Study of a Novel Tetravalent Dengue Vaccine in Healthy Children and Adolescents Aged 9 to 16 Years in Latin America

NCT01374516 | Completed Phase 3 Results DMC

• 2 other identifiers: CYD15UTN: U1111-1116-4986
• Study Type: interventional
• Target: 20,869
• Locations: 5 countries
• Sites: 22

Brief Summary

The aim of the study was to assess the efficacy of Sanofi Pasteur's CYD dengue vaccine in preventing symptomatic virologically-confirmed dengue cases for dengue-endemic areas of Latin America. Primary Objective: To assess the efficacy of CYD dengue vaccine after 3 vaccinations at 0, 6, and 12 months in preventing symptomatic virologically-confirmed dengue (VCD) cases, regardless of the severity, due to any of the four serotypes in children and adolescents aged 9 to 16 years at the time of inclusion. Secondary Objectives:

• To describe the efficacy of CYD dengue vaccine in preventing symptomatic VCD cases after the third dose to the end of the Active Phase, after at least 1 dose, and after 2 doses.
• To describe the occurrence of hospitalized VCD cases and the occurrence of severe (clinically severe or as per World Health Organization (WHO) criteria) VCD cases, throughout the Surveillance Expansion Period (SEP) and throughout the trial (from Day 0 until the end of the study).
• To describe the antibody response to each dengue serotype after Dose 2, after Dose 3, and 1 and 5 years after Dose 3.
• To describe the occurrence of serious adverse events (SAEs), including SAEs of special interest in all participants throughout the trial period.

Conditions

Dengue Fever; Dengue Hemorrhagic Fever; Dengue

Keywords

Dengue Virus; Dengue fever; Dengue Hemorrhagic Fever; CYD dengue vaccine; Flavivirus; Dengue Disease

Outcome Measures

Primary Outcomes (1)

• Number of Symptomatic Virologically Confirmed Dengue (VCD) Cases Due to Any Serotype During the Active Phase Post-dose 3 Following Injection With Either CYD Dengue Vaccine or a Placebo

  Symptomatic VCD cases were defined as occurrence of acute febrile illness (temperature \>=38°C on at least 2 consecutive days) and confirmation of dengue virus infection by dengue reverse transcriptase polymerase chain reaction (RT-PCR) and/or dengue non-structural (NS) protein 1 antigen enzyme-linked immunosorbent assay (ELISA). Vaccine efficacy was defined as 1 minus the ratio of density incidence due to any serotype after at least 1 dose in the CYD Dengue Vaccine Group over the density incidence of the Placebo Group.

  28 days and up to 13 months post-injection 3

Secondary Outcomes (13)

• Number of Symptomatic VCD Cases Due to Any Serotype During the Active Phase Following Injection With Either CYD Dengue Vaccine or a Placebo

  Day 0 up to 13 months post-injection 3

• Number of Symptomatic VCD Cases Due to Any Serotype Occurring 28 Days Post-dose 1 Following Injection With Either CYD Dengue Vaccine or a Placebo

  28 days post-injection 1 and up to 13 months post-injection 3

• Number of Symptomatic VCD Cases Due to Any Serotype Post-dose 2 Following Injection With Either CYD Dengue Vaccine or a Placebo

  28 days post-injection 2 and up to 13 months post-injection 3

• Number of Symptomatic VCD Cases Meeting World Health Organization (WHO) Criteria Throughout the Trial Due to Any Serotype Following Injection With Either CYD Dengue Vaccine or a Placebo

  Day 0 to the end of study (up to 72 months)

• Number of Symptomatic VCD Cases Meeting WHO Criteria During the Surveillance Expansion Period Due to Any Serotype Following Injection With Either CYD Dengue Vaccine or a Placebo

  From consent to participate in the Surveillance Expansion Period to the end of study (up to 72 months)

Study Arms (2)

CYD Dengue Vaccine Group

EXPERIMENTAL

Participants were to receive 3 doses of CYD dengue vaccine; one each at 0, 6, and 12 months.

Biological: Live, attenuated, dengue serotype 1, 2, 3, 4 virus

Placebo Group

PLACEBO COMPARATOR

Participants were to receive a placebo vaccine at 0, 6, and 12 months.

