Study of a Novel Tetravalent Dengue Vaccine in Healthy Children Aged 2 to 14 Years in Asia

• ClinicalTrials.gov Identifier: NCT01373281
• Recruitment Status: Completed
• First Posted: June 14, 2011
• Results First Posted: November 16, 2015
• Last Update Posted: March 21, 2022
• Sponsor: Sanofi Pasteur, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Sanofi Pasteur, a Sanofi Company )

Study Description

Brief Summary:

The aim of the trial was to assess the efficacy of the CYD dengue vaccine in preventing symptomatic, virologically-confirmed dengue (VCD) cases.

Primary Objective:

To assess the efficacy of CYD dengue vaccine after 3 vaccinations at 0, 6, and 12 months in preventing symptomatic VCD cases, regardless of the severity, due to any of the four serotypes in children aged 2 to 14 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 serious adverse events (SAEs), including SAEs of special interest in all participants throughout the trial period.
• To describe the occurrence of hospitalized virologically-confirmed dengue (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 to 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.

Condition or disease	Intervention/treatment	Phase
Dengue; Dengue Fever; Dengue Hemorrhagic Fever	Biological: Live, attenuated, dengue serotype 1, 2, 3, 4 virus; Biological: Placebo: Sodium chloride (NaCl) 0.9%	Phase 3

Detailed Description:

Participants were randomized to either receive 3 injections of CYD dengue vaccine or a placebo at 0, 6, and 12 months.

A subset of participants from each country were also evaluated for reactogenicity and immunogenicity.

Participants who consented to participate in the SEP were actively followed for dengue case detection (i.e. at least weekly contact and capturing any acute febrile illness, not just hospitalized febrile cases, as in the Active Phase). The SEP was designed to maximize the detection of symptomatic confirmed dengue (hospitalized or not) in order to describe CYD dengue vaccine efficacy and safety in preventing symptomatic dengue. Participants who declined participating in the SEP continued surveillance as in the Hospital Phase until trial completion.

Symptomatic VCD cases occurring more than (>) 28 days after dose 3 (during the Active Phase) are defined as:

• Acute febrile illness (i.e. temperature >=38 C on at least 2 consecutive days)

• Virologically confirmed by dengue Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and/or dengue non-structural (NS)1 enzyme-linked immunosorbent assay (ELISA) Ag test

  1997 WHO Classification Dengue hemorrhagic fever (DHF) cases were defined as per the 1997 WHO criteria of clinical manifestations; a) Fever: acute onset, high (>= 38°C) and continuous, lasting 2 to 7 days and (b) any of the pre-listed hemorrhagic manifestations and laboratory findings of thrombocytopenia (platelet<=100 x 109/L) and plasma leakage as shown by hemoconcentation (hematocrit increased by 20 percent [%] or more) or pleural effusion (seen on chest X-ray [CXR]) and/or ascites and/or hypoaluminemia. The first two clinical criteria plus thrombocytopenia and signs of plasma leakage are enough to establish a clinical diagnosis of DHF.

DHF was graded as follows:- Grade I: Fever accompanied by non-specific constitutional symptoms; the only hemorrhagic manifestation is a positive tourniquet test; Grade II: Spontaneous bleeding in addition to the manifestations of Grade I participants, usually in the form of skin and/or other hemorrhages; Grade III: Circulatory failure manifested by rapid and weak pulse, narrowing of pulse pressure (20 mmHg or less) or hypotension, with the presence of cold clammy skin and restlessness; and Grade IV: Profound shock with undetectable blood pressure and pulse.

