Trial Outcomes & Findings for Study of a Novel Tetravalent Dengue Vaccine in Healthy Children Aged 2 to 14 Years in Asia (NCT NCT01373281)

Study participants were enrolled from 03 June 2011 to 01 December 2011 at 9 sites in Indonesia, 5 in Malaysia, 3 in Thailand, 5 in Philippines, and 2 in Vietnam.

A total of 10275 participants were enrolled; all but one met all of the inclusion criteria and none of the exclusion criteria. Three participants were not vaccinated and were excluded from the Full Analysis Set for Efficacy and the Safety Analysis Set.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.