Biological: Placebo: (NaCl) 0.9% solution

Interventions

Live, attenuated, dengue serotype 1, 2, 3, 4 virus BIOLOGICAL

0.5 mL, Subcutaneous

Also known as: CYD Dengue Vaccine

CYD Dengue Vaccine Group

Placebo: (NaCl) 0.9% solution BIOLOGICAL

0.5 mL, Subcutaneous

Placebo Group

Eligibility Criteria

• Age: 9 Years - 16 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• Participant in good health, based on medical history and physical examination
• Assent form or informed consent form has been signed and dated by the participant (based on local regulations), and informed consent form has been signed and dated by the parent(s) or another legally acceptable representative (and by an independent witness if required by local regulations)
• Participant was able to attend all scheduled visits and comply with all trial procedures.

You may not qualify if:

• Participant was pregnant, or lactating, or of childbearing potential (to be considered of non-childbearing potential, a female must be pre-menarche for at least 1 year, surgically sterile, or using an effective method of contraception or abstinence from at least 4 weeks prior to the first vaccination until at least 4 weeks after the last vaccination).
• Participation in another clinical trial investigating a vaccine, drug, medical device, or a medical procedure in the 4 weeks preceding the first trial vaccination
• Planned participation in another clinical trial during the present trial period
• Self-reported or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 6 months; or long-term systemic corticosteroids therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months)
• Self-reported seropositivity for Human Immunodeficiency Virus (HIV) infection
• Self-reported systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccine used in the trial or to a vaccine containing any of the same substances
• Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere with trial conduct or completion
• Receipt of blood or blood-derived products in the past 3 months, which might interfere with assessment of the immune response
• Planned receipt of any vaccine in the 4 weeks following any trial vaccination
• Deprived of freedom by administrative or court order, or in an emergency setting, or hospitalized involuntarily
• Current alcohol abuse or drug addiction that may interfere with the participant's ability to comply with trial procedures
• Identified as a site employee of the Investigator or study center, with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, as well as a family member (i.e., immediate, husband, wife and their children, adopted or natural) of the site employees or the Investigator.

Sponsors & Collaborators

• Sanofi Pasteur, a Sanofi Company: lead

Study Sites (22)

Unknown Facility

Fortaleza, Ceará, 60430 270, Brazil

Location

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Vitória, Espírito Santo, 29040 09, Brazil

Location

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Goiânia, Goiás, 74675 020, Brazil

Location

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Campo Grande, Mato Grosso do Sul, 79074 460, Brazil

Location

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Natal, Rio Grande do Norte, 59025 600, Brazil

Location

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Aguazul, Casanare Department, Colombia

Location

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Yopal, Casanare Department, Colombia

Location

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Girardot City, Cundinamarca, Colombia

Location

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Acacías, Meta Department, Colombia

Location

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Armenia, Quindío Department, Colombia

Location

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Calarcá, Quindío Department, Colombia

Location

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La Tebaida, Quindío Department, Colombia

Location

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Montenegro, Quindío Department, Colombia

Location

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Bucaramanga, Santander Department, Colombia

Location

Unknown Facility

Tegucigalpa, Municipalidad Del Distrito Central, Honduras

Location

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Temixco, Morelos, Mexico

Location

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Municipio de Cd. Mante, Tamaulipas, Mexico

Location

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Veracruz Puerto, Veracruz, Mexico

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Tizimín, Yucatán, Mexico

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Valladolid, Yucatán, Mexico

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Guayama, 00784, Puerto Rico

Location

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San Juan, 00918, Puerto Rico

Location

Related Publications (15)

• Villar L, Dayan GH, Arredondo-Garcia JL, Rivera DM, Cunha R, Deseda C, Reynales H, Costa MS, Morales-Ramirez JO, Carrasquilla G, Rey LC, Dietze R, Luz K, Rivas E, Miranda Montoya MC, Cortes Supelano M, Zambrano B, Langevin E, Boaz M, Tornieporth N, Saville M, Noriega F; CYD15 Study Group. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med. 2015 Jan 8;372(2):113-23. doi: 10.1056/NEJMoa1411037. Epub 2014 Nov 3.