Independent Data Monitoring Committee (IDMC) severity criteria The severity of VCD cases was assessed by an Independent IDMC using pre-defined standardized criteria. Following manifestations of severity were considered in all suspected VCD cases; 1) Platelet count <= 100000μl and bleeding (tourniquet, petechiae or any bleeding) plus plasma leakage (effusion on CXR OR clinically apparent ascites or hematocrit >=20% above baseline recovery level) 2) Shock (pulse pressure <= 20 mmHg in a child, or hypotension [<= 90 mmHg] with tachycardia, weak pulse and poor perfusion) 3) Bleeding requiring blood transfusion 4) Encephalopathy i.e. Unconsciousness or poor conscious state or convulsionsfitting not attributable to simple febrile convulsion as defined in the guidelines for definition and collection of febrile convulsions or focal neurological signs. Poor conscious state or unconsciousness must be supported by Glasgow Coma Scale (GCS) score. 5) Liver impairment (aspartate aminotransferase [AST] >1000IU/L or prothrombin time [PT] International normalized ratio [INR] >1.5) excluding other causes of viral hepatitis 6) Impaired kidney function (serum creatinine ≥ 1.5 mg/dL) 7) Myocarditis, pericarditis or clinical heart failure supported by CXR, echocardiography, electrocardiogram (ECG) or cardiac enzymes.

The designation of such cases as severe or otherwise will be made on a case by case basis by the IDMC.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10275 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Efficacy and Safety of a Novel Tetravalent Dengue Vaccine in Healthy Children Aged 2 to 14 Years in Asia
• Actual Study Start Date: June 3, 2011
• Actual Primary Completion Date: August 1, 2014
• Actual Study Completion Date: November 21, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dengue Vaccine Group; Participants were to receive CYD dengue vaccine at 0, 6, and 12 months.	Biological: Live, attenuated, dengue serotype 1, 2, 3, 4 virus; 0.5 mL, Subcutaneous; Other Name: CYD Dengue Vaccine
Placebo Comparator: Control Group; Participants were to receive a placebo vaccine at 0, 6, and 12 months.	Biological: Placebo: Sodium chloride (NaCl) 0.9%; 0.5 mL, Subcutaneous

Outcome Measures

Primary Outcome Measures :

1. Number of Symptomatic Virologically Confirmed Dengue (VCD) Cases Due to Any Serotype During the Active Phase Post-dose 3 Following Injection (Inj.) With Either CYD Dengue Vaccine or a Placebo [ Time Frame: 28 days and up to 13 months post-dose 3 ]
   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 and/or dengue NS protein 1 antigen enzyme-linked immunosorbent assay. 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 Vaccine Group.

Secondary Outcome Measures :

1. Geometric Mean Titers of Antibodies Against Each Serotype With the Parental Dengue Virus Strain Before and Following Injection With Either CYD Dengue Tetravalent Vaccine or a Placebo [ Time Frame: Pre-injection 1, 28 days post Injections 2 and 3, 13 months (Visit 07) and 60 months (Visit 12) post-injection 3 ]
   Geometric mean titers against each of the 4 serotypes of dengue virus strains were assessed using the plaque reduction neutralization test (PRNT) in a pre-defined subset of participants.
2. Percentage of Participants With Antibody Titers >= 10 1/Dilution (1/Dil) Against Each Dengue Virus Serotype Strain Before and Following Inj. With CYD Dengue Vaccine or Placebo [ Time Frame: Pre-injection 1, 28 days post Injections 2 and 3, 13 months (V 07) and 60 months (V 12) post-injection 3 ]
   Percentage of participants with antibody titers >= 10 (1/Dil) against each serotypes of the dengue virus strains were assessed using PRNT in a pre-defined subset of participants.
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 [ Time Frame: 28 days post-injection 1 and up to 13 months post-injection 3 ]
   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 and/or dengue NS1 enzyme-linked immunosorbent assay. 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 Vaccine Group.
4. Number of Symptomatic VCD Cases Due to Any Serotype 28 Days Post-dose 2 Following Injection With Either CYD Dengue Vaccine or a Placebo [ Time Frame: 28 days post-injection 2 and up to 13 months post-injection 3 ]
   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 and/or dengue NS1 enzyme-linked immunosorbent assay. 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 Vaccine Group.
5. Number of Symptomatic VCD Cases Due to Any Serotype During the Active Phase in Either CYD Dengue Vaccine or Placebo Group [ Time Frame: Day 0 up to 13 months post-injection 3 ]
   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 and/or dengue NS1 enzyme-linked immunosorbent assay. 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 Vaccine Group.
6. Number of Symptomatic VCD Cases Meeting 1997 WHO Criteria Throughout the Trial Due to Any Serotype Following Injection With Either CYD Dengue Vaccine or a Placebo [ Time Frame: Day 0 to the end of study (up to 72 months) ]

   Dengue hemorrhagic fever cases were defined as number of participants with at least one symptomatic VCD episode meeting the 1997 WHO criteria.

