title: Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease.
abstract: BACKGROUND
  A candidate tetravalent dengue vaccine is being assessed in three clinical trials involving more than 35,000 children between the ages of 2 and 16 years in Asian-Pacific and Latin American countries. We report the results of long-term follow-up interim analyses and integrated efficacy analyses.
  
  
  METHODS
  We are assessing the incidence of hospitalization for virologically confirmed dengue as a surrogate safety end point during follow-up in years 3 to 6 of two phase 3 trials, CYD14 and CYD15, and a phase 2b trial, CYD23/57. We estimated vaccine efficacy using pooled data from the first 25 months of CYD14 and CYD15.
  
  
  RESULTS
  Follow-up data were available for 10,165 of 10,275 participants (99%) in CYD14 and 19,898 of 20,869 participants (95%) in CYD15. Data were available for 3203 of the 4002 participants (80%) in the CYD23 trial included in CYD57. During year 3 in the CYD14, CYD15, and CYD57 trials combined, hospitalization for virologically confirmed dengue occurred in 65 of 22,177 participants in the vaccine group and 39 of 11,089 participants in the control group. Pooled relative risks of hospitalization for dengue were 0.84 (95% confidence interval [CI], 0.56 to 1.24) among all participants, 1.58 (95% CI, 0.83 to 3.02) among those under the age of 9 years, and 0.50 (95% CI, 0.29 to 0.86) among those 9 years of age or older. During year 3, hospitalization for severe dengue, as defined by the independent data monitoring committee criteria, occurred in 18 of 22,177 participants in the vaccine group and 6 of 11,089 participants in the control group. Pooled rates of efficacy for symptomatic dengue during the first 25 months were 60.3% (95% CI, 55.7 to 64.5) for all participants, 65.6% (95% CI, 60.7 to 69.9) for those 9 years of age or older, and 44.6% (95% CI, 31.6 to 55.0) for those younger than 9 years of age.
  
  
  CONCLUSIONS
  Although the unexplained higher incidence of hospitalization for dengue in year 3 among children younger than 9 years of age needs to be carefully monitored during long-term follow-up, the risk among children 2 to 16 years of age was lower in the vaccine group than in the control group. (Funded by Sanofi Pasteur; ClinicalTrials.gov numbers, NCT00842530, NCT01983553, NCT01373281, and NCT01374516.).
authors.affiliation: From Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta (S.R.H.); Instituto Nacional de Pediatria, Mexico City (J.L.A.-G.); Research Institute for Tropical Medicine, Muntinlupa City, the Philippines (M.R.C.); Caribbean Travel Medicine Clinic, San Juan, Puerto Rico (C.D.); Queen Sirikit National Institute of Child Health (T.C.), Faculty of Tropical Medicine, Mahidol University (K.L.), and Sanofi Pasteur (D.C.) - all in Bangkok, Thailand; Nucleo de Doencas Infecciosas, Universidade Federal do Espirito Santo, Vitoria, ES, Brazil (R.D.); Hospital Kuala Lumpur, Kuala Lumpur, Malaysia (H.I.H.M.I.); Centro de Atencion e Investigacion Medica SAS-CAIMED (H.R.), and Sanofi Pasteur (M.C.) - both in Bogota, Colombia; Organizacion para el Desarrollo y la Investigacion Salud en Honduras (ODIS), Tegucigalpa (D.M.R.-M.); Pasteur Institute in Ho Chi Minh City, Ho Chi Minh City, Vietnam (H.N.T.); Sanofi Pasteur, Singapore, Singapore (A.B., C.F., T.A.W.); Sanofi R&D, Chilly-Mazarin (K.F.), Marcy l'Etoile (R.F., E.P.), and Lyon (S.G., N.J., M.S.) - all in France; Sanofi Pasteur, Swiftwater, PA (F.N.); and Sanofi Pasteur, Montevideo, Uruguay (B.Z.).
authors.forename: Sri Rezeki
authors.initials: SR
authors.lastname: Hadinegoro
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Arredondo-García
authors.forename: Maria Rosario
authors.initials: MR
authors.lastname: Capeding
authors.forename: Carmen
authors.initials: C
authors.lastname: Deseda
authors.forename: Tawee
authors.initials: T
authors.lastname: Chotpitayasunondh
authors.forename: Reynaldo
authors.initials: R
authors.lastname: Dietze
authors.forename: H I Hj
authors.initials: HI
authors.lastname: Muhammad Ismail
authors.forename: Humberto
authors.initials: H
authors.lastname: Reynales
authors.forename: Kriengsak
authors.initials: K
authors.lastname: Limkittikul
authors.forename: Doris Maribel
authors.initials: DM
authors.lastname: Rivera-Medina
authors.forename: Huu Ngoc
authors.initials: HN
authors.lastname: Tran
authors.forename: Alain
authors.initials: A
authors.lastname: Bouckenooghe
authors.forename: Danaya
authors.initials: D
authors.lastname: Chansinghakul
authors.forename: Margarita
authors.initials: M
authors.lastname: Cortés
authors.forename: Karen
authors.initials: K
authors.lastname: Fanouillere
authors.forename: Remi
authors.initials: R
authors.lastname: Forrat
authors.forename: Carina
authors.initials: C
authors.lastname: Frago
authors.forename: Sophia
authors.initials: S
authors.lastname: Gailhardou
authors.forename: Nicholas
authors.initials: N
authors.lastname: Jackson
authors.forename: Fernando
authors.initials: F
authors.lastname: Noriega
authors.forename: Eric
authors.initials: E
authors.lastname: Plennevaux
authors.forename: T Anh
authors.initials: TA
authors.lastname: Wartel
authors.forename: Betzana
authors.initials: B
authors.lastname: Zambrano
authors.forename: Melanie
authors.initials: M
authors.lastname: Saville
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003715:Dengue / Q000453:epidemiology / Q000517:prevention & control*; D053059:Dengue Vaccines / Q000009:adverse effects / Q000276:immunology*; D003716:Dengue Virus / Q000145:classification; D005260:Female; D005500:Follow-Up Studies; D006760:Hospitalization / Q000706:statistics & numerical data*; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008297:Male; D065288:Serogroup; D014613:Vaccines, Attenuated / Q000009:adverse effects / Q000276:immunology
chemical_list: D053059:Dengue Vaccines; D014613:Vaccines, Attenuated