Japanese Encephalitis
Conditions
Brief summary
The proposed study is a four-arm double-blind randomized controlled single center trial to evaluate, by examining post-vaccination seroprotection titers, the lot-to-lot consistency of three lots of Japanese Encephalitis live attenuated SA 14-14-2 vaccine (LJEVac) manufactured in a new good manufacture practice (GMP) facility, and to establish non-inferiority of the new vaccine in comparison to a single lot of the same vaccine manufactured in the existing facility. The study aimed to enroll a total of 1,000 Bangladeshi infants aged 10 to 12 months. In addition to providing immunogenicity data, this study provided local safety data of JE live attenuated SA 14-14-2 vaccine among Bangladeshi children. This is the first step to secure licensure for this life-saving vaccine in Bangladesh as well as provide data to support WHO prequalification of JE live attenuated SA 14-14-2 vaccine.
Interventions
BIOLOGICALVaccine produced in existing facility
Live attenuated Japanese encephalitis vaccine SA 14-14-2 (LJEVac) produced in the existing facility by the Chengdu Institute of Biological Products (CDIBP), Chengdu, China
BIOLOGICALVaccine produced in new facility
Live attenuated Japanese encephalitis vaccine SA 14-14-2 (LJEVac) produced in the new facility by the Chengdu Institute of Biological Products (CDIBP), Chengdu, China
Sponsors
PATH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
10 Months to 12 Months
Healthy volunteers
Yes
Inclusion criteria
* Infant's parent(s) or legal guardian(s) willing to provide signed informed consent. * Healthy infants aged 10 to 12 months at enrolment residing in Matlab Health and Demographic Surveillance System (HDSS) intervention area who have completed all doses of Expanded Programme on Immunization (EPI) immunizations at least 4 weeks prior to enrolment: Bacillus Calmette-Guerin vaccine (BCG), Diphtheria-pertussis-tetanus vaccine (DPT), Hepatitis B (HBV), Haemophilus influenzae type (Hib), oral polio vaccine (OPV) and measles
Exclusion criteria
* Acute medical illness with or without fever within the last 72 hours or an axillary temperature (≥ 37.5°C ) at the time of vaccination. * Use of antibiotics or antipyretics within the last 72 hours prior to enrolment. * Severely or moderately malnourished infants (\<-3 Z score). * History of prematurity (\< 36 weeks of pregnancy). * Underlying medical condition such as failure to thrive, inborn errors of metabolism, bronchopulmonary dysplasia, or any major congenital abnormalities requiring surgery or chronic treatment. * History of serious chronic disease (e.g., cardiac, renal, neurologic, metabolic, rheumatologic, hematologic, or bleeding disorder). * Known or suspected impairment of immunologic function. * History of documented or suspected encephalitis or meningitis. * History of seizures, including history of febrile seizures, or any other neurologic disorder. * History of JE infection. * Prior receipt of a JE vaccine. * Received measles vaccine within 4 weeks prior to, or scheduled to receive a vaccination during, the conduct of this trial. * Prior or anticipated receipt of immune globulin or other blood products, or injected or oral corticosteroids or other immune modulator therapy within 6 weeks of administration of the study vaccine. * Serious adverse reactions (e.g. urticaria, angioedema, shock, breathlessness following vaccination or any life threatening condition) with any previous EPI vaccine. * Unable to attend the scheduled visits or comply with the study procedures. * Enrolled in another clinical trial involving any therapy. * Any condition that in the opinion of the investigator, would pose a health risk to the child, or interfere with the evaluation of the study objectives.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number/Percentage of Subjects With Demonstrated Seroprotection | 28 days post-vaccination | Seroprotection was defined as a serum antibody titer equal to or greater than 1:10, as measured by Plaque reduction neutralization test (PRNT). The end point for neutralization was the highest dilution of serum reducing the number of plaques by 50%, compared with a negative serum control. In 2004, a group of experts under the leadership of the WHO recommended that seroprotection (SP) against JEV be defined as a neutralizing anti-JEV antibody serum titer ≥1:10 as determined by PRNT \[Hombach et al. 2005\]. Accordingly, a titer of ≥1:10 was adopted as an indicator of seroprotection in this study. |
