Efficacy and Safety of Dengue Vaccine in Healthy Children

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

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.

The observer-blind design was chosen since the products have different appearances and could be recognized. The person who performed vaccinations knew which product was administered while neither the participant nor the Investigator in charge of safety evaluation knew which product was injected. To maintain the blind and minimize the potential bias, the control group used the same route and schedule as the study vaccine.

Participants (both Cohort 1 and 2) received 3 injections of the CYD Dengue vaccine, 1 injection each at 0, 6, and 12 months.

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.

Number of Symptomatic Virologically-Confirmed Dengue (VCD) Cases During the Active Phase Post-dose 3 Following Inj. With Either CYD Dengue Vaccine or a Placebo

Symptomatic VCD cases were defined as acute febrile illness with fever lasting for at least 1 day (temperature >= 37.5 degree Celsius (°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 more than 28 days after the third injection. Vaccine efficacy was reported as density incidence (cases/100 person-years at risk). Density incidence was defined as the number of VCD cases divided by the cumulative person-years at risk.

28 days Post-Inj. 3 up to the end of Active Phase (up to 13 months Post-Inj. 3, i.e. up to 25 months)

Number of Severe VCD Cases During the Active Phase Post-dose 3 Following Inj. With Either CYD Dengue Vaccine or a Placebo

The severity of VCD cases was assessed by WHO 1999 severity assessment and IDMC clinical assessment. Dengue Hemorrhagic Fever (DHF) Grade I, II, III, and IV : Clinical Manifestations: a) Fever: acute onset, high and continuous, lasting 2-7 days, b) Any of hemorrhagic manifestations: petechiae, purpura, ecchymosis, epistaxis, gum bleeding, and hematemesis and/or melena, 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 and/or hypoalbuminemia. IDMC severity criteria: 1) Thrombocytopenia: platelet count <= 50 000/mm^3; 2) Hemorrhage that needs blood transfusion; 3) Objective evidence of capillary permeability 4) Signs of circulatory failure; 5) Visceral Manifestations. Vaccine efficacy was reported as density incidence (cases/100 person-years at risk). Density incidence was defined as the number of VCD cases divided by the cumulative person-years at risk.

28 days Post-Inj. 3 up to the end of Active Phase (up to 13 months Post-Inj. 3, i.e. up to 25 months)

Number of Symptomatic VCD Cases During the Active Phase Following at Least Two Inj. With Either CYD Dengue Vaccine or a Placebo

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 dengue reverse transcriptase-polymerase chain reaction and/or dengue NS1 enzyme-linked immunosorbent assay antigen test, and occurring more than 28 days after the third injection. Vaccine efficacy was reported as density incidence (cases/100 person-years at risk). Density incidence was defined as the number of VCD cases divided by the cumulative person-years at risk.

Geometric Mean Titers (GMTs) of Antibodies Against Each Serotype With the Parental Dengue Virus Strain Before and Following Inj. With Either CYD Dengue Vaccine or a Placebo

GMT of antibodies against each serotype with the parental dengue virus strain were assessed by the plaque reduction neutralization test (PRNT).

GMTs of Antibodies Against Each Serotype With the Parental Dengue Virus Strain in Dengue-Immune Participants Before and Following Inj. With Either CYD Dengue Vaccine or a Placebo

GMTs of antibodies against each serotype with the parental dengue virus strain were assessed by the PRNT. Dengue immune participants were defined as those participants with titers >= 10 (1/dilution) against at least one dengue serotype at baseline.

GMTs of Antibodies Against Each Serotype With the Parental Dengue Virus Strain in Dengue Non-Immune Participants Before and Following Inj. With Either CYD Dengue Vaccine or a Placebo

GMTs of antibodies against each serotype with the parental dengue virus strain were assessed by the PRNT. Dengue non-immune participants were defined as participants with titers < 10 (1/dilution) against all four dengue serotypes at baseline.