   (a) Fever: acute onset, high (>= 38°C) and continuous, lasting 2 to 7 days and (b) any of the pre-listed hemorrhagic manifestations and laboratory findings of thrombocytopenia (platelet <=100 x 109/L) and plasma leakage as shown by hemoconcentation (hematocrit increased by 20% or more) or pleural effusion (seen on CXR) and/or ascites and/or hypoaluminemia. The first two clinical criteria plus thrombocytopenia and signs of plasma leakage are enough to establish a clinical diagnosis of DHF. Dengue hemorrhagic fever was graded as follows: Grade I: Fever accompanied by non-specific constitutional symptoms; the only hemorrhagic manifestation is a positive tourniquet test; Grade II: Spontaneous bleeding in addition to the manifestations of Grade I participants, usually in the form of skin and/or other hemorrhage.

7. Number of Symptomatic VCD Cases Meeting 1997 WHO Criteria During the Surveillance Expansion Period Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo [ Time Frame: From consent to participate int the Surveillance Expansion Period to 60 months post-injection 3 (up to Month 72) ]
   The 1997 WHO criteria are: a) Fever: acute onset, high (>= 38°C) and continuous, for 2 to 7 days and (b) any of the following: thrombocytopenia (platelet <=100 x 109/L) and plasma leakage as shown by hematocrit increased by 20% or more or pleural effusion and/or ascites and/or hypoaluminemia. The first two clinical criteria plus thrombocytopenia and signs of plasma leakage are enough to establish diagnosis of DHF. Dengue hemorrhagic fever was graded as follows:Grade I: Fever accompanied by non-specific constitutional symptoms; the only hemorrhagic manifestation is a positive tourniquet test; Grade II: Spontaneous bleeding in addition to the manifestations of Grade I participant,usually in the form of skin and/or other hemorrhages; Grade III: Circulatory failure manifested by rapid and weak pulse, narrowing of pulse pressure (20 mmHg or less) or hypotension, with the presence of cold clammy skin and restlessness; and Grade IV: Profound shock with undetectable blood pressure and pulse.
8. Number of Clinically Severe VCD Cases Throughout the Trial Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo [ Time Frame: Day 0 to the end of study (up to 72 months) ]
   The severity of VCD cases was assessed by an IDMC based on a medical review of cases and any of the following criteria:1) Platelet count <=100000 μl and bleeding (tourniquet, petechiae or any bleeding) plus plasma leakage 2) Shock (pulse pressure <= 20 mmHg in a child, or hypotension [<= 90 mmHg] with tachycardia, weak pulse and poor perfusion) 3) Bleeding requiring blood transfusion 4) Encephalopathy i.e. Unconsciousness or poor conscious state or fitting not attributable to simple febrile convulsion or focal neurological signs. Poor conscious state or unconsciousness must be supported by GCS score 5) Liver impairment (AST >1000 IU/L or PT INR >1.5) excluding other causes of viral hepatitis 6) Impaired kidney function (serum creatinine >= 1.5 mg/dL) 7) Myocarditis, pericarditis or clinical heart failure supported by CXR, echocardiography, ECG or cardiac enzymes.
9. Number of Clinically Severe VCD Cases During the Surveillance Expansion Period Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo [ Time Frame: From consent to participate in the Surveillance Expansion Period to 60 months post-injection 3 (up to Month 72) ]
   The severity of VCD cases was assessed by an IDMC based on a medical review of cases and any of the following criteria:1) Platelet count <=100000μl and bleeding (tourniquet, petechiae or any bleeding) plus plasma leakage 2) Shock (pulse pressure <= 20mmHg in a child, or hypotension [<= 90 mmHg] with tachycardia, weak pulse and poor perfusion) 3) Bleeding requiring blood transfusion 4) Encephalopathy i.e. Unconsciousness or poor conscious state or fitting not attributable to simple febrile convulsion or focal neurological signs. Poor conscious state or unconsciousness must be supported by GCS score 5) Liver impairment (AST >1000 IU/L or PT INR >1.5) excluding other causes of viral hepatitis 6) Impaired kidney function (serum creatinine >= 1.5 mg/dL) 7) Myocarditis, pericarditis or clinical heart failure supported by CXR, echocardiography, ECG or cardiac enzymes.
10. Number of Participants With Solicited Injection Site Reactions Following Any and Each Inj. With Either CYD Dengue Vaccine or a Placebo [ Time Frame: Within 7 days after injection ]
    Solicited injection site reactions: Pain, Erythema, and Swelling. Grade 3 reactions (2-11 years): Pain, Incapacitating, unable to perform usual activities; Erythema and Swelling, >= 50 mm. Grade 3 Solicited injection site reactions (12-14 years): Pain, Significant, prevents daily activity; Erythema and Swelling, >100 mm.
11. Number of Participants With Systemic Reactions Following Any and Each Inj. With Either CYD Dengue Vaccine or a Placebo [ Time Frame: Within 14 days after injection ]
    Solicited systemic reactions: Fever (Temperature), Headache, Malaise, Myalgia, and Asthenia. Grade 3 reactions: Fever, >= 39°C; Headache, Malaise, Myalgia, and Asthenia, Significant, prevents daily activity.
12. Number of Hospitalized VCD Cases Throughout the Trial Due to Any Serotype Following Injection With Either CYD Dengue Vaccine or a Placebo [ Time Frame: Day 0 to the end of study (up to 72 months) ]
    Hospitalized VCD cases were defined as VCD confirmed by dengue RT-PCR and/or dengue NS1 ELISA in participants with acute febrile illness (temperature >=38°C on at least 2 consecutive days) requiring hospitalization.
13. Number of Hospitalized VCD Cases During the Surveillance Expansion Period Due to Any Serotype Following Injection With Either CYD Dengue Vaccine or a Placebo [ Time Frame: From consent to participate in the Surveillance Expansion Period to 60 months post-injection 3 (up to Month 72) ]
    Hospitalized VCD cases were defined as VCD confirmed by dengue RT-PCR and/or dengue NS1 ELISA in participants with acute febrile illness (temperature >= 38°C on at least 2 consecutive days) requiring hospitalization.

