Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial

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.

[1]  S. Yoksan,et al.  The Use of Dengue Nonstructural Protein 1 Antigen for the Early Diagnosis During the Febrile Stage in Patients With Dengue Infection , 2008, The Pediatric infectious disease journal.

[2]  D. Francis,et al.  Candidate HIV/AIDS vaccines: lessons learned from the World's first phase III efficacy trials , 2003, AIDS.

[3]  A. Barrett,et al.  Yellow fever vaccine , 2005 .

[4]  V. Barban,et al.  Broad neutralization of wild-type dengue virus isolates following immunization in monkeys with a tetravalent dengue vaccine based on chimeric yellow fever 17D/dengue viruses. , 2012, Virology.

[5]  Saravudh Suvannadabba,et al.  Dengue Infection in Children in Ratchaburi, Thailand: A Cohort Study. II. Clinical Manifestations , 2012, PLoS neglected tropical diseases.

[6]  G. Crane.  Dengue haemorrhagic fever: diagnosis, treatment, prevention and control , 1999 .

[7]  Inacio Mandomando,et al.  Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial , 2004, The Lancet.

[8]  F. Guirakhoo,et al.  Recombinant Chimeric Yellow Fever-Dengue Type 2 Virus Is Immunogenic and Protective in Nonhuman Primates , 2000, Journal of Virology.

[9]  H. Margolis,et al.  Dengue Infection in Children in Ratchaburi, Thailand: A Cohort Study. I. Epidemiology of Symptomatic Acute Dengue Infection in Children, 2006–2009 , 2012, PLoS neglected tropical diseases.

[10]  Aidan McDermott,et al.  The Impact of the Demographic Transition on Dengue in Thailand: Insights from a Statistical Analysis and Mathematical Modeling , 2009, PLoS medicine.

[11]  A. Nisalak,et al.  A plaque reduction test for dengue virus neutralizing antibodies. , 1967, Journal of immunology.

[12]  J. Hombach.  Guidelines for clinical trials of dengue vaccine in endemic areas. , 2009, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[13]  Charles H. Hoke,et al.  SEROTYPE-SPECIFIC DENGUE VIRUS CIRCULATION AND DENGUE DISEASE IN BANGKOK, THAILAND FROM 1973 TO 1999 , 2003 .

[14]  I. Bosch,et al.  Population dynamics of DENV-1 genotype V in Brazil is characterized by co-circulation and strain/lineage replacement , 2012, Archives of Virology.

[15]  L. Peruski,et al.  Development and Evaluation of Serotype- and Group-Specific Fluorogenic Reverse Transcriptase PCR (TaqMan) Assays for Dengue Virus , 2001, Journal of Clinical Microbiology.

[16]  H. Margolis,et al.  Best Practices in Dengue Surveillance: A Report from the Asia-Pacific and Americas Dengue Prevention Boards , 2010, PLoS neglected tropical diseases.

[17]  Duane J. Gubler,et al.  The Economic Burden of Dengue , 2012, The American journal of tropical medicine and hygiene.

[18]  C. Lanata,et al.  Immunogenicity and safety of tetravalent dengue vaccine in 2-11 year-olds previously vaccinated against yellow fever: randomized, controlled, phase II study in Piura, Peru. , 2012, Vaccine.

[19]  P. Gething,et al.  Refining the Global Spatial Limits of Dengue Virus Transmission by Evidence-Based Consensus , 2012, PLoS neglected tropical diseases.

[20]  N. Breslow,et al.  Statistical methods in cancer research. Volume II--The design and analysis of cohort studies. , 1987, IARC scientific publications.

[21]  Richard G Jarman,et al.  Analysis of repeat hospital admissions for dengue to estimate the frequency of third or fourth dengue infections resulting in admissions and dengue hemorrhagic fever, and serotype sequences. , 2007, The American journal of tropical medicine and hygiene.

[22]  M. Diamond,et al.  Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions , 2012, Proceedings of the National Academy of Sciences.

[23]  D. Clements,et al.  Dengue vaccines: progress and challenges. , 2011, Current opinion in immunology.

[24]  J. Lang,et al.  Live-attenuated Tetravalent Dengue Vaccine in Dengue-naïve Children, Adolescents, and Adults in Mexico City: Randomized Controlled Phase 1 Trial of Safety and Immunogenicity , 2011, The Pediatric infectious disease journal.

[25]  L. Shek,et al.  Immunogenicity and safety of recombinant tetravalent dengue vaccine (CYD-TDV) in individuals aged 2–45 years , 2012, Human Vaccines & Immunotherapeutics.

[26]  A. Barrett,et al.  Guidelines for Plaque-Reduction Neutralization Testing of Human Antibodies to Dengue Viruses. , 2008, Viral immunology.

[27]  M. Guzmán,et al.  The epidemiology of dengue in the americas over the last three decades: a worrisome reality. , 2010, The American journal of tropical medicine and hygiene.

[28]  B. Murphy,et al.  Immune response to dengue virus and prospects for a vaccine. , 2011, Annual review of immunology.

[29]  N. Lennon,et al.  Emergence of the Asian 1 Genotype of Dengue Virus Serotype 2 in Viet Nam: In Vivo Fitness Advantage and Lineage Replacement in South-East Asia , 2010, PLoS neglected tropical diseases.

[30]  B. Guy,et al.  From research to phase III: preclinical, industrial and clinical development of the Sanofi Pasteur tetravalent dengue vaccine. , 2011, Vaccine.

[31]  B. Guy,et al.  Evaluation of interferences between dengue vaccine serotypes in a monkey model. , 2009, The American journal of tropical medicine and hygiene.

[32]  S. Halstead,et al.  Japanese encephalitis: new options for active immunization. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[33]  Cameron P. Simmons,et al.  Current concepts: Dengue , 2012 .

[34]  J. Lang,et al.  Live-attenuated, tetravalent dengue vaccine in children, adolescents and adults in a dengue endemic country: randomized controlled phase I trial in the Philippines. , 2011, Vaccine.

[35]  Stephen J. Thomas,et al.  Critical issues in dengue vaccine development , 2011, Current opinion in infectious diseases.

[36]  A. D. de Silva,et al.  The Human Antibody Response to Dengue Virus Infection , 2011, Viruses.

[37]  Stephen J. Thomas,et al.  Vaccines for the prevention of dengue: Development update , 2011, Human vaccines.