double-blind trial 3359 ESRD patients were randomized (1:1) to receive vaccine or placebo at week 0 and 35. VE in preventing S. aureus bacteremia was assessed between 3–35 weeks and 3–60 weeks post-dose-1. Anti-T5 and anti-T8 antibodies were measured. Serious adverse events (SAEs) were recorded for 42 days post-vaccination and deaths until study end. No significant difference in the incidence of S. aureus bacteremia was observed between vaccine and placebo groups between weeks 3–35 weeks post-dose 1 (VE -23%, 95%CI: -98;23, p = 0.39) or at 3–60 weeks post-dose-1 (VE -8%, 95%CI: -57;26, p = 0.70). Day 42 geometric mean antibody concentrations were 272.4 μg/ml and 242.0 μg/ml (T5 and T8, respectively) in vaccinees. SAEs were reported by 24%/25.3% of vaccinees/placebo recipients. These data do not show a protective effect of either 1 or 2 vaccine doses against S. aureus bacteremia in ESRD patients. The vaccine induced a robust immune response and had an acceptable safety profile. Further investigation suggested possible suboptimal vaccine quality (manufacturing) and a need to expand the antigen composition of the vaccine. This study is registered at www.clinicaltrials.gov NCT00071214.

Keywords:

• end stage renal disease
• hemodialysis
• immunogenicity
• Staphylococcus aureus
• vaccine
• vaccine safety

Abbreviations:

• T5/T8, Staphylococcus aureus type 5 and 8 capsular polysaccharides
• CI, confidence interval
• ClfA, S. aureus clumping factor A
• ELISA, enzyme-linked immunosorbent assay
• ESRD, end-stage renal disease
• GMC, geometric mean concentration
• OPK, opsonophagocytic killing
• SAE, Serious adverse event
• VE, vaccine efficacy

Disclosure of Potential Conflicts of Interest

AF and KT were full-time employees of Nabi Biopharmaceuticals at time of study conduct. AF is currently employed by NanoBio Corporation. KT is currently employed by National Institute of Allergy and Infectious Diseases (NIAID). AM and JB received a study grant paid to their institution from Nabi Biopharmaceuticals for participation in this study, but declare no other conflicts of interest. SD and DB are full-time employees of GlaxoSmithKline Vaccines. DB declares ownership of GSK Vaccines stocks. DB is also an inventor of certain GSK patents.

Acknowledgments

The authors thank the volunteers who participated in the study, as well as the investigators, study nurses and other (including former) staff members from Nabi Biopharmaceuticals. The authors also thank Sophie Germain and Hugues Wallemacq from GlaxoSmithKline Vaccines R&D for their input in the manuscript, Dr Joanne Wolter (independent) for writing the first draft of the manuscript, Dr Wouter Houthoofd (XPE Pharma & Science) for publication coordination on behalf of GlaxoSmithKline Vaccines.

Funding

Nabi Biopharmaceuticals was the funding source and was involved in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals SA funded all costs associated with the development and the publishing of the present manuscript. All authors had full access to the data and the corresponding author was responsible for submission of the publication.