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

Summary

Background

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.

Methods

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.

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 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.

Interpretation

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.

Funding

Sanofi Pasteur.

Introduction

An estimated 390 million dengue infections take place every year and roughly 96 million people have clinically apparent disease.1, 2, 3 About 70% of the overall disease burden, which has increased by 30 times in the past 50 years, is reported in the Asia-Pacific region.1, 3 Four viral serotypes cause disease in proportions that change unpredictably over time and from place to place, even within the same country. Incidence has increased in older age groups in many countries where dengue is endemic.1, 4

No licensed vaccines and no specific treatments are available to prevent dengue infection. The vaccine candidate assessed here is a recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV) that has been consistently well tolerated and immunogenic in clinical studies in Asia and Latin America.5, 6, 7, 8, 9 A first, proof-of-concept efficacy trial¹ including 4002 Thai children aged 4–11 years, did not meet its primary outcome, with a vaccine efficacy of 30·2% (95% CI −13·4 to 56·6). In exploratory intention-to-treat analyses, the lower bound of the 95% CI for the serotype-specific vaccine efficacy for serotypes 1, 3, and 4 was greater than 0 after the first injection, but not after the third injection, possibly because of the lower number of cases.¹⁰

We did this phase 3 efficacy trial of dengue vaccine to assess the efficacy of the CYD dengue vaccine against symptomatic, virologically confirmed dengue, irrespective of serotype or disease severity. In an ongoing second study phase, long-term safety surveillance for trial participants admitted to hospital for acute febrile illness will continue for an additional 4 years (ie, a total of 5 years follow-up after the third dose).