Materials & methods
®, typhoid
ADVERSE EVENTS, CHRONIC ILLNESS, SECONDARY, TYPHOID, EVENTS
This was a randomized, observer-blind, active-controlled, non-inferiority, phase 3 clinical trial to compare the immunogenicity and safety of Vi-DT vaccine (SK Bioscience) to the locally available licensed Vi-TT vaccine Typbar TCV (Bharat Biotech International). It was done over a period of one year (2019–2020) at BPKIHS, Dharan, Nepal. Regulatory approvals were obtained from Nepal Health Research Council (Nepal), Department of Drug Administration (Nepal), Institutional Review Board of IVI (Korea) and the Institutional Review Committee at BPKIHS. This study is part of the phase 3 clinical trial conducted at four different sites in Nepal.Eligible participants were healthy individuals aged 6 months to 45 years volunteers. Individuals with an acute or chronic illness that could interfere with interpretation of the study endpoints, those with known history of typhoid or household contact with or intimate exposure to an individual with typhoid or had previously received a typhoid vaccine or who were already involved in any other clinical trial were excluded. Written informed consent or assent was obtained from all participants, parents, or legal guardians before participation in the screening activities with a copy of the document given to them for their records.Eligible participants from different villages of Sunsari and Morang districts of eastern Nepal were randomized into four study groups (groups A – D) in a 1:1:1:1 ratio and within the groups separated into 3 age strata (6 months to <2 years, 2 years to <18 years, and 18 years to 45 years). Groups A-C received a single dose of Vi-DT test vaccine composed of 25 µg Vi polysaccharide/0.5 ml, presented in 3 ml multiple dose glass vial from one of the 3 lots (lot numbers S121901, S121902, and S121903). Group D received a single dose of the comparator Typbar-TCV® vaccine composed of 25 µg Vi polysaccharide/0.5 ml, presented in a single dose glass vial (lot number 76C19023A).Randomization was done using block randomization process, with random block sizes of four and eight for ensuring effective balance between the interventions. An independent statistician generated the randomization list with unique sequential numbers for each participant and vaccination group (A – D). The blinded study team was provided with separate randomization list without information on vaccine allocation for enrollment while the blinded study team had the randomization list with vaccine allocation information for vaccine administration.All the randomized participants underwent baseline blood sampling followed by administration of 0·5 mL of either Vi-DT or Vi-TT vaccine by the unblinded study nurse in a separate room. Participants received intramuscular injection in the left anterolateral thigh (for participants below 2 years of age) or the left deltoid region and were observed at the study site for a minimum of 30 minutes after vaccination. The participants, investigators, and clinical staff involved in postvaccination safety evaluation were all blinded to group assignment.Post-vaccination adverse events were recorded in a diary card in the form of immediate reactions (within 30 minutes), solicited adverse events (during the first 7 days), unsolicited adverse events (till 4 weeks), and serious adverse events (throughout the 24-week study period). For safety evaluation, weight, height, heart rate, respiratory rate, and body temperature of each participant were taken and recorded at each study visit. All adverse events were classified by system organ class and preferred terms of the Medical Dictionary for Regulatory Activities (version 22.0). The assessment of vaccine safety and monitoring of safety events was done by an independent data safety monitoring board, which included independent clinical experts and a biostatistician.For immunogenicity analysis, blood samples were taken from each participant before vaccination at baseline (day 0) and after vaccination at day 28 (week 4) and day 168 (week 24). An in-house ELISA was used to measure anti-Vi IgG antibody concentrations.The primary endpoint of this study was anti-Vi IgG seroconversion rates of Vi-DT vaccine (pooled groups A – C) compared to Vi-TT vaccine (group D) at 4 weeks postvaccination. Seroconversion was defined as a four-fold or greater increase in antibody titers in comparison to the baseline titers. Anti-Vi IgG seroconversion rate at 24 weeks post-vaccination was taken as the secondary endpoint.Safety endpoints were frequency of local and systemic adverse events (immediate, unsolicited, solicited, or serious) reported in the study.Sample size calculation was done based upon 99% power for determining non-inferiority of immunogenicity of Vi-DT vaccine (pooled groups A-C) compared to Vi-TT vaccine (group D); the details of the sample size calculation for the main study have been mentioned elsewhere. (2) Based upon the WHO Technical Report Series 924, the predefined non-inferiority margin of −10% was taken and non-inferiority of the Vi-DT vaccine compared to Vi-TT vaccine was considered if the lower limit of 97.5% CI for the difference between the seroconversion rates was above this limit. A one-sided test of non-inferiority was used with a significance level of 0.0125.Data were analyzed using both intention-to-treat and per-protocol analysis methods; the definitions for the analysis sets are mentioned elsewhere.For statistical analysis, SAS 9.4 statistical software was used along with chi-square tests for determining p-value for categorical variables.This trial is registered with ClinicalTrials.gov, NCT03933098.