Immunogenicity and Safety of Japanese Encephalitis Vaccine When Given With Measles-Mumps-Rubella (MMR) Vaccine

Study Overview
=================
Brief Summary
-----------------
This study aims to provide evidence that co-administration of measles-mumps-rubella vaccine (MMR) and live attenuated SA 14-14-2 Japanese encephalitis vaccine (CD-JEV) does not adversely affect immunogenicity or safety.

Detailed Description
-----------------
When incorporating a new vaccine in the Expanded Programme on Immunization (EPI), it is important to provide evidence that it can be introduced concurrently with other routine pediatric vaccines without significantly impairing the immune response to any vaccine while maximizing coverage and minimizing cost. This non-inferiority study aims to compare CD-JEV and MMR responses in a population of children in a country where MMR introduction is ongoing or planned. This information will help the ministries of health evaluate the addition of CD-JEV into routine EPI.

Official Title
-----------------
Immunogenicity and Safety of Concurrent Administration of Live, Attenuated SA 14-14-2 Japanese Encephalitis Vaccine and Measles-Mumps-Rubella Vaccine in Infants 9-12 Months of Age in the Philippines

Conditions
-----------------
Mumps, Measles, Rubella, Encephalitis, Japanese

Intervention / Treatment
-----------------
* Biological: Live attenuated SA 14-14-2 Japanese Encephalitis vaccine
* Biological: Measles, mumps, rubella vaccine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 9 months to < 10 months at the time of enrollment. Residence in the study area. At least one parent or guardian willing to provide written informed consent. Generally healthy and free of obvious health problems as established by medical history, physical examination, and clinical judgment. A parent or guardian is willing to attend all planned study visits and allow home visits and phone contacts, as required by the protocol. Exclusion Criteria: Previous receipt of any measles-mumps-rubella containing vaccine. Previous receipt of any Japanese encephalitis vaccine. History of measles, mumps, rubella, or Japanese encephalitis infection. Administration of any other vaccine within 28 days prior to administration of a study vaccine or planned vaccination of any vaccine other than catch-up doses of routine EPI vaccines or oral polio vaccine during the 28 days after study vaccination. History of allergic disease or known hypersensitivity to any component of the study vaccines and/or following administration of vaccines included in the local program of immunization. Use of any investigational or non-registered drug within 90 days prior to the administration of study vaccines or planned administration during the study period. Administration of immunoglobulins and/or any blood products within 90 days prior to the administration of study vaccines or planned administration during the study period. Chronic administration (defined as > 7 days) of immunosuppressing or other immune-modifying agents within 14 days before or after vaccination (including systemic corticosteroids equivalent to prednisone ≥ 0.5 mg/kg/day; topical and inhaled steroids are allowed). Primary or acquired immunodeficiency, including human immunodeficiency virus (HIV) infection, or a family history of congenital or hereditary immunodeficiency as reported by parent. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic, or renal functional abnormality, as determined by medical history or physical examination, which might interfere with the study objectives. Severely malnourished infants as measured by World Health Organization weight-for-height tables (Z-score < -3). Any condition or criterion that, in the opinion of the study physician, might compromise the well-being of the participant, compliance with study procedures, or interpretation of the outcomes of the study. Acute illness at the time of enrollment defined as the presence of a moderate or severe illness with fever (axillary temperature ≥ 38.0°C) or without fever (severity determined at the discretion of the study physician). Acute illness is a temporary exclusion. Vaccination should be postponed at least 7 days after recovery. A visit for reassessment may be scheduled 7 days or more after temporary exclusion illness is resolved. Eligibility for study participation must be reassessed again at the next visit.

