Safety and immunogenicity of the Vi-DT typhoid conjugate vaccine in healthy volunteers in Nepal: an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial

Abstract

Background Typhoid fever is an endemic disease in many low-income and middle-income countries. The 2018 WHO position paper recommends that countries should consider typhoid vaccination in high-risk groups and for outbreak control. To address the typhoid vaccine supply and demand gap, a typhoid Vi polysaccharide-diphtheria toxoid (Vi-DT) conjugate vaccine development effort was undertaken to achieve WHO prequalification and contribute to the global supply of typhoid conjugate vaccine. The main aim of this study was to show immune non-inferiority of the Vi-DT vaccine compared with the WHO prequalified Vi polysaccharide-tetanus toxoid (Vi-TT) conjugate vaccine (Typbar TCV; Bharat Biotech India, Hyderabad, India) in participants of various ages from an endemic country. Methods We did an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial at four hospitals in Kathmandu, Dhulikhel, Dharan, and Nepalgunj in Nepal. Eligible participants were healthy individuals aged 6 months to 45 years for whom informed consent was obtained, were willing to follow the study procedures and were available for the duration of the study. Patients with an acute or chronic illness that could interfere with interpretation of the study endpoints, or who were involved in any other clinical trial were excluded. Participants were randomly assigned (1:1:1:1) by block randomisation (block size of four and eight), stratified by age (6 months to <2 years, 2 years to <18 years, and 18 years to 45 years), into one of four groups (A-D). Participants in groups A-C received a single dose (25 μg; 0•5 mL) of Vi-DT test vaccine via intramuscular injection from one of three good manufacturing practice lots (group A received lot 1, group B received lot 2, and group C received lot 3), and those in group D received a single dose (25 μg; 0•5 mL) of the Vi-TT vaccine via intramuscular injection. All participants, site staff (except for those who administered the study vaccines), and those assessing the outcomes were masked to group assignment. The co-primary endpoints were: (1) non-inferiority of immunogenicity of the Vi-DT vaccine (pooled groups A-C) versus the Vi-TT vaccine (group D), measured by the anti-Vi IgG seroconversion rate at 4 weeks after vaccination; and(2) the lot-to-lot consistency of the Vi-DT vaccine, measured by immune equivalence of the anti-Vi IgG geometric mean titre (GMT) at 4 weeks after receipt of the three Vi-DT vaccine lots (lot 1 vs lot 2, lot 1 vs lot 3, and lot 2 vs lot 3). Non-inferiority of the Vi-DT vaccine compared with the Vi-TT vaccine was shown if the lower limit of the 97•5% CI for the difference between the seroconversion rates in Vi-DT vaccine groups A-C combined versus Vi-TT vaccine group D was above the predefined non-inferiority margin of -10%. Lot-to-lot immune equivalence was shown if the upper and lower bounds of the two-sided 99•17% CI around the GMT ratio for each pairwise lot-to-lot comparison was between 0•67 and 1•50, which is the predefined equivalence margin recommended by WHO. The co-pri...

Safety and Immunogenicity of Inactivated and Recombinant Protein SARS-CoV-2 Vaccines in Patients With Thyroid Cancer

“…Previous studies found that the multiple types of SARS-CoV-2 vaccines had satisfactory safety and immunogenicity in healthy adults (22). Our study focused on the effect of inactivated (25).…”

Safety and immunogenicity of conjugate vaccine for typhoid (Vi-DT): Finding from an observer-blind, active-controlled, randomized, non-inferiority, phase III clinical trial among healthy volunteers

“…As a part of the safety evaluation, each participant’s height, weight, and vital signs were assessed at each study visit, detailed schedule of visit is described previously. 28 …”

“…The study also demonstrated safety and immunological non-inferiority of Vi-DT compared to Vi-TT conjugate typhoid vaccine. 28 As many randomized clinical trials have provided data on toddlers and children, allotting the major bulk of the study to the adult population was critical to address the scarcity of data on the safety and immunogenicity of typhoid-conjugated vaccines in Nepalese adults. 6–8 , 25 , 29 Hence, we report age stratum specific safety and immunogenicity, mainly focusing adult age group, of a single dose of Vi-DT with a single dose of Vi-TT from subset study conducted at Dhulikhel Hospital, Kathmandu University Hospital, Nepal.…”

Typhoid fever control in the 21st century: where are we now?

“…There is currently a comparatively robust TCV development pipeline. Four companies have programmes with a TCV candidate with phase III clinical trials ongoing or completed – BioTCV [Vi polysaccharide conjugated to diphtheria toxoid (Vi-DT), PT Biofarma, Indonesia], EuTYPH-C (Vi-CRM197, EuBiologics, South Korea) [59], SKYTyphoid (Vi-DT, SK Bioscience, South Korea) [60], and ZYVAC TCV (Vi-TT, Zydus Cadila, India, licensed in India). All four manufacturers are seeking WHO prequalification.…”