  PMID: 25365753 RESULT

• Hadinegoro SR, Arredondo-Garcia JL, Capeding MR, Deseda C, Chotpitayasunondh T, Dietze R, Muhammad Ismail HI, Reynales H, Limkittikul K, Rivera-Medina DM, Tran HN, Bouckenooghe A, Chansinghakul D, Cortes M, Fanouillere K, Forrat R, Frago C, Gailhardou S, Jackson N, Noriega F, Plennevaux E, Wartel TA, Zambrano B, Saville M; CYD-TDV Dengue Vaccine Working Group. Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. N Engl J Med. 2015 Sep 24;373(13):1195-206. doi: 10.1056/NEJMoa1506223. Epub 2015 Jul 27.

  PMID: 26214039 RESULT

• Arredondo-Garcia JL, Hadinegoro SR, Reynales H, Chua MN, Rivera Medina DM, Chotpitayasunondh T, Tran NH, Deseda CC, Wirawan DN, Cortes Supelano M, Frago C, Langevin E, Coronel D, Laot T, Perroud AP, Sanchez L, Bonaparte M, Limkittikul K, Chansinghakul D, Gailhardou S, Noriega F, Wartel TA, Bouckenooghe A, Zambrano B; CYD-TDV Dengue Vaccine Study Group. Four-year safety follow-up of the tetravalent dengue vaccine efficacy randomized controlled trials in Asia and Latin America. Clin Microbiol Infect. 2018 Jul;24(7):755-763. doi: 10.1016/j.cmi.2018.01.018. Epub 2018 Feb 8.

  PMID: 29408333 RESULT

• L'Azou M, Moureau A, Sarti E, Nealon J, Zambrano B, Wartel TA, Villar L, Capeding MR, Ochiai RL; CYD14 Primary Study Group; CYD15 Primary Study Group. Symptomatic Dengue in Children in 10 Asian and Latin American Countries. N Engl J Med. 2016 Mar 24;374(12):1155-66. doi: 10.1056/NEJMoa1503877.

  PMID: 27007959 RESULT

• Sridhar S, Luedtke A, Langevin E, Zhu M, Bonaparte M, Machabert T, Savarino S, Zambrano B, Moureau A, Khromava A, Moodie Z, Westling T, Mascarenas C, Frago C, Cortes M, Chansinghakul D, Noriega F, Bouckenooghe A, Chen J, Ng SP, Gilbert PB, Gurunathan S, DiazGranados CA. Effect of Dengue Serostatus on Dengue Vaccine Safety and Efficacy. N Engl J Med. 2018 Jul 26;379(4):327-340. doi: 10.1056/NEJMoa1800820. Epub 2018 Jun 13.

  PMID: 29897841 RESULT

• Savarino SJ, Bonaparte M, Wang H, Dayan GH, Forrat R, Zhu M, Hodge S, Ataman-Onal Y, DiazGranados CA. Accuracy and efficacy of pre-dengue vaccination screening for previous dengue infection with a new dengue rapid diagnostic test: a retrospective analysis of phase 3 efficacy trials. Lancet Microbe. 2022 Jun;3(6):e427-e434. doi: 10.1016/S2666-5247(22)00033-7. Epub 2022 May 4.

  PMID: 35659904 DERIVED

• Laydon DJ, Dorigatti I, Hinsley WR, Nedjati-Gilani G, Coudeville L, Ferguson NM. Efficacy profile of the CYD-TDV dengue vaccine revealed by Bayesian survival analysis of individual-level phase III data. Elife. 2021 Jul 2;10:e65131. doi: 10.7554/eLife.65131.

  PMID: 34219653 DERIVED

• Henein S, Adams C, Bonaparte M, Moser JM, Munteanu A, Baric R, de Silva AM. Dengue vaccine breakthrough infections reveal properties of neutralizing antibodies linked to protection. J Clin Invest. 2021 Jul 1;131(13):e147066. doi: 10.1172/JCI147066.

  PMID: 34003796 DERIVED

• Forrat R, Dayan GH, DiazGranados CA, Bonaparte M, Laot T, Capeding MR, Sanchez L, Coronel DL, Reynales H, Chansinghakul D, Hadinegoro SRS, Perroud AP, Frago C, Zambrano B, Machabert T, Wu Y, Luedtke A, Price B, Vigne C, Haney O, Savarino SJ, Bouckenooghe A, Noriega F. Analysis of Hospitalized and Severe Dengue Cases Over the 6 years of Follow-up of the Tetravalent Dengue Vaccine (CYD-TDV) Efficacy Trials in Asia and Latin America. Clin Infect Dis. 2021 Sep 15;73(6):1003-1012. doi: 10.1093/cid/ciab288.