| Geometric Mean Titers (GMT) | 28 days post-vaccination | Geometric Mean Titers of Neutralizing anti-JEV antibody |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number/Percentage of Subjects With an Immediate Solicited Local or Systemic Reactogenicity Event (RE) | Within 30 minutes of vaccination | Subjects were monitored for the following adverse events and categorized as events almost certainly related to receipt of the vaccine: Redness Swelling Tenderness Dyspnea Cyanosis Loose Stools Vomiting Convulsion Fever (37 degrees Celsius or greater, axillary) Hives (urticaria) Angioedema |
| Number/Percentage of Subjects With a Solicited Local or Systemic Reactogenicity Event Within 7 Days After Vaccination | Within 7 days of vaccination | Collected by a home visit to observe the subject and interview his/her parent or guardian occurrence and severity of solicited injection site reactogenicity events (REs) related to vaccination and solicited systemic REs or other AEs that might or might not be related to the prior receipt of vaccine |
| Number/Percentage of Subjects With Other Adverse Events (AE) During the Study | Between 7 and 28 days of vaccination | Adverse events other than solicited reactogenicities were obtained through review of medical history when subject returned to clinic. They were graded for severity and rated by the PI for possible relationship to vaccination throughout the 28 days study period. |
Countries
Bangladesh
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Reference Lot Lot of Vaccine produced in existing facility
Vaccine produced in existing facility: Live attenuated Japanese encephalitis vaccine SA 14-14-2 (LJEVac) produced in the existing facility by the Chengdu Institute of Biological Products (CDIBP), Chengdu, China | 146 |
| New Lot #1 First lot of vaccine produced in new facility
Vaccine produced in new facility: Live attenuated Japanese encephalitis vaccine SA 14-14-2 (LJEVac) produced in the new facility by the Chengdu Institute of Biological Products (CDIBP), Chengdu, China | 195 |
| New Lot #2 Second lot of vaccine produced in new facility
Vaccine produced in new facility: Live attenuated Japanese encephalitis vaccine SA 14-14-2 (LJEVac) produced in the new facility by the Chengdu Institute of Biological Products (CDIBP), Chengdu, China | 192 |
| New Lot #3 Third lot of vaccine produced in new facility
Vaccine produced in new facility: Live attenuated Japanese encephalitis vaccine SA 14-14-2 (LJEVac) produced in the new facility by the Chengdu Institute of Biological Products (CDIBP), Chengdu, China | 194 |
| Total | 727 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Evaluated for Immunogenicity | Missing blood sample | 17 | 24 | 16 | 28 |
| Evaluated for Immunogenicity | Sero+ for anti-JEV at Visit 1 | 0 | 1 | 3 | 2 |
Baseline characteristics
| Characteristic | Reference Lot | New Lot #1 | New Lot #2 | New Lot #3 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 10.8 months STANDARD_DEVIATION 0.68 | 10.9 months STANDARD_DEVIATION 0.73 | 10.8 months STANDARD_DEVIATION 0.65 | 10.9 months STANDARD_DEVIATION 0.7 | 10.9 months STANDARD_DEVIATION 0.7 |
| Region of Enrollment Bangladesh | 146 participants | 195 participants | 192 participants | 194 participants | 727 participants |
| Sex: Female, Male Female | 76 Participants | 100 Participants | 92 Participants | 98 Participants | 366 Participants |
| Sex: Female, Male Male | 70 Participants | 95 Participants | 100 Participants | 96 Participants | 361 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 163 | 0 / 220 | 0 / 211 | 0 / 224 |
| other Total, other adverse events | 60 / 163 | 84 / 220 | 92 / 211 | 77 / 224 |
| serious Total, serious adverse events | 2 / 163 | 4 / 220 | 4 / 211 | 0 / 224 |
Outcome results
Primary
Geometric Mean Titers (GMT)
Geometric Mean Titers of Neutralizing anti-JEV antibody
Time frame: 28 days post-vaccination
Population: Per-Protocol Population
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Reference Lot | Geometric Mean Titers (GMT) | 77.3 titer |
| New Lot #1 | Geometric Mean Titers (GMT) | 52.8 titer |
| New Lot #2 | Geometric Mean Titers (GMT) | 53.4 titer |
| New Lot #3 | Geometric Mean Titers (GMT) | 62.8 titer |
| All New Lots | Geometric Mean Titers (GMT) | 56.2 titer |
Primary
Number/Percentage of Subjects With Demonstrated Seroprotection
Seroprotection was defined as a serum antibody titer equal to or greater than 1:10, as measured by Plaque reduction neutralization test (PRNT). The end point for neutralization was the highest dilution of serum reducing the number of plaques by 50%, compared with a negative serum control. In 2004, a group of experts under the leadership of the WHO recommended that seroprotection (SP) against JEV be defined as a neutralizing anti-JEV antibody serum titer ≥1:10 as determined by PRNT \[Hombach et al. 2005\]. Accordingly, a titer of ≥1:10 was adopted as an indicator of seroprotection in this study.
