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.
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.



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 aluminium 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 ClinicalTrials.gov, 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.



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.



Biomedizinische Forschungs GmbH.
Department of Clinical Pharmacology, Medical University of Vienna, Austria.
Michael
M
Schwameis
Biomedizinische Forschungs GmbH, Vienna, Austria.
Bernhard
B
Roppenser
Department of Clinical Pharmacology, Medical University of Vienna, Austria.
Christa
C
Firbas
Biomedizinische Forschungs GmbH, Vienna, Austria.
Corina S
CS
Gruener
Biomedizinische Forschungs GmbH, Vienna, Austria.
Nina
N
Model
Biomedizinische Forschungs GmbH, Vienna, Austria.
Norbert
N
Stich
Biomedizinische Forschungs GmbH, Vienna, Austria.
Andreas
A
Roetzer
Department of Clinical Pharmacology, Medical University of Vienna, Austria.
Nina
N
Buchtele
Department of Clinical Pharmacology, Medical University of Vienna, Austria. Electronic address: bernd.jilma@meduniwien.ac.at.
Bernd
B
Jilma
Biomedizinische Forschungs GmbH, Vienna, Austria. Electronic address: martha.eibl@meduniwien.ac.at.
Martha M
MM
Eibl
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000293:Adolescent; D000328:Adult; D001427:Bacterial Toxins / Q000302:isolation & purification; D004311:Double-Blind Method; D004768:Enterotoxins / Q000302:isolation & purification; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007115:Immunization Schedule; D007117:Immunization, Secondary / Q000379:methods*; D008297:Male; D008875:Middle Aged; D012772:Shock, Septic / Q000517:prevention & control*; D018089:Superantigens / Q000302:isolation & purification; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D055815:Young Adult
D000276:Adjuvants, Immunologic; D001427:Bacterial Toxins; D004768:Enterotoxins; D018089:Superantigens; D014614:Vaccines, Synthetic; C030107:enterotoxin F, Staphylococcal