  PMID: 33822015 DERIVED

• DiazGranados CA, Bonaparte M, Wang H, Zhu M, Lustig Y, Schwartz E, Forrat R, Dayan GH, Hodge S, Ataman-Onal Y, Savarino SJ. Accuracy and efficacy of pre-dengue vaccination screening for previous dengue infection with five commercially available immunoassays: a retrospective analysis of phase 3 efficacy trials. Lancet Infect Dis. 2021 Apr;21(4):529-536. doi: 10.1016/S1473-3099(20)30695-2. Epub 2020 Nov 16.

  PMID: 33212068 DERIVED

• Reynales H, Carrasquilla G, Zambrano B, Cortes S M, Machabert T, Jing J, Pallardy S, Haney O, Faccini M, Quintero J, Noriega F. Secondary Analysis of the Efficacy and Safety Trial Data of the Tetravalent Dengue Vaccine in Children and Adolescents in Colombia. Pediatr Infect Dis J. 2020 Apr;39(4):e30-e36. doi: 10.1097/INF.0000000000002580.

  PMID: 32040014 DERIVED

• Plennevaux E, Moureau A, Arredondo-Garcia JL, Villar L, Pitisuttithum P, Tran NH, Bonaparte M, Chansinghakul D, Coronel DL, L'Azou M, Ochiai RL, Toh ML, Noriega F, Bouckenooghe A. Impact of Dengue Vaccination on Serological Diagnosis: Insights From Phase III Dengue Vaccine Efficacy Trials. Clin Infect Dis. 2018 Apr 3;66(8):1164-1172. doi: 10.1093/cid/cix966.

  PMID: 29300876 DERIVED

• Rabaa MA, Girerd-Chambaz Y, Duong Thi Hue K, Vu Tuan T, Wills B, Bonaparte M, van der Vliet D, Langevin E, Cortes M, Zambrano B, Dunod C, Wartel-Tram A, Jackson N, Simmons CP. Genetic epidemiology of dengue viruses in phase III trials of the CYD tetravalent dengue vaccine and implications for efficacy. Elife. 2017 Sep 5;6:e24196. doi: 10.7554/eLife.24196.

  PMID: 28871961 DERIVED

• Harenberg A, de Montfort A, Jantet-Blaudez F, Bonaparte M, Boudet F, Saville M, Jackson N, Guy B. Cytokine Profile of Children Hospitalized with Virologically-Confirmed Dengue during Two Phase III Vaccine Efficacy Trials. PLoS Negl Trop Dis. 2016 Jul 26;10(7):e0004830. doi: 10.1371/journal.pntd.0004830. eCollection 2016 Jul.

  PMID: 27459266 DERIVED

• Olivera-Botello G, Coudeville L, Fanouillere K, Guy B, Chambonneau L, Noriega F, Jackson N; CYD-TDV Vaccine Trial Group. Tetravalent Dengue Vaccine Reduces Symptomatic and Asymptomatic Dengue Virus Infections in Healthy Children and Adolescents Aged 2-16 Years in Asia and Latin America. J Infect Dis. 2016 Oct 1;214(7):994-1000. doi: 10.1093/infdis/jiw297. Epub 2016 Jul 14.

  PMID: 27418050 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Dengue; Severe Dengue

Interventions

Solutions

Condition Hierarchy (Ancestors)

Mosquito-Borne Diseases; Vector Borne Diseases; Infections; Arbovirus Infections; Virus Diseases; Flavivirus Infections; Flaviviridae Infections; RNA Virus Infections; Hemorrhagic Fevers, Viral

Intervention Hierarchy (Ancestors)

Pharmaceutical Preparations

Results Point of Contact

• Title: Medical Director
• Organization: Sanofi Pasteur Inc.

RegistryContactUs@sanofipasteur.com

Study Officials

• Medical Director

  Sanofi Pasteur Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 14, 2011
• First Posted: June 16, 2011
• Study Start: June 8, 2011
• Primary Completion: November 1, 2014
• Study Completion: March 5, 2018
• Last Updated: March 21, 2022
• Results First Posted: March 27, 2019

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share

Locations

HO (1); CO (9); BR (5); ME (5); PR (2)