Study of a Novel Tetravalent Dengue Vaccine in Healthy Children Aged 2 to 14 Years in Asia
Condition: Dengue; Dengue Fever; Dengue Hemorrhagic Fever
MeSH terms: Dengue; Hemorrhagic Fevers, Viral; Severe Dengue; Fever; Hyperthermia
Study type: Interventional
Phase: Phase 3

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.
    

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.
    

Intervention name(s): Live, attenuated, dengue serotype 1, 2, 3, 4 virus; Placebo: Sodium chloride (NaCl) 0.9%
Intervention type(s): Biological; Biological
Intervention description(s): 0.5 mL, Subcutaneous; 0.5 mL, Subcutaneous
Other intervention name(s): CYD Dengue Vaccine
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Dengue; Dengue fever; Dengue Hemorrhagic Fever; CYD dengue vaccine; Flavivirus