Dengue Fever
Conditions
Keywords
dengue, vaccine
Brief summary
To assess the safety, reactogenicity and immunogenicity of two doses of the dengue vaccine in Flavi-virus antibody-naive children between 6 and 9 years of age.
Detailed description
This study was a Phase I/II, open-label trial with one treatment group; 7, healthy, flavivirus naïve children between the ages of 6 and 7 years residing in Bangkok, Thailand. Seronegative status was determined by measuring neutralizing (N) antibody titers to dengue 1-4 and JE virus (JE) using hemagglutination inhibition (HAI) (1st) and PRNT (2nd) assays. Titers \<10 and \<10, respectively, were considered negative. Enrolled children received two doses of tetravalent dengue vaccine at study months 0 and 6, and two doses of JE vaccine (study benefit) at study months 7 and 7.5. Enrolled children attended 20 study visits, received 4 injections, and 7 venipunctures (one additional blood sample for screening). In the acute period (1 month) following vaccination, safety was assessed using symptom diary cards and clinical and laboratory evaluations. Viremia was measured 10 days post dengue vaccination. Solicited and unsolicited adverse events were assessed for 30 days following each dengue vaccination. Serious adverse events were assessed throughout the study period. In the case of illness, investigators would complete additional clinical and virologic evaluations. Dengue vaccine immunogenicity was assessed 30 days following each dengue vaccination using the PRNT50 assay. The According to Protocol (ATP) cohort was determined by evaluating the occurrence of intermittent natural dengue infection using ELISA IgM/IgG titer ratios. A long-term follow-up of dengue vaccine recipients is described in a separate protocol (Dengue-005 protocol).
Interventions
BIOLOGICALDengue Vaccine Formulation 17
Tetravalent live attenuated DEN vaccine candidate. Containing dengue serotypes 1,2, and 3 vaccines produced at the Salk Institute and dengue serotype 4 produced at the WRAIR Pilot Bioproduction Facility. Dosage 1 mL administered via injection at Day 0 and Day 60.
BIOLOGICALLicensed Japanese Encephalitis (JE) Vaccine
Produced by the Thailand GPO using a Beijing strain of JE in liquid form; dosed at 0.5 mL ot 7 and 7.5 months.
Sponsors
GlaxoSmithKline
U.S. Army Medical Research and Development Command
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 10 Years
Healthy volunteers
Yes
Inclusion criteria
* A male or female child six to nine years of age (greater than or equal to 6 years of age and less than 10 years of age) at the time of the first vaccination. * Free of obvious health problems as established by medical history and physical examination before entering into the study. * Seronegative by HAI and screening PRNT for antibodies to dengue types 1-4 and Japanese Encephalitis (JE) virus * Written informed consents by the parent of the subject for screening and enrollment into the study.
Exclusion criteria
* Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose or planned administration during the study (For corticosteroids, this will mean prednisone, or equivalent, greater than or equal to 0.5 mg/kg/day. Inhaled and topical steroids are allowed.) * Use of any investigational or non-registered drug or vaccine other than the protocol-specified vaccines within 30 days preceding the administration of the first dengue vaccine dose or planned use during the study period. * Planned administration of a vaccine not foreseen by the study protocol and within 30 days prior or after any dengue/JE vaccine administration. * Any current medical condition determined to be serious by the investigator (e.g. seizures) * History of chronic headaches or a first order family member (parent or sibling) with a history of chronic headaches * Abnormal clinical laboratory screening test result (based on normal values set by the laboratory) that is deemed clinically significant by the investigator or Medical Monitor (including seropositivity for HBsAg or anti-HCV) * Previous vaccination against yellow fever virus, JEV, or tick-borne encephalitis virus (TBE) or existence of any flavivirus antibody * Any suspected or confirmed immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection * Family history of a congenital or hereditary immunodeficiency * Acute illness at time of enrollment (defined as the presence of a moderate or severe illness with or without fever). All vaccines can be administered to persons with a minor illness such as diarrhea or mild upper respiratory infection without fever, i.e., oral temperature \<37.5°C. * Administration of immunoglobulins and/or blood products within 6 months prior to study entry or planned administration during the study period * History of allergic disease or reactions likely to be exacerbated by any component of the vaccines (including neomycin, streptomycin, gentamicin, amikacin, tobramycin, kanamycin and bacitracin; allergy to dogs or monkeys or hypersensitivity to proteins of rodent or neural origin or to thimerosal, allergy to porcine gelatin) * Child whose parent has no easy access to a fixed or mobile telephone * Plans to move from Bangkok during the first 8.5 months after initial vaccination * Parental illiteracy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Solicited Adverse Events Within 21 Days After the First Dose of Dengue Vaccine. | 21 days | Number of solicited general symptoms within the 21-day follow-up after dengue dose 1 (total vaccinated cohort). