Efficacy and Safety of Dengue Vaccine in Healthy Children
Condition: Dengue Virus; Dengue Fever; Dengue Hemorrhagic Fever; Dengue Diseases
MeSH terms: Dengue; Hemorrhagic Fevers, Viral; Severe Dengue; Fever; Hyperthermia
Study type: Interventional
Phase: Phase 2

Summary: 
      The primary objective of the study was to assess the efficacy of CYD dengue vaccine after
      three injections in preventing symptomatic virologically-confirmed dengue (VCD) cases,
      regardless of the severity, due to any of the four serotypes in children aged 4 to 11 years
      at the time of inclusion.

      Secondary objectives included to assess:

        -  Vaccine efficacy against severe VCD cases

        -  Vaccine efficacy against VCD cases following at least two injections with CYD dengue
           vaccine

        -  Immune response to CYD dengue vaccine

        -  Safety profile of CYD dengue vaccine. Safety assessments include solicited reactions
           within 7 or 14 days after each injection, unsolicited adverse events within 28 days
           after each injection, and serious adverse events during the study period.

      Other objectives included:

        -  Vaccine efficacy against VCD cases following at least one injection with CYD dengue
           vaccine

        -  Vaccine efficacy against VCD cases due to each serotype

        -  Participants with clinical signs and symptoms for VCD
    

Detailed description: 
      Participants (both cohort 1 and 2) received 3 injections of CYD dengue vaccine. Participants
      (Cohort 1) received rabies vaccine at Month 0 and placebo at 6 and 12 months. Participants
      (cohort 2) received placebo at 0, 6, and 12 months.

      Dengue cases were collected for assessment of efficacy during the Active Phase from first
      injection until at least 13 months after the third injection. A subset of participants were
      also evaluated for reactogenicity and immunogenicity.

      Symptomatic VCD cases were defined as acute febrile illness with fever lasting for at least 1
      day (temperature >= 37.5°C measured at least twice with an interval of at least 4 hours),
      confirmed by reverse transcriptase-polymerase chain reaction and/or dengue non-structural
      protein 1 (NS1) enzyme-linked immunosorbent assay antigen test, and occurring >28 days after
      the third injection.

      Dengue hemorrhagic fever (DHF) Grade I, II, III, and IV according to the 1999 World Health
      Organization (WHO) definition:

      Clinical Manifestations: a) Fever: acute onset, high and continuous, lasting 2 to 7 days. b)
      Any of the following hemorrhagic manifestations (including at least a positive tourniquet
      test): petechiae, purpura, ecchymosis, epistaxis, gum bleeding, and hematemesis and/or
      melena.

      Laboratory Findings: c) thrombocytopenia (platelet count = 100 000/mm3 or less) d) Plasma
      leakage as shown by hemoconcentration (hematocrit increased by 20% or more) or pleural
      effusion (seen on chest X-ray) and/or hypoalbuminemia.

      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. Grade IV: Profound shock with undetectable
      blood pressure and pulse.

      Independent Data Monitoring Committee (IDMC) severity criteria:- 1) Thrombocytopenia:
      platelet count ≤ 50 000/mm^3 ; 2) Any hemorrhage that needs blood transfusion; 3) Objective
      evidence of capillary permeability documented by one or several of the following: a) Increase
      in hematocrit by >= 20 percent (%) compared to normal for age, or [(Maximum hematocrit -
      minimum hematocrit)/min]*100% >= 20%, b) Pleural or abdominal (ascites) effusion (diagnosed
      either by clinical signs or radiography or other imaging method), c) Hypoproteinemia; 4)
      Signs of circulatory failure manifested by: a) Narrow pulse pressure <20mm Hg, or hypotension
      for age (as defined by systolic pressure <80 mm Hg in children <5 years and systolic pressure
      < 90 mm Hg in children >= 5 years), and b) Rapid and weak pulse, and c) Signs of poor
      capillary perfusion (cold and clammy extremities, delayed capillary refill); 5) Visceral
      Manifestations such as: a) Neurological symptoms (convulsions or change in level of
      consciousness), b) Hepatic failure or elevation of hepatic enzyme (>5-fold normal level), c)
      Metabolic (hypoglycemia) or electrolyte (hyponatremia, hypocalcemia) disturbances or volume
      overload (acute pulmonary edema or congestive heart failure), d) Other visceral
      manifestations such as cardiomyopathy, acute renal failure, acute respiratory failure,
      cholecystitis.
    

Intervention name(s): CYD Dengue Vaccine; Inactivated rabies virus vaccine; Placebo
Intervention type(s): Biological; Biological; Biological
Intervention description(s): 0.5 mL, Subcutaneous; 0.5 mL, Subcutaneous; Sodium chloride 0.9%
Other intervention name(s): Dengvaxia; Verorab®
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: Dengue virus; Dengue fever; Dengue hemorrhagic fever; Dengue diseases; Dengue vaccine