Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: A phase 3, randomised, observer-masked, placebo-controlled trial

Abstract

© © 2014 Elsevier Ltd. Background An estimated 100 million people have symptomatic dengue infection every year. This is the fi rst report of a phase 3 vaccine effi cacy trial of a candidate dengue vaccine. We aimed to assess the effi cacy of the CYD dengue vaccine against symptomatic, virologically confi rmed dengue in children.Methods We did an observer-masked, randomised controlled, multicentre, phase 3 trial in fi ve countries in the Asia- Pacifi c region. Between June 3, and Dec 1, 2011, healthy children aged 214 years were randomly assigned (2:1), by computer-generated permuted blocks of six with an interactive voice or web response system, to receive three injections of a recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV), or placebo, at months 0, 6, and 12. Randomisation was stratifi ed by age and site. Participants were followed up until month 25. Trial staff responsible for the preparation and administration of injections were unmasked to group allocation, but were not included in the follow-up of the participants; allocation was concealed from the study sponsor, investigators, and parents and guardians. Our primary objective was to assess protective effi cacy against symptomatic, virologically confi rmed dengue, irrespective of disease severity or serotype, that took place more than 28 days after the third injection. The primary endpoint was for the lower bound of the 95% CI of vaccine effi cacy to be greater than 25%. Analysis was by intention to treat and per procotol. This trial is registered with ClinicalTrials.gov, number NCT01373281.Findings We randomly assigned 10 275 children to receive either vaccine (n=6851) or placebo (n=3424), of whom 6710 (98%) and 3350 (98%), respectively, were included in the primary analysis. 250 cases of virologically confi rmed dengue took place more than 28 days after the third injection (117 [47%] in the vaccine group and 133 [53%] in the control group). The primary endpoint was achieved with 565% (95% CI 438664) effi cacy. We recorded 647 serious adverse events (402 [62%] in the vaccine group and 245 [38%] in the control group). 54 (1%) children in the vaccine group and 33 (1%) of those in the control group had serious adverse events that happened within 28 days of vaccination. Serious adverse events were consistent with medical disorders in this age group and were mainly infections and injuries.Interpretation Our fi ndings show that dengue vaccine is effi cacious when given as three injections at months 0, 6, and 12 to children aged 214 years in endemic areas in Asia, and has a good safety profi le. Vaccination could reduce the incidence of symptomatic infection and hospital admission and has the potential to provide an important public health benefi t.Funding Sanofi Pasteur.