Lot-to-lot consistency of a tetravalent dengue vaccine in healthy adults in Australia: a randomised study

Abstract

Background: The recombinant yellow fever-17D-dengue virus, live, attenuated, tetravalent dengue vac-cine (CYD-TDV) has undergone extensive clinical trials. Here safety and consistency of immunogenicityof phase III manufacturing lots of CYD-TDV were evaluated and compared with a phase II lot and placeboin a dengue-naïve population.Methods: Healthy 18–60 year-olds were randomly assigned in a 3:3:3:3:1 ratio to receive three sub-cutaneous doses of either CYD-TDV from any one of three phase III lots or a phase II lot, or placebo,respectively in a 0, 6, 12 month dosing schedule. Neutralising antibody geometric mean titres (PRNT50GMTs) for each of the four dengue serotypes were compared in sera collected 28 days after the thirdvaccination—equivalence among lots was demonstrated if the lower and upper limits of the two-sided95% CIs of the GMT ratio were ≥0.5 and ≤2.0, respectively.Results: 712 participants received vaccine or placebo and 614 (86%) completed the study; 17 (2.4%) par-ticipants withdrew after adverse events. Equivalence of phase III lots was demonstrated for 11 of 12pairwise comparisons. One of three comparisons for serotype 2 was not statistically equivalent. GMTsfor serotype 2 in phase III lots were close to each other (65.9, 44.1 and 58.1, respectively).Conclusions: Phase III lots can be produced in a consistent manner with predictable immune responseand acceptable safety profile similar to previously characterised phase II lots. The phase III lots maybe considered as not clinically different as statistical equivalence was shown for serotypes 1, 3 and 4across the phase III lots. For serotype 2, although equivalence was not shown between two lots, the GMTsobserved in the phase III lots were consistently higher than those for the phase II lot. As such, in our view,biological equivalence for all serotypes was demonstrated.