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neutralizing Antibody (GMT) to JE and 4 Dengue Types, 30 Days After the Second Dose of JE Vaccine. | Approximately Day 225 and Day 255 | Geometric mean titers (GMT) for neutralizing (N) Ig to DEN-1, N Ig to DEN-2, N Ig to DEN-3, N Ig to DEN-4, and N Ig to JE vaccine antibody titers. |
| Number of Unsolicited Adverse Events Within 30 Days After Each Dose of Dengue Vaccine | 30 days | Number of subjects with unsolicited symptoms classified by MedDRA Primary System Organ Class and Preferred Term, within 30 days after dengue vaccine (total vaccinated cohort) |
| Percentage of Individuals With Neutralizing Antibody (Seroconversion) to Japanese Encephalitis (JE) and 4 Dengue Types, 30 Days After the Second Dose of JE Vaccine. | 30 days after the second dose of JE vaccine | Percentage of individuals with ≥ 10 dilution (DIL) for neutralizing (N) Ig to DEN-1, N Ig to DEN-2, N Ig to DEN-3, N Ig to DEN-4, and N Ig to Japanese encephalitis (JE) vaccine antibody titers. |
| Number of Solicited Symptoms 7 Days (0-6) After First Dose of Japanese Encephalitis (JE) Vaccine. | Approximately Day 225 and Day 255 | Number of solicited general symptoms within the 7-day follow-up after the first dose of Japanese encephalitis (JE) vaccine doses (total vaccinated cohort) |
| Number of Solicited Symptoms 7 Days (0-6) After Second Dose of Japanese Encephalitis (JE) Vaccine. | Approximately Day 225 and Day 255 | Number of solicited general symptoms within the 7-day follow-up after the second dose of Japanese encephalitis (JE) vaccine doses (total vaccinated cohort) |
| Number of Solicited Adverse Events for 21 Days (0-20) After the Second Dose of Dengue Vaccine | 21 Days (0-20) After the Second Dose of Dengue Vaccine | Number of solicited general symptoms within the 21-day follow-up of dengue dose 2 vaccine dose (total vaccinated cohort) |
Countries
Thailand
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dengue Vaccine and Japanese Encephalitis Vaccine 1 mL subcutaneous injection Dengue Vaccine Formulation 17 on Day 0 and Day 60. 0.5 mL subcutaneous injection Licensed Japanese Encephalitis (JE) Vaccine on months 7 and 7.5. | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | Dengue Vaccine and Japanese Encephalitis Vaccine |
|---|---|
| Age, Categorical <=18 years | 7 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 6.6 years STANDARD_DEVIATION 0.5 |
| Region of Enrollment Thailand | 7 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 0 / 7 |
Outcome results
Primary
Number of Solicited Adverse Events Within 21 Days After the First Dose of Dengue Vaccine.
Number of solicited general symptoms within the 21-day follow-up after dengue dose 1 (total vaccinated cohort).
Time frame: 21 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events Within 21 Days After the First Dose of Dengue Vaccine. | Abdominal Pain | 1 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events Within 21 Days After the First Dose of Dengue Vaccine. | Fatigue | 3 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events Within 21 Days After the First Dose of Dengue Vaccine. | Headache | 5 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events Within 21 Days After the First Dose of Dengue Vaccine. | Muscle and/or Joint Aches | 3 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events Within 21 Days After the First Dose of Dengue Vaccine. | Pain Behind Eyes | 2 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events Within 21 Days After the First Dose of Dengue Vaccine. | Photophobia | 0 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events Within 21 Days After the First Dose of Dengue Vaccine. | Pruritus | 2 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events Within 21 Days After the First Dose of Dengue Vaccine. | Elevated Temperature | 4 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events Within 21 Days After the First Dose of Dengue Vaccine. | Vomiting and/or Nausea | 1 adverse events |
Secondary
Neutralizing Antibody (GMT) to JE and 4 Dengue Types, 30 Days After the Second Dose of JE Vaccine.
Geometric mean titers (GMT) for neutralizing (N) Ig to DEN-1, N Ig to DEN-2, N Ig to DEN-3, N Ig to DEN-4, and N Ig to JE vaccine antibody titers.
