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 μg) or the adjuvant comparator aluminum hydroxide (Al(OH)3) (200 μg, 600 μg, 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, number NCT02340338. 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 μg Al(OH)3), three to cohort 2 (two to receive 300 ng rTSST-1v and one to receive 600 μg Al(OH)3), four to cohort 3 (three to receive 1 μg rTSST-1v and one to receive 1 mg Al(OH)3), 12 to cohort 4 (nine to receive 3 μg rTSST-1v and three to receive 1 mg Al(OH)3), 12 to cohort 5 (nine to receive 10 μg rTSST-1v and three to receive 1 mg Al(OH)3), and 12 to cohort 6 (nine to receive 300 μg rTSST-1v and three to receive 1 mg 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.

There were no safety concerns related to the administration of rTSST-1 Variant Vaccine in the dose range from 10 µg-300 µg as there were no clinically relevant differences in comparison to the incidence of systemic adverse events in the placebo group, particularly in the incidence of suspected related systemic AE. The reported mild and moderate events were typically those observed with common vaccinations and posed no particular problems to the involved subjects or the physicians performing the study. Likewise, injection site reactions were typically those observed in vaccination trials, although their incidence was moderately higher in dose groups receiving rTSST-1 Variant Vaccine when compared the placebo control. As no dose limiting cumulating toxicity was observed, the absolute dose of 300 µg rTSST-1 Variant Vaccine administered in this study is therefore not considered as the maximum tolerated dose. Considering the immune response, however, two immunizations might be sufficient to produce high and persisting rTSST-1 antibody titers with an elimination half-life of at least one year. As for Phase I, seroconversion in Phase II was defined as increase of the TSST-1 Ab titer of <20 (or <min) to ≥40 or a 4-fold increase in TSST-1 antibody titer in comparison to baseline (day 0, the day of the first immunization). When compared with the placebo group receiving only the adjuvant Al(OH)3, a statistically significant effect on immunogenicity was observed three months after the first immunization and continued throughout the whole treatment and follow-up period at a significance level of p<0.0001 (rTSST-1 Variant Vaccine versus placebo). This effect was therefore consistently confirmed at high statistical significance before the second immunization until the end of the observation period in dependent of the administered dose. The maximum seroconversion in subjects receiving low-dose vaccine (10 µg-30 µg rTSST-1 Variant Vaccine) was 83.3% and was in 88.2% of the subjects receiving high-dose vaccine (100 µg-300 µg rTSST-1 Variant Vaccine).