Safety, tolerability, and immunogenicity of a recombinant toxic shock syndrome toxin (rTSST)-1 variant vaccine: a randomised, double-blind, adjuvant-controlled, dose escalation first-in-man trial

Background Staphylococcal toxic shock syndrome is a superantigen-driven potentially life-threatening disease affecting mainly young and otherwise healthy individuals. Currently, no specific treatment or preventive measure is available. We aimed to assess the safety, tolerability, and immunogenicity of a recombinant detoxified toxic shock syndrome toxin-1 variant (rTSST-1v) vaccine in adult volunteers. Methods In this randomised, double-blind, adjuvant-controlled, dose-escalation first-in-human trial, healthy adults aged 18-64 years were enrolled from the Medical University of Vienna, Austria. Participants were randomly assigned (2:1 and 3:1) by block randomisation (block sizes of three and 12) to receive increasing doses of rTSST-1v (100 ng to 30 mu g) or the adjuvant comparator aluminium hydroxide (Al(OH)(3)) (200 mu g, 600 mu g, or 1 mg). Investigators and participants were masked to group allocation. The per-protocol population received a booster immunisation 42 days after the first vaccination. The primary endpoint was safety and tolerability of rTSST-1v. The per-protocol population included all participants who had adhered to the study protocol without any major protocol deviations. The per protocol population was the primary analysis population for immunogenicity. The trial is registered with EudraCT, number 2013-003716-50, and ClinicalTrials.gov, number NCT02340338. Findings Between Aug 19, 2014, and April 14, 2015, 46 participants were enrolled (safety population), of whom three were assigned to cohort 1 (two to receive 100 ng rTSST-1v and one to receive 200 mu g Al(OH)(3)), three to cohort 2 (two to receive 300 ng rTSST-1v and one to receive 600 mu g Al(OH)(3)), four to cohort 3 (three to receive 1 mu g rTSST-1v and one to receive 1 mg Al(OH)(3)), 12 to cohort 4 (nine to receive 3 mu g rTSST-1v and three to receive 1 mg Al(011),), 12 to cohort 5 (nine to receive 10 mu g rTSST-1v and three to receive 1 mg Al(OH),), and 12 to cohort 6 (nine to receive 300 mu g rTSST-1v and three to receive 1 mu g Al(OH)(3)). 45 participants (98%) were included in the per-protocol population. rTSST-1v had a good safety profile, and no vaccination-related severe or serious adverse events occurred. Adverse event rates were similar between participants who received rTSST-1v and those who received placebo (26 [76%] vs 10 [83%]; p=0.62) independent of pre-existing TSST-1 immunity. Interpretation rTSST-1v was safe, well-tolerated, and immunogenic. This study represents an important step in vaccine development to prevent or treat a potentially lethal disease.