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 14 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Aged 2 to 14 years on the day of inclusion and resident of the site zone
• Participant was 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 attended all scheduled visits and to comply with all trial procedures.

Exclusion Criteria:

• Participant was pregnant, or lactating, or was 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 might interfere with the 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.

Contacts and Locations

Locations

Indonesia

Denpasar, Bali, Indonesia, 80114

Bandung, West Java, Indonesia, 40161

Jakarta, Indonesia, 10430

Malaysia

Kuala Lumpur, Malaysia, 50586

Pulau Pinang, Malaysia, 10450

Philippines

Cebu City, Philippines, 6000

San Pablo City, Philippines, 4000

Thailand

Nai Muang, Kamphaeng Phet Province, Thailand, 6200

Ban Pong, Ratchaburi Province, Thailand, 70110

Photharam, Ratchaburi Province, Thailand, 70120

Vietnam

Long Xuyên, An Giang Province, Vietnam

Mỹ Tho, Tien Giang Province, Vietnam

Sponsors and Collaborators

Sanofi Pasteur, a Sanofi Company

Investigators

• Study Director: Medical Director; Sanofi Pasteur SA

More Information

Publications of Results:

Capeding MR, Tran NH, Hadinegoro SR, Ismail HI, Chotpitayasunondh T, Chua MN, Luong CQ, Rusmil K, Wirawan DN, Nallusamy R, Pitisuttithum P, Thisyakorn U, Yoon IK, van der Vliet D, Langevin E, Laot T, Hutagalung Y, Frago C, Boaz M, Wartel TA, Tornieporth NG, Saville M, Bouckenooghe A; CYD14 Study Group. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet. 2014 Oct 11;384(9951):1358-65. doi: 10.1016/S0140-6736(14)61060-6. Epub 2014 Jul 10.

