Lot-to-lot Consistency Trial of Japanese Encephalitis Live Attenuated SA 14-14-2 Vaccine

Study Overview
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Brief Summary
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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.

Official Title
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A Clinical Trial in Healthy Infants to Assess Lot-to-lot Consistency of Japanese Encephalitis Live Attenuated SA 14-14-2 Vaccine and Non-inferiority With Respect to an Earlier Product.

Conditions
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Japanese Encephalitis

Intervention / Treatment
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* Biological: Vaccine produced in existing facility
* Biological: Vaccine produced in new facility


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 10 Months
Maximum Age: 12 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Reference Lot<br>Lot of Vaccine produced in existing facility | Biological: Vaccine produced in existing facility<br>* 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<br>|
| Experimental: New Lot #1<br>First lot of vaccine produced in new facility | Biological: Vaccine produced in new facility<br>* 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<br>|
| Experimental: New Lot #2<br>Second lot of vaccine produced in new facility | Biological: Vaccine produced in new facility<br>* 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<br>|
| Experimental: New Lot #3<br>Third lot of vaccine produced in new facility | Biological: Vaccine produced in new facility<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 28 days post-vaccination | 
| Geometric Mean Titers (GMT) | Geometric Mean Titers of Neutralizing anti-JEV antibody | 28 days post-vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Within 30 minutes of vaccination | 
| 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 | Within 7 days of vaccination | 
| 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. | Between 7 and 28 days of vaccination |