title: 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: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Sanofi Pasteur.
authors.affiliation: Research Institute for Tropical Medicine, Alabang, Muntinlupa City, Philippines.
authors.forename: Maria Rosario
authors.initials: MR
authors.lastname: Capeding
authors.affiliation: Pasteur Institute Ho Chi Minh City, Ho Chi Minh City, Vietnam.
authors.forename: Ngoc Huu
authors.initials: NH
authors.lastname: Tran
authors.affiliation: Department of Child Health, Medical School, University of Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
authors.forename: Sri Rezeki S
authors.initials: SR
authors.lastname: Hadinegoro
authors.affiliation: Pediatric Institute, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia.
authors.forename: Hussain Imam H J Muhammad
authors.initials: HI
authors.lastname: Ismail
authors.affiliation: Queen Sirikit National Institute of Child Health, Bangkok, Thailand.
authors.forename: Tawee
authors.initials: T
authors.lastname: Chotpitayasunondh
authors.affiliation: Chong Hua Hospital, Cebu City Guadalupe Health Center Annex, Guadalupe, Cebu City, Philippines.
authors.forename: Mary Noreen
authors.initials: MN
authors.lastname: Chua
authors.affiliation: Pasteur Institute Ho Chi Minh City, Ho Chi Minh City, Vietnam.
authors.forename: Chan Quang
authors.initials: CQ
authors.lastname: Luong
authors.affiliation: Child Health Department, Hasan Sadikin Hospital-Faculty of Medicine, Padjadjaran University, Bandung, Indonesia.
authors.forename: Kusnandi
authors.initials: K
authors.lastname: Rusmil
authors.affiliation: Department of Preventive Medicine, School of Medicine, Udayana University, Denpasar, Bali, Indonesia.
authors.forename: Dewa Nyoman
authors.initials: DN
authors.lastname: Wirawan
authors.affiliation: Department of Paediatrics, Penang Hospital, Penang, Malaysia.
authors.forename: Revathy
authors.initials: R
authors.lastname: Nallusamy
authors.affiliation: Vaccine Trial Centre, Faculty of Tropical Medicine, Mahidol University, Ratchathewi, Bangkok, Thailand.
authors.forename: Punnee
authors.initials: P
authors.lastname: Pitisuttithum
authors.affiliation: Dengue Project Banpong-Photharam, Faculty of Tropical Medicine, Mahidol University, Ratchathewi, Bangkok, Thailand.
authors.forename: Usa
authors.initials: U
authors.lastname: Thisyakorn
authors.affiliation: Department of Virology, US Army Medical Component-Armed Forces Research Institute of Medical Sciences (USAMC-AFRIMS), US Army Medical Component, Bangkok, Thailand.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Yoon
authors.affiliation: Sanofi Pasteur, Marcy-l'Étoile, France. Electronic address: diane.vandervliet@sanofipasteur.com.
authors.forename: Diane
authors.initials: D
authors.lastname: van der Vliet
authors.affiliation: Sanofi Pasteur, Marcy-l'Étoile, France.
authors.forename: Edith
authors.initials: E
authors.lastname: Langevin
authors.affiliation: Sanofi Pasteur, Makati City, Philippines.
authors.forename: Thelma
authors.initials: T
authors.lastname: Laot
authors.affiliation: Sanofi Pasteur, Singapore, Singapore.
authors.forename: Yanee
authors.initials: Y
authors.lastname: Hutagalung
authors.affiliation: Sanofi Pasteur, Singapore, Singapore.
authors.forename: Carina
authors.initials: C
authors.lastname: Frago
authors.affiliation: Sanofi Pasteur, Swiftwater, PA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Boaz
authors.affiliation: Sanofi Pasteur, Singapore, Singapore.
authors.forename: T Anh
authors.initials: TA
authors.lastname: Wartel
authors.affiliation: Sanofi Pasteur, Marcy-l'Étoile, France.
authors.forename: Nadia G
authors.initials: NG
authors.lastname: Tornieporth
authors.affiliation: Sanofi Pasteur, Lyon, France.
authors.forename: Melanie
authors.initials: M
authors.lastname: Saville
authors.affiliation: Sanofi Pasteur, Singapore, Singapore.
authors.forename: Alain
authors.initials: A
authors.lastname: Bouckenooghe
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003715:Dengue / Q000517:prevention & control*; D053059:Dengue Vaccines / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D053208:Kaplan-Meier Estimate; D008297:Male; D016896:Treatment Outcome
chemical_list: D053059:Dengue Vaccines