Time frame: 28 days post-vaccination
Population: Per protocol population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Reference Lot | Number/Percentage of Subjects With Demonstrated Seroprotection | Seroprotection | 126 Participants |
| Reference Lot | Number/Percentage of Subjects With Demonstrated Seroprotection | No seroprotection | 20 Participants |
| New Lot #1 | Number/Percentage of Subjects With Demonstrated Seroprotection | Seroprotection | 160 Participants |
| New Lot #1 | Number/Percentage of Subjects With Demonstrated Seroprotection | No seroprotection | 35 Participants |
| New Lot #2 | Number/Percentage of Subjects With Demonstrated Seroprotection | Seroprotection | 154 Participants |
| New Lot #2 | Number/Percentage of Subjects With Demonstrated Seroprotection | No seroprotection | 38 Participants |
| New Lot #3 | Number/Percentage of Subjects With Demonstrated Seroprotection | No seroprotection | 30 Participants |
| New Lot #3 | Number/Percentage of Subjects With Demonstrated Seroprotection | Seroprotection | 164 Participants |
| All New Lots | Number/Percentage of Subjects With Demonstrated Seroprotection | Seroprotection | 478 Participants |
| All New Lots | Number/Percentage of Subjects With Demonstrated Seroprotection | No seroprotection | 103 Participants |
Comparison: Null hypotheses: each new lot does not differ in seroprotection (SP) rates among each other by more than 10%.~Slower than anticipated enrollment resulted in a smaller number of subjects with antibody response data for analysis. Consequently, additional power estimates were made in anticipation of the occurrence of smaller sample sizes. With a total study population of only 772 subjects, the power of the study to test lot-to-lot consistency declined from 90% to 85%.95% CI: [-5.97, 9.66]
Comparison: Null hypotheses: each new lot does not differ in seroprotection (SP) rates among each other by more than 10%.~Slower than anticipated enrollment resulted in a smaller number of subjects with antibody response data for analysis. Consequently, additional power estimates were made in anticipation of the occurrence of smaller sample sizes. With a total study population of only 772 subjects, the power of the study to test lot-to-lot consistency declined from 90% to 85%.p-value: <0.0595% CI: [-9.92, 4.98]t-test, 2 sided
Comparison: Null hypotheses: each new lot does not differ in seroprotection (SP) rates among each other by more than 10%.~Slower than anticipated enrollment resulted in a smaller number of subjects with antibody response data for analysis. Consequently, additional power estimates were made in anticipation of the occurrence of smaller sample sizes. With a total study population of only 772 subjects, the power of the study to test lot-to-lot consistency declined from 90% to 85%.p-value: <0.0595% CI: [-11.94, 3.31]t-test, 2 sided
Comparison: Null hypothesis: reference lot vs. Lot 1, 2, and 3 combined do differ in seroprotection (SP) rates among each other by more than 10%.~Slower than anticipated enrollment resulted in a smaller number of subjects with antibody response data for analysis. Consequently, additional power estimates were made in anticipation of the occurrence of smaller sample sizes. The power of the study to test non-inferiority of the combined new lots compared to the reference lot dropped from 99% to 87%.p-value: <0.0595% CI: [-9.74, 3.1]t-test, 2 sided
Secondary
Number/Percentage of Subjects With an Immediate Solicited Local or Systemic Reactogenicity Event (RE)
Subjects were monitored for the following adverse events and categorized as events almost certainly related to receipt of the vaccine: Redness Swelling Tenderness Dyspnea Cyanosis Loose Stools Vomiting Convulsion Fever (37 degrees Celsius or greater, axillary) Hives (urticaria) Angioedema
Time frame: Within 30 minutes of vaccination
Population: All study subjects receiving vaccine were included in this measure.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Reference Lot | Number/Percentage of Subjects With an Immediate Solicited Local or Systemic Reactogenicity Event (RE) | Any immediate RE | 0 Participants |
| Reference Lot | Number/Percentage of Subjects With an Immediate Solicited Local or Systemic Reactogenicity Event (RE) | No immediate RE | 163 Participants |
