Articles www.thelancet.com Published online September 11, 2012 http://dx.doi.org/10.1016/S0140-6736(12)61428-7 1 Published Online September 11, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61428-7 See Online/Comment http://dx.doi.org/10.1016/ S0140-6736(12)61510-4 Department of Tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand (Prof A Sabchareon MD, C Sirivichayakul MD, K Limkittikul MD, P Chanthavanich MD, Prof K Pengsaa MD); Asia-Pacific Clinical Development, Sanofi Pasteur, Singapore (D Wallace MB BS, A Bouckenooghe MD); Ministry of Public Health, Division of Diseases Control, Nonthaburi, Thailand (S Suvannadabba MD); Ratchaburi Hospital, Ratchaburi, Thailand (V Jiwariyavej MD, W Dulyachai MD); Asia-Pacific Clinical Development, Sanofi Pasteur, Bangkok, Thailand (T A Wartel MD); Global Clinical R&D Department (A Moureau MS, M Saville MB BS, S Viviani MD), and Research and Development (J Lang MD), Sanofi Pasteur, Marcy l’Etoile, France; and Global Clinical R&D Department, Sanofi Pasteur, Swiftwater, PA, USA (N G Tornieporth MD) Correspondence to: Dr Derek Wallace, Sanofi Pasteur, 048580, Singapore derek.wallace@sanofipasteur. com Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial Arunee Sabchareon, Derek Wallace, Chukiat Sirivichayakul, Kriengsak Limkittikul, Pornthep Chanthavanich, Saravudh Suvannadabba, Vithaya Jiwariyavej, Wut Dulyachai, Krisana Pengsaa, T Anh Wartel, Annick Moureau, Melanie Saville, Alain Bouckenooghe, Simonetta Viviani, Nadia G Tornieporth, Jean Lang Summary Background Roughly half the world’s population live in dengue-endemic countries, but no vaccine is licensed. We investigated the efficacy of a recombinant, live, attenuated tetravalent dengue vaccine. Methods In this observer-masked, randomised, controlled, monocentre, phase 2b, proof-of-concept trial, healthy Thai schoolchildren aged 4–11 years were randomly assigned (2:1) to receive three injections of dengue vaccine or control (rabies vaccine or placebo) at months 0, 6, and 12. Randomisation was by computer-generated permuted blocks of six and participants were assigned with an interactive response system. Participants were actively followed up until month 25. All acute febrile illnesses were investigated. Dengue viraemia was confirmed by serotype-specific RT-PCR and non-structural protein 1 ELISA. The primary objective was to assess protective efficacy against virologically confirmed, symptomatic dengue, irrespective of severity or serotype, occurring 1 month or longer after the third injection (per-protocol analysis). This trial is registered at ClinicalTrials.gov, NCT00842530. Findings 4002 participants were assigned to vaccine (n=2669) or control (n=1333). 3673 were included in the primary analysis (2452 vaccine, 1221 control). 134 cases of virologically confirmed dengue occurred during the study. Efficacy was 30·2% (95% CI −13·4 to 56·6), and differed by serotype. Dengue vaccine was well tolerated, with no safety signals after 2 years of follow-up after the first dose. Interpretation These data show for the first time that a safe vaccine against dengue is possible. Ongoing large-scale phase 3 studies in various epidemiological settings will provide pivotal data for the CYD dengue vaccine candidate. Funding Sanofi Pasteur. Introduction Dengue has become one of the most important and widespread arthropod-borne viral diseases of human beings, with about half the world’s population now at risk. 1 WHO estimates that 50–100 million dengue infections occur each year in more than 100 countries, and that half a million people develop severe dengue necessitating hospital admission, although the true figures could be higher. 1–3 Symptomatic infection is classified as either dengue or severe dengue, depending on whether the patient recovers after the initial 3–7-day febrile phase, or develops complications as a result of a systemic vascular leakage syndrome. 1,4 There is no specific treatment and, in absence of a vaccine, prevention relies on individual protection against mosquitoes and vector control strat- egies that, in view of the continuing expansion of dengue, have shown their limits as standalone measures. The major challenges facing vaccine research and development include the existence of four pathogenic dengue virus serotypes (DENV1–4) that compete and interact at the immunological level, as well as more practical challenges, such as the lack of suitable animal models or a correlate of protection. 5–7 In more than half a century of research, various vaccine approaches have been attempted and several candidate vaccines are in early clinical or preclinical development. 8 One candidate vaccine, CYD-TDV, is a recombinant, live, attenuated, tetravalent dengue vaccine based on the yellow fever 17D vaccine strain and produced in Vero cells. 7 Phase 1 and 2 trials have been undertaken in southeast Asia and Latin America in cohorts of adults and children who were either immunologically naive against dengue and other flaviviruses before vaccination or who had some degree of pre-existing flaviviral immunity due to vaccin- ation against yellow fever or Japanese encephalitis or natural exposure in endemic areas. 7,9–13 These studies have shown that a three-dose regimen given over 12 months is well tolerated and elicits balanced neutralising antibody responses against the four serotypes in diverse epidemi- ological settings. We present the primary report of the first clinical trial of the protective efficacy of this investigational dengue vaccine. The trial was designed and undertaken in an endemic area according to WHO recommendations. 14 The primary objective was to assess protective efficacy after three injections against virologically confirmed sympto- matic dengue, irrespective of severity or serotype. Passive surveillance for admissions to hospital owing to fever due to dengue is ongoing.