Oct 11, 2014 Volume 384 Number 9951 p1321 – 1400 e49 – 51
Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial
Maria Rosario Capeding MD a, Prof Ngoc Huu Tran MD b, Prof Sri Rezeki S Hadinegoro MD c, Hussain Imam HJ Muhammad Ismail FRCPCH d, Tawee Chotpitayasunondh MD e, Mary Noreen Chua MD f, Chan Quang Luong MD b, Prof Kusnandi Rusmil PhD g, Prof Dewa Nyoman Wirawan MD h, Revathy Nallusamy MBBS i, Punnee Pitisuttithum MD j, Prof Usa Thisyakorn MD k, In-Kyu Yoon MD l, Dr Diane van der Vliet MD m, Edith Langevin MSc m, Thelma Laot MD n, Yanee Hutagalung MD o, Carina Frago MD o, Mark Boaz PhD p, T Anh Wartel MD o, Nadia G Tornieporth MD m, Melanie Saville MBBS q, Alain Bouckenooghe MD o, the CYD14 Study Group
An estimated 100 million people have symptomatic dengue infection every year. This is the first report of a phase 3 vaccine efficacy trial of a candidate dengue vaccine. We aimed to assess the efficacy of the CYD dengue vaccine against symptomatic, virologically confirmed dengue in children.
We did an observer-masked, randomised controlled, multicentre, phase 3 trial in five countries in the Asia-Pacific region. Between June 3, and Dec 1, 2011, healthy children aged 2—14 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 stratified 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 efficacy against symptomatic, virologically confirmed 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 efficacy to be greater than 25%. Analysis was by intention to treat and per procotol. This trial is registered with ClinicalTrials.gov, number NCT01373281.
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 confirmed 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 56•5% (95% CI 43•8—66•4) efficacy. 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.
Our findings show that dengue vaccine is efficacious when given as three injections at months 0, 6, and 12 to children aged 2—14 years in endemic areas in Asia, and has a good safety profile. Vaccination could reduce the incidence of symptomatic infection and hospital admission and has the potential to provide an important public health benefit.