| New Lot #1 | Number/Percentage of Subjects With an Immediate Solicited Local or Systemic Reactogenicity Event (RE) | No immediate RE | 214 Participants |
| New Lot #1 | Number/Percentage of Subjects With an Immediate Solicited Local or Systemic Reactogenicity Event (RE) | Any immediate RE | 6 Participants |
| New Lot #2 | Number/Percentage of Subjects With an Immediate Solicited Local or Systemic Reactogenicity Event (RE) | Any immediate RE | 5 Participants |
| New Lot #2 | Number/Percentage of Subjects With an Immediate Solicited Local or Systemic Reactogenicity Event (RE) | No immediate RE | 206 Participants |
| New Lot #3 | Number/Percentage of Subjects With an Immediate Solicited Local or Systemic Reactogenicity Event (RE) | Any immediate RE | 2 Participants |
| New Lot #3 | Number/Percentage of Subjects With an Immediate Solicited Local or Systemic Reactogenicity Event (RE) | No immediate RE | 222 Participants |
Secondary
Number/Percentage of Subjects With a Solicited Local or Systemic Reactogenicity Event Within 7 Days After Vaccination
Collected by a home visit to observe the subject and interview his/her parent or guardian occurrence and severity of solicited injection site reactogenicity events (REs) related to vaccination and solicited systemic REs or other AEs that might or might not be related to the prior receipt of vaccine
Time frame: Within 7 days of vaccination
Population: All subjects receiving the vaccine were assessed for this measure.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Reference Lot | Number/Percentage of Subjects With a Solicited Local or Systemic Reactogenicity Event Within 7 Days After Vaccination | Any RE | 51 Participants |
| Reference Lot | Number/Percentage of Subjects With a Solicited Local or Systemic Reactogenicity Event Within 7 Days After Vaccination | No RE | 112 Participants |
| New Lot #1 | Number/Percentage of Subjects With a Solicited Local or Systemic Reactogenicity Event Within 7 Days After Vaccination | No RE | 145 Participants |
| New Lot #1 | Number/Percentage of Subjects With a Solicited Local or Systemic Reactogenicity Event Within 7 Days After Vaccination | Any RE | 75 Participants |
| New Lot #2 | Number/Percentage of Subjects With a Solicited Local or Systemic Reactogenicity Event Within 7 Days After Vaccination | Any RE | 81 Participants |
| New Lot #2 | Number/Percentage of Subjects With a Solicited Local or Systemic Reactogenicity Event Within 7 Days After Vaccination | No RE | 130 Participants |
| New Lot #3 | Number/Percentage of Subjects With a Solicited Local or Systemic Reactogenicity Event Within 7 Days After Vaccination | Any RE | 61 Participants |
| New Lot #3 | Number/Percentage of Subjects With a Solicited Local or Systemic Reactogenicity Event Within 7 Days After Vaccination | No RE | 163 Participants |
Secondary
Number/Percentage of Subjects With Other Adverse Events (AE) During the Study
Adverse events other than solicited reactogenicities were obtained through review of medical history when subject returned to clinic. They were graded for severity and rated by the PI for possible relationship to vaccination throughout the 28 days study period.
Time frame: Between 7 and 28 days of vaccination
Population: All subjects receiving the vaccine were evaluated for this measure.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Reference Lot | Number/Percentage of Subjects With Other Adverse Events (AE) During the Study | Any AE | 60 Participants |
| Reference Lot | Number/Percentage of Subjects With Other Adverse Events (AE) During the Study | No AE | 103 Participants |
| New Lot #1 | Number/Percentage of Subjects With Other Adverse Events (AE) During the Study | No AE | 136 Participants |
| New Lot #1 | Number/Percentage of Subjects With Other Adverse Events (AE) During the Study | Any AE | 84 Participants |
| New Lot #2 | Number/Percentage of Subjects With Other Adverse Events (AE) During the Study | Any AE | 92 Participants |
| New Lot #2 | Number/Percentage of Subjects With Other Adverse Events (AE) During the Study | No AE | 119 Participants |
| New Lot #3 | Number/Percentage of Subjects With Other Adverse Events (AE) During the Study | Any AE | 77 Participants |
| New Lot #3 | Number/Percentage of Subjects With Other Adverse Events (AE) During the Study | No AE | 147 Participants |