Ages Eligible for Study
-----------------
Minimum Age: 9 Months
Maximum Age: 9 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 - MMR and CD-JEV<br>Participants receiving one dose of CD-JEV vaccine and one dose of MMR vaccine concurrently at Day 0; Group 1 will also receive a second dose of MMR per the routine immunization schedule at Day 84 (12 months of age). | Biological: Live attenuated SA 14-14-2 Japanese Encephalitis vaccine<br>* Single 0.5 mL dose of World Health Organization prequalified live, attenuated SA 14-14-2 JE vaccine manufactured by Chengdu Institute of Biological Products, Chengdu, China, administered by subcutaneous injection<br>* Other names: RS.JEV®;Biological: Measles, mumps, rubella vaccine<br>* Single 0.5 mL dose of live, attenuated measles-mumps-rubella vaccine (Schwarz measles virus, RIT 4385 mumps strain, and Wistar RA 27/3 rubella virus) manufactured by GlaxoSmithKline, Inc., administered by subcutaneous injection.<br>* Other names: Priorix®;|
| Experimental: Group 2 - MMR then CD-JEV<br>Participants receiving one dose of MMR vaccine at Day 0 and one dose of CD-JEV 56 days later. Group 2 will receive a second dose of MMR per the routine immunization schedule at Day 84 (12 months of age). | Biological: Live attenuated SA 14-14-2 Japanese Encephalitis vaccine<br>* Single 0.5 mL dose of World Health Organization prequalified live, attenuated SA 14-14-2 JE vaccine manufactured by Chengdu Institute of Biological Products, Chengdu, China, administered by subcutaneous injection<br>* Other names: RS.JEV®;Biological: Measles, mumps, rubella vaccine<br>* Single 0.5 mL dose of live, attenuated measles-mumps-rubella vaccine (Schwarz measles virus, RIT 4385 mumps strain, and Wistar RA 27/3 rubella virus) manufactured by GlaxoSmithKline, Inc., administered by subcutaneous injection.<br>* Other names: Priorix®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Measles Seropositivity 56 Days Post-vaccination | Measles immunogenicity was assessed by the percentage of participants with demonstrated seropositivity for measles at 56 days post-vaccination. Seropositivity was defined by a concentration of ≥ 120 mIU/mL of anti-measles neutralizing antibody titer, as measured by the plaque reduction neutralization test (PRNT) (dilution converted to concentration using the 3rd International Standard Reference serum). | 56 days after MMR dose 1 vaccination (Day 56) | 
| Percentage of Participants With Rubella Seropositivity 56 Days Post-vaccination | Rubella immunogenicity was assessed by the percentage of participants with demonstrated seropositivity for rubella at 56 days post-vaccination. Seropositivity was defined as antirubella immunoglobulin G (IgG) concentration of ≥ 10 IU/mL (corresponding to an optical density ratio ≥ 1.10) using a commercial IgG enzyme-linked immunosorbent assay (ELISA). | 56 days after MMR dose 1 vaccination (Day 56) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Mumps Seropositivity 56 Days Post-vaccination | Mumps immunogenicity was assessed by the percentage of participants with demonstrated seropositivity for mumps at 56 days post-vaccination. Seropositivity was defined as an optical density ratio ≥ 1.10 using a commercial ELISA. | 56 days after MMR dose 1 vaccination (Day 56) | 
| Geometric Mean Concentration (GMC) for Anti-measles Neutralizing Antibody Concentration at 56 Days Post-vaccination | Anti-measles neutralizing antibody concentration was measured by the plaque reduction neutralization test (PRNT). | 56 days after MMR dose 1 vaccination (Day 56) | 
| GMC for Anti-rubella IgG Antibody Concentration at 56 Days Post-vaccination | Anti-rubella immunoglobulin G (IgG) concentration was measured using a commercial IgG enzyme-linked immunosorbent assay (ELISA). | 56 days after MMR dose 1 vaccination (Day 56) | 
| Seroconversion Rate for Measles 56 Days Post-vaccination | The seroconversion rate for measles at 56 days post-vaccination was defined as the percentage of participants with a change in serostatus from negative to positive 56 days after vaccination or a four-fold rise in concentration 56 days after vaccination if seropositive for measles at baseline. Seropositivity was defined by a concentration of ≥ 120 mIU/mL of anti-measles neutralizing antibody titer, as measured by the plaque reduction neutralization test (PRNT). | 56 days after MMR dose 1 vaccination (Day 56) | 
| Seroconversion Rate for Mumps 56 Days Post-vaccination | The seroconversion rate for mumps at 56 days post-vaccination was defined as the percentage of participants with a change in serostatus from negative to positive 56 days after vaccination. Seropositivity was defined as an optical density ratio ≥ 1.10, measured using a commercial ELISA. Participants with equivocal serostatus at baseline are counted as non-responders. | 56 days after MMR dose 1 vaccination (Day 56) | 
| Seroconversion Rate for Rubella 56 Days Post-vaccination | The seroconversion rate for rubella at 56 days post-vaccination was defined as the percentage of participants with a change in serostatus from negative to positive 56 days after vaccination or a four-fold rise in concentration 56 days after vaccination if seropositive for rubella at baseline. Seropositivity is defined as a post-vaccination concentration of ≥ 10 IU/mL measured using a commercial ELISA. | 56 days after MMR dose 1 vaccination (Day 56) | 
| Percentage of Participants With Japanese Encephalitis Seropositivity 28 Days Post-vaccination | Japanese encephalitis (JE) immunogenicity was assessed by the percentage of participants with demonstrated seropositivity 28 days after CD-JEV vaccination. Seropositivity was defined as an anti-JE serum neutralizing antibody titer of ≥ 1:10, as measured by JE PRNT-50. | 28 days after CD-JEV vaccination (Day 28 for Group 1 and Day 84 for Group 2) | 
