Safety and immunogenicity of Vi-DT conjugate vaccine among 6-23-month-old children: Phase II, randomized, dose-scheduling, observer-blind Study

Abstract

Background: Typhoid causes significant mortality among young children in resource-limited settings. Conjugate typhoid vaccines could significantly reduce typhoid-related child deaths, but only one WHO-prequalified typhoid conjugate vaccine exists for young children. To address this gap, we investigated the safety, immunogenicity and dose-scheduling of Vi-DT typhoid conjugate vaccine among children aged 6-23 months.

Methods: In this single center, observer blind, phase II trial, participants were randomly assigned (2:2:1) to receive one or two doses of Vi-DT or comparator vaccine. Anti-Vi IgG titer and geometric mean titers (GMT) were determined at 0, 4, 24 and 28 weeks. Data were analyzed using per-protocol and immunogenicity (a subset of intention-to-treat analysis) sets. The trial is registered with ClinicalTrials.gov (NCT03527355).

Findings: Between April and July 2018, 285 children were randomized; 114 received one or two doses of Vi-DT while 57 received comparator. 277 completed the study follow-up per protocol; 112 and 110 from single- and two-dose Vi-DT schedules, respectively and 55 from the placebo group were included in the per protocol analysis. Safety profile is satisfactory. Thirteen serious adverse events were reported during the 28-week follow-up, none of which were related to Vi-DT. The seroconversion rate four weeks after the first dose was 100% (95% CI 98·3-100) in Vi-DT recipients and 7·0% (95% CI 2·8-16·7) in comparator recipients (p<0·0001). Similarly, the seroconversion rate 4 weeks after the second dose was 98·2% (95% CI 93· 6-99·5) and 21·8% (95% CI 13·0-34·4) among Vi-DT and comparator groups, respectively (p<0·0001). Anti-Vi IgG GMT was significantly higher in Vi-DT than in control group at all post-vaccination visits (p<0·0001).

Interpretation: Both single and two doses of Vi-DT vaccine are safe, well tolerated, and immunogenic for infants and toddlers in a moderately endemic setting.

Keywords: Infants and toddlers; Typhoid; Vi-DT; typhoid conjugate vaccine.

Figure 1

Flow diagram of participant disposition (CONSORT flow diagram). * Screen failure – included participants that had abnormal laboratory values on screening, which included abnormal hematological profile, liver enzymes, renal function test and others; † One participant in each age strata 1 and 2 did not receive the 2nd dose of Test Vaccine; ‡ 5 participants (2 in Vi-DT Single dose Group, 2 in Vi-DT Two-dose Group, 1 in Comparator Group) who had delayed the 2nd vaccination. Four participants did not receive the second dose of Vi-DT – once participant due to violation of the selection criteria (i.e., moved out of study area) and three due to withdrawal of consent.

Figure 2

Seroconversion rate by vaccine group, age strata and follow-up time point – Immunogenicity Analysis Set. Seroconversion was defined as 4-fold rise in the anti-Vi IgG titer at week 4 as compared to baseline value. The bars represent the seroconversion rate by age group at different follow up time points; the error bars represent the 95% confidence interval for the point estimate of seroconversion.

Figure 3

GMT of anti-Vi IgG response by vaccine group, age strata and follow-up time point– Immunogenicity set. The line represents the GMT (IU/mL) values at each follow up time points and the error bars represent the 95% Confidence Interval.