Randomized, double-blind, placebo-controlled, phase 3 trial to demonstrate lot-to-lot consistency of 3 lots of the simplified formulation of Butantan-dengue vaccine

Abstract

Background We aimed to evaluate the consistency of the immune response on Day 28 postvaccination with three consecutive lots of simplified formulation of Butantan-Dengue Vaccine (Butantan-DV) and to describe the frequency of vaccine-related adverse events from vaccination through Day 21 postvaccination in comparison to placebo.

Methods: We included 700 participants allocated in a ratio 2:2:2:1 in parallel arms to receive any of three lots of simplified Butantan-DV or placebo, aged 18 to 59 years, without previous exposure to dengue in two study sites from a non-endemic area in Southern of Brazil. The consistency of three lots of the Butantan-DV were evaluated by analyzing the serum neutralizing antibody titers against four dengue virus serotypes by virus reduction neutralization test (VRNT₆₀), on the Day 28 post-vaccination. Criterion for lot-to-lot consistency was two-sided 95 % confidence interval (95 % CI) of geometric mean titers (GMT) ratio within the margins of equivalence of >1/2 and < 2.0 for 12 possible pairwise comparison for the three lots and four serotypes in the Per-Protocol Set. Adverse events were analysed according to the frequency and Miettinen & Nurminen method to build 95 % CI for the difference in the binomial proportions of each lot with the placebo group. This trial is registered with ClinicalTrials.gov, NCT02406729.

Findings: Between November 4th, 2022 and January 16th, 2023, 700 participants were randomized and vaccinated, while 607 (86.7 %) were included in the Per-Protocol Set. From the 12 possible pairwise comparison between three lots and four serotypes of DENV, 10 met the endpoint of equivalence of lots and 2 failed marginally. The overall frequency of vaccine-related adverse events was 90.8 % (544/599) in Butantan-DV group and 76 % (76/100) in placebo group.

Interpretation: Three lots of simplified formulation were safe and achieved the endpoint of equivalence of lots.

Funding: Intramural Research Program US NIH National Institute of Allergy and Infectious Diseases, Brazilian National Bank for Economic and Social Development, and Fundação Butantan.