Maria Rosario Capeding1, Ngoc Huu Tran2, Sri Rezeki S Hadinegoro3, Hussain Imam H J Muhammad Ismail4, Tawee Chotpitayasunondh5, Mary Noreen Chua6, Chan Quang Luong2, Kusnandi Rusmil7, Dewa Nyoman Wirawan8, Revathy Nallusamy9, Punnee Pitisuttithum10, Usa Thisyakorn11, In-Kyu Yoon12, Diane van der Vliet13, Edith Langevin14, Thelma Laot15, Yanee Hutagalung16, Carina Frago16, Mark Boaz17, T Anh Wartel16, Nadia G Tornieporth14, Melanie Saville18, Alain Bouckenooghe16. 1. Research Institute for Tropical Medicine, Alabang, Muntinlupa City, Philippines. 2. Pasteur Institute Ho Chi Minh City, Ho Chi Minh City, Vietnam. 3. Department of Child Health, Medical School, University of Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia. 4. Pediatric Institute, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia. 5. Queen Sirikit National Institute of Child Health, Bangkok, Thailand. 6. Chong Hua Hospital, Cebu City Guadalupe Health Center Annex, Guadalupe, Cebu City, Philippines. 7. Child Health Department, Hasan Sadikin Hospital-Faculty of Medicine, Padjadjaran University, Bandung, Indonesia. 8. Department of Preventive Medicine, School of Medicine, Udayana University, Denpasar, Bali, Indonesia. 9. Department of Paediatrics, Penang Hospital, Penang, Malaysia. 10. Vaccine Trial Centre, Faculty of Tropical Medicine, Mahidol University, Ratchathewi, Bangkok, Thailand. 11. Dengue Project Banpong-Photharam, Faculty of Tropical Medicine, Mahidol University, Ratchathewi, Bangkok, Thailand. 12. Department of Virology, US Army Medical Component-Armed Forces Research Institute of Medical Sciences (USAMC-AFRIMS), US Army Medical Component, Bangkok, Thailand. 13. Sanofi Pasteur, Marcy-l'Étoile, France. Electronic address: diane.vandervliet@sanofipasteur.com. 14. Sanofi Pasteur, Marcy-l'Étoile, France. 15. Sanofi Pasteur, Makati City, Philippines. 16. Sanofi Pasteur, Singapore, Singapore. 17. Sanofi Pasteur, Swiftwater, PA, USA. 18. Sanofi Pasteur, Lyon, France.
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. 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.
RCT Entities:
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.
Authors: Alba Grifoni; Michael Angelo; John Sidney; Sinu Paul; Bjoern Peters; Aruna D de Silva; Elizabeth Phillips; Simon Mallal; Sean A Diehl; Jason Botten; Jonathan Boyson; Beth D Kirkpatrick; Stephen S Whitehead; Anna P Durbin; Alessandro Sette; Daniela Weiskopf Journal: J Virol Date: 2017-03-29 Impact factor: 5.103
Authors: Ge Liu; Langzhou Song; David W C Beasley; Robert Putnak; Jason Parent; John Misczak; Hong Li; Lucia Reiserova; Xiangyu Liu; Haijun Tian; Wenzhe Liu; Darlene Labonte; Lihua Duan; Youngsun Kim; Linda Travalent; Devin Wigington; Bruce Weaver; Lynda Tussey Journal: Clin Vaccine Immunol Date: 2015-03-11