Time frame: Approximately Day 225 and Day 255
Population: 1 subjects experience an asymptomatic, sub-clinical, DEN-2 virus infection prior to dengue vaccine dose 1 and was eliminated from the according to protocol (ATP) analysis of immunogenicity.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Dengue and Japanese Encephalitis Vaccine | Neutralizing Antibody (GMT) to JE and 4 Dengue Types, 30 Days After the Second Dose of JE Vaccine. | N Ig to DEN-4 | 36.9 titer |
| Dengue and Japanese Encephalitis Vaccine | Neutralizing Antibody (GMT) to JE and 4 Dengue Types, 30 Days After the Second Dose of JE Vaccine. | N Ig to DEN-1 | 55.8 titer |
| Dengue and Japanese Encephalitis Vaccine | Neutralizing Antibody (GMT) to JE and 4 Dengue Types, 30 Days After the Second Dose of JE Vaccine. | N Ig to DEN-2 | 107.4 titer |
| Dengue and Japanese Encephalitis Vaccine | Neutralizing Antibody (GMT) to JE and 4 Dengue Types, 30 Days After the Second Dose of JE Vaccine. | N Ig to DEN-3 | 37.0 titer |
| Dengue and Japanese Encephalitis Vaccine | Neutralizing Antibody (GMT) to JE and 4 Dengue Types, 30 Days After the Second Dose of JE Vaccine. | N Ig to JE | 8.7 titer |
Secondary
Number of Solicited Adverse Events for 21 Days (0-20) After the Second Dose of Dengue Vaccine
Number of solicited general symptoms within the 21-day follow-up of dengue dose 2 vaccine dose (total vaccinated cohort)
Time frame: 21 Days (0-20) After the Second Dose of Dengue Vaccine
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events for 21 Days (0-20) After the Second Dose of Dengue Vaccine | Abdominal Pain | 0 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events for 21 Days (0-20) After the Second Dose of Dengue Vaccine | Fatigue | 3 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events for 21 Days (0-20) After the Second Dose of Dengue Vaccine | Headache | 3 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events for 21 Days (0-20) After the Second Dose of Dengue Vaccine | Muscle and/or Joint Aches | 2 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events for 21 Days (0-20) After the Second Dose of Dengue Vaccine | Pain Behind Eyes | 1 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events for 21 Days (0-20) After the Second Dose of Dengue Vaccine | Photophobia | 1 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events for 21 Days (0-20) After the Second Dose of Dengue Vaccine | Pruritus | 2 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events for 21 Days (0-20) After the Second Dose of Dengue Vaccine | Elevated Temperature | 3 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Adverse Events for 21 Days (0-20) After the Second Dose of Dengue Vaccine | Vomiting and/or Nausea | 1 adverse events |
Secondary
Number of Solicited Symptoms 7 Days (0-6) After First Dose of Japanese Encephalitis (JE) Vaccine.
Number of solicited general symptoms within the 7-day follow-up after the first dose of Japanese encephalitis (JE) vaccine doses (total vaccinated cohort)
Time frame: Approximately Day 225 and Day 255
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Symptoms 7 Days (0-6) After First Dose of Japanese Encephalitis (JE) Vaccine. | Abdominal Pain | 1 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Symptoms 7 Days (0-6) After First Dose of Japanese Encephalitis (JE) Vaccine. | Fatigue | 1 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Symptoms 7 Days (0-6) After First Dose of Japanese Encephalitis (JE) Vaccine. | Headache | 2 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Symptoms 7 Days (0-6) After First Dose of Japanese Encephalitis (JE) Vaccine. | Muscle and/or Joint Aches | 1 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Symptoms 7 Days (0-6) After First Dose of Japanese Encephalitis (JE) Vaccine. | Photophobia | 1 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Symptoms 7 Days (0-6) After First Dose of Japanese Encephalitis (JE) Vaccine. | Pruritus | 1 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Symptoms 7 Days (0-6) After First Dose of Japanese Encephalitis (JE) Vaccine. | Elevated Temperature | 1 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Symptoms 7 Days (0-6) After First Dose of Japanese Encephalitis (JE) Vaccine. | Vomiting and/or Nausea | 1 adverse events |
Secondary
Number of Solicited Symptoms 7 Days (0-6) After Second Dose of Japanese Encephalitis (JE) Vaccine.
