A randomized, double-blind study on the safety and immunogenicity of rTSST-1 variant vaccine: phase 2 results

Abstract

Background: Toxic shock syndrome toxin-1 (TSST-1) is a superantigen produced by Staphylococcus aureus that causes the life-threatening toxic shock syndrome. The development of a safe and immunogenic vaccine against TSST-1 remains an unmet medical need. We investigated the safety, tolerability and immunogenicity of a recombinant TSST-1 variant vaccine (rTSST-1v) after 1-3 injections in healthy volunteers.

Methods: In this randomised, double-blind, adjuvant-controlled, parallel-group, phase 2 trial, healthy adults aged 18-64 were randomly allocated to undergo 1-3 injections of either 10 or 100 μg rTSST-1v or Al(OH)₃. The primary endpoint was safety and tolerability of rTSST-1v in the intention-to-treat population. The per-protocol population was used for the immunogenicity analysis. The trial is registered with EudraCT#: 2015-003714-24; ClinicalTrials.gov#: NCT02814708.

Findings: Between April and November 2017,140 subjects were enrolled and 126 completed the trial. rTSST-1v showed a good safety and tolerability profile. A total of 855 systemic adverse events occurred, 280 of which were suspected related adverse events, without dose dependency. Two participants were discontinued early because of allergic reactions. Seroconversion occurred in >81% of subjects within 3 months of the first immunisation which was sustained until 18 months after the third immunisation in over 70% of subjects in the pooled low-dose group and in over 85% in the pooled high-dose group.

Interpretation: rTSST-1v in cumulative doses of up to 300 μg was safe, well-tolerated and highly immunogenic. Two immunisations with 100 μg rTSST-1v provided the most persistent immune response and may be evaluated in future trials.

Funding: Biomedizinische Forschung & Bio-Produkte AG funded this study.

Keywords: Staphylococcus aureus; Superantigen; TSST-1; Toxic shock syndrome; Vaccine.

Fig. 1

Trial profile.

Fig. 2

Increase of TSST-1 binding antibody titres after the first immunisation and following the second and third immunisation in the per-protocol population divided by rTSST-1v recipients and the control group. Scatter dot blots are shown with GMTs and 95% CI.

Fig. 3

In vitro inhibition of T-cell proliferation (A) and IL-2 gene expression (B) by 1000-fold and 3000-fold diluted sera in rTSST-1v recipients and the control group obtained before the first immunisation (day 0), 3 months after day 0 (idealized; = 3 months after the first immunisation), 12 months after day 0 (idealized; = 3 months after the third immunisation), and 24 months after day 0 (idealized; = 15 months after the third immunisation). Horizontal lines correspond to geometric means and 95% confidence intervals. For detailed methodology, please refer to the appendix.

Fig. 4

Neutralising antibody titres for the expression of T cell-associated cytokines IFN-γ, IL-2, IL-6, and TNF-α in rTSST-1v recipients and the control group obtained before the first immunisation (day 0), 3 months after day 0 (idealized; = 3 months after the first immunisation), 12 months after day 0 (idealized; = 3 months after the third immunisation), and 24 months after day 0 (idealized; = 15 months after the third immunisation). For detailed methodology, please refer to the appendix. Horizontal lines correspond to geometric means and 95% confidence intervals.