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.

Coudeville L, Baurin N, Vergu E. Estimation of parameters related to vaccine efficacy and dengue transmission from two large phase III studies. Vaccine. 2016 Dec 7;34(50):6417-6425. doi: 10.1016/j.vaccine.2015.11.023. Epub 2015 Nov 21.

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.

Guy B, Jackson N. Dengue vaccine: hypotheses to understand CYD-TDV-induced protection. Nat Rev Microbiol. 2016 Jan;14(1):45-54. doi: 10.1038/nrmicro.2015.2. Epub 2015 Dec 7.

Gailhardou S, Skipetrova A, Dayan GH, Jezorwski J, Saville M, Van der Vliet D, Wartel TA. Safety Overview of a Recombinant Live-Attenuated Tetravalent Dengue Vaccine: Pooled Analysis of Data from 18 Clinical Trials. PLoS Negl Trop Dis. 2016 Jul 14;10(7):e0004821. doi: 10.1371/journal.pntd.0004821. eCollection 2016 Jul.

Vigne C, Dupuy M, Richetin A, Guy B, Jackson N, Bonaparte M, Hu B, Saville M, Chansinghakul D, Noriega F, Plennevaux E. Integrated immunogenicity analysis of a tetravalent dengue vaccine up to 4 y after vaccination. Hum Vaccin Immunother. 2017 Sep 2;13(9):2004-2016. doi: 10.1080/21645515.2017.1333211. Epub 2017 Jun 9.

Guy B, Noriega F, Ochiai RL, L'azou M, Delore V, Skipetrova A, Verdier F, Coudeville L, Savarino S, Jackson N. A recombinant live attenuated tetravalent vaccine for the prevention of dengue. Expert Rev Vaccines. 2017 Jul;16(7):1-13. doi: 10.1080/14760584.2017.1335201. Epub 2017 Jun 7. Erratum In: Expert Rev Vaccines. 2017 Jul;16(7):ix.

Nealon J, Taurel AF, Capeding MR, Tran NH, Hadinegoro SR, Chotpitayasunondh T, Chong CK, Wartel TA, Beucher S, Frago C, Moureau A, Simmerman M, Laot T, L'Azou M, Bouckenooghe A. Symptomatic Dengue Disease in Five Southeast Asian Countries: Epidemiological Evidence from a Dengue Vaccine Trial. PLoS Negl Trop Dis. 2016 Aug 17;10(8):e0004918. doi: 10.1371/journal.pntd.0004918. eCollection 2016 Aug.

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.

Coudeville L, Baurin N, L'Azou M, Guy B. Potential impact of dengue vaccination: Insights from two large-scale phase III trials with a tetravalent dengue vaccine. Vaccine. 2016 Dec 7;34(50):6426-6435. doi: 10.1016/j.vaccine.2016.08.050. Epub 2016 Sep 3.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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.

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.

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.

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.

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.

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.

• Responsible Party: Sanofi Pasteur, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT01373281
• Other Study ID Numbers: CYD14; UTN: U1111-1116-4957 ( Other Identifier: WHO ); 2014-001708-24 ( EudraCT Number )
• First Posted: June 14, 2011
• Results First Posted: November 16, 2015
• Last Update Posted: March 21, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Keywords provided by Sanofi ( Sanofi Pasteur, a Sanofi Company ):

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

Additional relevant MeSH terms:

Dengue; Hemorrhagic Fevers, Viral; Severe Dengue; Fever; Hyperthermia; Body Temperature Changes; Heat Stress Disorders; Wounds and Injuries; Arbovirus Infections; Vector Borne Diseases; Infections; Virus Diseases; Flavivirus Infections; Flaviviridae Infections; RNA Virus Infections; Vaccines; Immunologic Factors; Physiological Effects of Drugs