Number of solicited general symptoms within the 7-day follow-up after the second dose of Japanese encephalitis (JE) vaccine doses (total vaccinated cohort)
Time frame: Approximately Day 225 and Day 255
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Symptoms 7 Days (0-6) After Second Dose of Japanese Encephalitis (JE) Vaccine. | Abdominal Pain | 0 Number of solicited general symptoms |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Symptoms 7 Days (0-6) After Second Dose of Japanese Encephalitis (JE) Vaccine. | Fatigue | 0 Number of solicited general symptoms |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Symptoms 7 Days (0-6) After Second Dose of Japanese Encephalitis (JE) Vaccine. | Headache | 1 Number of solicited general symptoms |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Symptoms 7 Days (0-6) After Second Dose of Japanese Encephalitis (JE) Vaccine. | Muscle and/or Joint Aches | 0 Number of solicited general symptoms |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Symptoms 7 Days (0-6) After Second Dose of Japanese Encephalitis (JE) Vaccine. | Photophobia | 0 Number of solicited general symptoms |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Symptoms 7 Days (0-6) After Second Dose of Japanese Encephalitis (JE) Vaccine. | Pruritus | 1 Number of solicited general symptoms |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Symptoms 7 Days (0-6) After Second Dose of Japanese Encephalitis (JE) Vaccine. | Elevated Temperature | 0 Number of solicited general symptoms |
| Dengue and Japanese Encephalitis Vaccine | Number of Solicited Symptoms 7 Days (0-6) After Second Dose of Japanese Encephalitis (JE) Vaccine. | Vomiting and/or Nausea | 0 Number of solicited general symptoms |
Secondary
Number of Unsolicited Adverse Events Within 30 Days After Each Dose of Dengue Vaccine
Number of subjects with unsolicited symptoms classified by MedDRA Primary System Organ Class and Preferred Term, within 30 days after dengue vaccine (total vaccinated cohort)
Time frame: 30 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dengue and Japanese Encephalitis Vaccine | Number of Unsolicited Adverse Events Within 30 Days After Each Dose of Dengue Vaccine | At least one symptom | 7 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Unsolicited Adverse Events Within 30 Days After Each Dose of Dengue Vaccine | Infections and Infestations | 2 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Unsolicited Adverse Events Within 30 Days After Each Dose of Dengue Vaccine | Nervous System Disorders | 1 adverse events |
| Dengue and Japanese Encephalitis Vaccine | Number of Unsolicited Adverse Events Within 30 Days After Each Dose of Dengue Vaccine | Respiratory, Thoracic and Mediastinal Disorders | 6 adverse events |
Secondary
Percentage of Individuals With Neutralizing Antibody (Seroconversion) to Japanese Encephalitis (JE) and 4 Dengue Types, 30 Days After the Second Dose of JE Vaccine.
Percentage of individuals with ≥ 10 dilution (DIL) for neutralizing (N) Ig to DEN-1, N Ig to DEN-2, N Ig to DEN-3, N Ig to DEN-4, and N Ig to Japanese encephalitis (JE) vaccine antibody titers.
Time frame: 30 days after the second dose of JE vaccine
Population: 1 subjects experience an asymptomatic, sub-clinical, DEN-2 virus infection prior to dengue vaccine dose 1 and was eliminated from the according to protocol (ATP) analysis of immunogenicity.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dengue and Japanese Encephalitis Vaccine | Percentage of Individuals With Neutralizing Antibody (Seroconversion) to Japanese Encephalitis (JE) and 4 Dengue Types, 30 Days After the Second Dose of JE Vaccine. | N Ig to DEN-1 | 100 percentage of participants |
| Dengue and Japanese Encephalitis Vaccine | Percentage of Individuals With Neutralizing Antibody (Seroconversion) to Japanese Encephalitis (JE) and 4 Dengue Types, 30 Days After the Second Dose of JE Vaccine. | N Ig to DEN-2 | 100 percentage of participants |
| Dengue and Japanese Encephalitis Vaccine | Percentage of Individuals With Neutralizing Antibody (Seroconversion) to Japanese Encephalitis (JE) and 4 Dengue Types, 30 Days After the Second Dose of JE Vaccine. | N Ig to DEN-3 | 100 percentage of participants |
| Dengue and Japanese Encephalitis Vaccine | Percentage of Individuals With Neutralizing Antibody (Seroconversion) to Japanese Encephalitis (JE) and 4 Dengue Types, 30 Days After the Second Dose of JE Vaccine. | N Ig to DEN-4 | 83.3 percentage of participants |
| Dengue and Japanese Encephalitis Vaccine | Percentage of Individuals With Neutralizing Antibody (Seroconversion) to Japanese Encephalitis (JE) and 4 Dengue Types, 30 Days After the Second Dose of JE Vaccine. | N Ig to JE | 33.3 percentage of participants |