| Geometric Mean Titer (GMT) for Serum Neutralizing Antibody Titer to JE Virus at 28 Days Post-vaccination | Anti-JE serum neutralizing antibody titer was measured using JE PRNT-50. | 28 days after CD-JEV vaccination (Day 28 for Group 1 and Day 84 for Group 2) | 
| Number of Participants With Immediate Reactions Within 30 Minutes of Each Vaccination | Participants were observed for 30 minutes after each vaccination for immediate reactions. Immediate reactions included both local (injection site) and systemic reactions. MMR vaccine was injected on left upper thigh and CD-JEV was injected on right upper thigh. Serious reactions were those meeting one of the following conditions: Death. Life threatening Required inpatient hospitalization or prolongation of existing hospitalization. Resulted in a persistent or significant disability or incapacity. Important medical events that, based upon appropriate medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed above. | 30 minutes following each study vaccination | 
| Number of Participants With Solicited Local and Systemic Reactions Within 14 Days of Each Vaccination | Reactogenicity post-vaccination was assessed from 30 minutes through 14 days following vaccination. Parents used a structured reactogenicity diary card to record the following solicited (pre-listed) local and system reactions. Local reactions (at injection site): Ecchymosis (bruising) Erythema (redness) Edema (swelling) Induration (hardness) Pain/tenderness Systemic reactions: Fever Rash Cough Runny nose Change in eating habits Diarrhea Sleepiness Irritability Unusual crying Vomiting | 30 minutes through 14 days following each vaccination | 
| Number of Participants With Solicited Local Reactions Within 14 Days of Each Vaccination by Maximum Severity | Parents recorded local reactions on a diary card. Local ecchymosis, erythema, edema, and induration were graded as follows: Grade 1: ≤2.5 cm in diameter. Grade 2: >2.5 cm in diameter with 50% of surface area of extremity segment involved. Grade 3: ≥50% surface area of extremity segment involved OR ulceration OR secondary infection OR phlebitis OR sterile abscess OR drainage. Grade 4: potentially life-threatening (e.g., abscess, exfoliative dermatitis, necrosis involving dermis or deeper tissue). Injection site pain/tenderness (pain without touching or tenderness when the area is touched) were graded as follows: Grade 1: pain/tenderness causing no or minimal limitation of use of limb. Grade 2: pain/tenderness causing greater than minimal limitation of use of limb. Grade 3: pain/tenderness causing inability to perform usual social and functional activities. Grade 4: pain/tenderness causing inability to perform basic self-care OR hospitalization indicated. | 30 minutes through 14 days following each vaccination | 
| Number of Participants With Systemic Reactions Within 14 Days of Each Vaccination by Maximum Severity | Parents recorded systemic reactions on a diary card. Fever was recorded and graded as follows (axillary temperature): Grade 1: 37.5°C to 37.9°C Grade 2: 38.0°C to 38.4°C Grade 3: 38.5°C to 40.0°C Grade 4: >40.0°C Rash, cough, runny nose, change in eating habits, diarrhea, sleepiness, irritability, unusual crying, vomiting, and any other unsolicited reaction occurring from 30 minutes through 14 days post vaccination were graded as follows: Grade 1: symptoms causing no or minimal interference with usual social and functional activities. Grade 2: symptoms causing greater than minimal interference with usual social and functional activities. Grade 3: symptoms causing inability to perform usual social and functional activities with intervention or hospitalization indicated. Grade 4: symptoms causing inability to perform basic self-care functions OR medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death. | 30 minutes through 14 days following each vaccination | 
| Number of Participants With Unsolicited Adverse Events Within 28 Days of Each Vaccination | Each adverse event (AE) was assessed for relationship to vaccine by the study clinician according to the following: Definitely Related: An adverse event or unanticipated problem clearly related to the research procedures. Possibly Related: There is a reasonable possibility that the adverse event or unanticipated problem, incident, experience, or outcome may have been caused by the procedures involved in the research. Not Related: Any adverse event or unanticipated problem clearly not related to study procedures. Related adverse events includes events that were assessed as definitely or possibly related. | 28 days following each vaccination | 
| Number of Participants With Serious Adverse Events Throughout the Study | A serious adverse event (SAE) was defined as an AE that met one of the following: Death Life threatening Required inpatient hospitalization or prolongation of existing hospitalization Resulted in persistent or significant disability or incapacity Important medical events that, based upon appropriate medical judgment, jeopardized the participant and required medical or surgical intervention to prevent an outcomes listed above AEs were assessed for relationship to vaccine by the study clinician according to the following: Definitely Related: An AE or unanticipated problem clearly related to the research procedures. Possibly Related: There is a reasonable possibility that the AE or unanticipated problem, incident, experience, or outcome may have been caused by the procedures involved in the research. Not Related: Any AE or unanticipated problem clearly not related to study procedures. Related SAEs includes events that were assessed as definitely or possibly related. | Up to 112 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
vaccine