Percentage of Participants With Solicited Inj. Site Reactions Following Any and Each Inj. With Either CYD Dengue Vaccine or a Placebo

Solicited Inj. site reactions: Pain, Erythema, and Swelling. Pain: - Grade 1: easily tolerated, Grade 2: sufficiently discomforting to interfere with normal behavior or activities, Grade 3: incapacitating, unable to perform usual activities. Erythema and Swelling: - Grade 1: > 0.0 to < 2.5 cm, Grade 2: >= 2.5 to < 5 cm, Grade 3: >= 5 cm.

Percentage of Participants With Solicited Systemic Reactions Following Any and Each Inj. With Either CYD Dengue Vaccine or a Placebo

Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Fever:- Grade 1: >=37.5°C to <=38.0°C, Grade 2: >38.0°C to <=39.0°C, Grade 3: >39.0°C. Headache, malaise, myalgia and asthenia: - Grade 1: noticeable but does not interfere with daily activities, Grade 2: interferes with daily activities, Grade 3: prevents daily activities.

Number of Symptomatic VCD Cases During the Active Phase Following at Least One Inj. With Either CYD Dengue Vaccine or a Placebo

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 NS1 enzyme-linked immunosorbent assay antigen test, and occurring more than 28 days after the third injection. Vaccine efficacy was reported as density incidence (cases/100 person-years at risk). Density incidence was defined as the number of VCD cases divided by the cumulative person-years at risk.

Day 0 (Post-Inj.) up to end of Active phase (up to 25 months); 28 days post-Inj. 1 up to end of Active phase (up to 25 months)

Number of Participants With One VCD Episode During the Active Phase Due to Each Serotypes Following Inj. With Either CYD Dengue Vaccine or a Placebo

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 NS1 enzyme-linked immunosorbent assay antigen test, and occurring more than 28 days after the third injection. VCD cases confirmed only by NS1 method were classified in the Not Identified category. Cases were defined as the number of participants with at least one symptomatic VCD episode more than 28 days after Inj. 3 (during the Active Phase).

Mean Number of Days for Clinical Signs and Symptoms (Fever, Clinical Syndrome and Hospitalization) of VCD During the Active Phase Following Inj. With Either CYD Dengue Vaccine or a Placebo

Clinical signs and symptoms for VCD included the following: fever, clinical syndrome and hospitalization. Duration of each symptom (in days) is reported in this outcome measure.

Number of Participants Requiring Hospitalization for VCD During the Active Phase Following Inj. With Either CYD Dengue Vaccine or a Placebo

Inclusion Criteria : Aged 4 to 11 years on the day of inclusion. Participant in good health, based on medical history and physical examination. Provision of assent form signed by the participants (for participants >= 7 years old) and informed consent form signed by the parent or another legally acceptable representative. Participant and parent/ legally acceptable representative able to attend all scheduled visits and to comply with all trial procedures. Participant attended one of the schools involved in the trial and living in the Ratchaburi Province. For a female participant of child-bearing potential (girls post-menarche), avoid becoming pregnant (use of an effective method of contraception or abstinence) for at least 4 weeks prior to first vaccination, until at least 4 weeks after the last vaccination. Exclusion Criteria : Febrile illness (temperature >= 37.5°C) or moderate or severe acute illness/infection on the day of vaccination, according to Investigator judgment. For a female participant of child-bearing potential (girls post-menarche), known pregnancy or positive urine pregnancy test on the day of the first trial vaccination. Personal or family history of thymic pathology (thymoma), thymectomy, or myasthenia. Planned participation in another clinical trial during the present trial period. Known or suspected congenital or acquired immunodeficiency, immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy, or long-term systemic corticosteroids therapy. Known systemic hypersensitivity to any of the vaccine components or history of a life-threatening reaction to the trial vaccines or to a vaccine containing any of the same substances. Chronic illness at a stage that could interfere with trial conduct or completion, in the opinion of the Investigator. Receipt of blood or blood-derived products in the past 3 months. Participant deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized without his/her consent. Participation in another clinical trial investigating a vaccine, drug, medical device, or a medical procedure in the 4 weeks preceding the first trial vaccination. Receipt of any vaccine in the 4 weeks preceding the first trial vaccination. Planned receipt of any vaccine in the 4 weeks following the first trial vaccination.e Participant who plans to attend another school (outside the trial area) or move to another city in the coming 30 months.

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

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