Dataset Information

Safety and Immunogenicity of a Recombinant Tetanus Vaccine in Healthy Adults in China: A Randomized, Double-Blind, Dose Escalation, Placebo- and Positive-Controlled, Phase 1/2 Trial.

ABSTRACT: Tetanus is a fatal but vaccine-preventable disease. The currently available tetanus vaccines are tetanus toxoid (TT)-based. Although these vaccines are generally effective, challenges in vaccine development and access remain. A randomized, double-blind, dose escalation, placebo- and positive-controlled, phase 1/2 trial (ChiCTR1800015865) is performed to evaluate the safety and immunogenicity of an alternative recombinant tetanus vaccine based on the Hc domain of tetanus neurotoxin (TeNT-Hc) in healthy adult volunteers. The primary outcome is the safety profile of the recombinant tetanus vaccine, and immunogenicity is the secondary outcome. 150 eligible participants were enrolled and randomly assigned to receive one of the three doses of recombinant tetanus vaccine (TeNT-Hc 10/20/30 µg), TT vaccine, or placebo. The recombinant tetanus vaccine shows a good safety profile. The frequency of any solicited and unsolicited adverse events after each vaccination does not differ across the vaccine and placebo recipients. No serious treatment-related adverse events occur. The recombinant tetanus vaccine shows strong immune responses (seroconversion rates, geometric mean titer, and antigen-specific CD4+/CD8+ T-cell responses), which are roughly comparable to those of the TT vaccine. In conclusion, the findings from this study support that recombinant tetanus vaccine is safe and immunogenic; thereby, it represents a novel vaccine candidate against tetanus.

SUBMITTER: Xu X

PROVIDER: S-EPMC8336487 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Safety and Immunogenicity of a Recombinant Tetanus Vaccine in Healthy Adults in China: A Randomized, Double-Blind, Dose Escalation, Placebo- and Positive-Controlled, Phase 1/2 Trial.

Xu Xiaowei X Yu Rui R Xiao Lanlan L Wang Jie J Yu Meihong M Xu Junjie J Tan Yajun Y Ma Xiao X Wu Xiaoxin X Lian Jiangshan J Huang Kaizhou K Ouyang Xiaoxi X Bi Sheng S Wu Shipo S Wang Xiaoyan X Jin Jiandi J Yu Ling L Zhang Huafen H Wei Qi Q Shi Jinfa J Chen Wei W Li Lanjuan L

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20210603 15

Tetanus is a fatal but vaccine-preventable disease. The currently available tetanus vaccines are tetanus toxoid (TT)-based. Although these vaccines are generally effective, challenges in vaccine development and access remain. A randomized, double-blind, dose escalation, placebo- and positive-controlled, phase 1/2 trial (ChiCTR1800015865) is performed to evaluate the safety and immunogenicity of an alternative recombinant tetanus vaccine based on the Hc domain of tetanus neurotoxin (TeNT-Hc) in h ...[more]

PMID: 34081408

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Project description:BackgroundDasiglucagon is a novel glucagon analog that is stable in aqueous formulation and approved for use in severe hypoglycemia. Concentration QTc analyses are critical for assessing risk of drug-induced QTc prolongation and potential for fatal cardiac arrhythmias such as torsades de pointes.ObjectiveThe aim of this study was to determine whether dasiglucagon treatment resulted in any clinically relevant effect on cardiac repolarization in healthy volunteers.MethodsThis double-blind, placebo-controlled, dose-escalation Phase I trial was conducted at a single center in Germany between November 2018 and June 2019. Sixty healthy volunteers aged 18 to 45 years were randomized within dose cohorts to receive intravenous dasiglucagon, intravenous placebo, or subcutaneous dasiglucagon. In the intravenous administration cohorts, doses ranged from 0.03 mg to 1.5 mg. The subcutaneous administration cohort received the approved 0.6 mg dose. In the intravenous administration cohorts, serial electrocardiograms were extracted from continuous Holter monitors at prespecified time points beginning the day before dosing and through 24 hours postdose. Heart rate, PR interval, and QRS duration were evaluated. Concentration-QT analyses corrected by Fridericia's formula (QTcF) were performed using both a linear mixed-effects and a maximum estimated effect (Emax) model.ResultsAt the doses studied, dasiglucagon did not have any clinically relevant effect on heart rate, PR interval, or QRS duration. A minor prolongation of the QTcF interval was observed without any clear dose or concentration dependency. Both the linear and Emax models predicted mean and 90% CIs of placebo-corrected change in QTcF remained below 10 ms (the threshold of regulatory concern), although the linear model did not fit the data well at low dasiglucagon plasma concentrations. In the Emax model, the Emax of dasiglucagon was 3.6 ms (90% CI, 1.23-5.95 ms), and the amount to produce half the effect of Emax) was 426.0 pmol/L (90% CI, -48.8 to 900.71 pmol/L). The treatment effect-specific intercept was -0.44 ms (90% CI, -2.37 to 1.49 ms). The most frequently observed treatment-emergent adverse events reported in the trial were gastrointestinal disorders such as nausea and vomiting.ConclusionsDasiglucagon does not cause clinically relevant QTc prolongation in concentrations up to ≈30,000 pmol/L, a level 5-fold higher than the highest observed plasma concentrations in clinical trials investigating use of the approved 0.6 mg SC dose. ClinicalTrials.gov Identifier: NCT03735225; EudraCT identifier: 2018-002025-32. (Curr Ther Res Clin Exp. 2022; 83:XXX-XXX).

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Dataset Information

Safety and Immunogenicity of a Recombinant Tetanus Vaccine in Healthy Adults in China: A Randomized, Double-Blind, Dose Escalation, Placebo- and Positive-Controlled, Phase 1/2 Trial.

Publications

Safety and Immunogenicity of a Recombinant Tetanus Vaccine in Healthy Adults in China: A Randomized, Double-Blind, Dose Escalation, Placebo- and Positive-Controlled, Phase 1/2 Trial.

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