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
Phase: PHASE4
Conditions: Encephalitis, Japanese, Measles, Mumps, Rubella
Sponsor: PATH

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 
 Protocol Number: JEV06 
Sponsor: PATH 
Vaccine Manufacturer: Chengdu Institute of Biological Products 
Funding Mechanism: Bill & Melinda Gates Foundation 
Investigator: Maria Rosario Capeding, Research Institute for Tropical Medicine 
Version Number: 2.0 
Date: 18 January 2017 
ClinicalTrials.gov: NCT02880865

 
 
 
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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following:  
 
The Declaration of Helsinki 
 
International Ethical Guidelines for Biomedical Research Involving Human Subjects, CIOMS 
2002 
 
International Ethical Guidelines for Epidemiological Studies Involving Human Subjects, 2008 
 
International Conference on Harmonization (ICH) E6 (Good Clinical Practice) 
 
The Philippines National Ethical Guidelines for Health Research 
 
All key personnel (all investigators responsible for the design and conduct of this study) will have 
completed Human Subjects Protection and GCP training prior to interaction with any participants or 
to having access to their confidential study data.  
 
 
 

 
 
 
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TABLE OF CONTENTS 
 
 
Key Roles ............................................................................................................................ 2 
 
Background Information and Scientific Rationale ................................................................ 4 
2.1. 
Background Information ........................................................................................... 4 
2.1.1. Measles Virus and Vaccination .................................................................... 4 
2.1.2. Mumps Virus and Vaccination ...................................................................... 4 
2.1.3. Rubella Virus and Vaccination ..................................................................... 4 
2.1.4. Clinical Aspects of Japanese Encephalitis (JE) ........................................... 5 
2.1.5. Epidemiological Profile of JE ........................................................................ 5 
2.1.6. Live, Attenuated SA 14-14-2 JE Vaccine ..................................................... 6 
2.1.7. JE Disease in the Philippines ....................................................................... 7 
2.2. 
Scientific Rationale ................................................................................................... 8 
2.3. 
Potential Risks and Benefits .................................................................................... 9 
2.3.1. Potential Risks .............................................................................................. 9 
2.3.2. Known Potential Benefits ............................................................................. 9 
 
Objectives .......................................................................................................................... 10 
3.1. 
Study Objectives .................................................................................................... 10 
3.1.1. Primary Objectives ..................................................................................... 10 
3.1.2. Secondary Objectives ................................................................................ 10 
3.1.3. Exploratory Objectives ............................................................................... 11 
3.2. 
Study Outcome Measures ...................................................................................... 11 
3.2.1. Primary Outcome Measures ....................................................................... 11 
3.2.2. Secondary Outcome Measures .................................................................. 11 
 
Study Design ..................................................................................................................... 12 
4.1. 
Study Site ............................................................................................................... 13 
 
Study Enrollment and Withdrawal ...................................................................................... 13 
5.1. 
Participant Inclusion Criteria .................................................................................. 13 
5.2. 
Participant Exclusion Criteria ................................................................................. 13 
5.3. 
Treatment Assignment Procedures ........................................................................ 14 
5.3.1. Randomization Procedures ........................................................................ 14 
5.3.2. Allocation and Masking Procedures ........................................................... 15 
5.3.3. Adherence to Randomization ..................................................................... 15 
5.3.4. Reasons for Withdrawal ............................................................................. 15 
5.3.5. Handling of Withdrawals ............................................................................. 15 
5.3.6. Suspension or Termination of Study .......................................................... 16 
 
Study Vaccines .................................................................................................................. 16 
6.1. 
Study Vaccine Descriptions ................................................................................... 16 
6.1.1. Live, Attenuated SA 14-14-2 JE Vaccine ................................................... 16 
6.1.2. Measles, Mumps, Rubella Vaccine ............................................................ 16 
6.1.3. Acquisition .................................................................................................. 17 
6.1.4. Packaging and Labeling ............................................................................. 17 
6.1.5. Product Storage and Stability ..................................................................... 17 
6.2. 
Dosage, Preparation, and Administration of Study Vaccines ................................. 17 
6.3. 
Accountability Procedures for the Study Vaccines ................................................. 18 
6.4. 
Concomitant Medications/Treatments .................................................................... 18 
 
Study Schedule .................................................................................................................. 18 
7.1. 
Screening ............................................................................................................... 18 
7.2. 
Consent .................................................................................................................. 18 
7.3. 
Eligibility/Enrollment/Baseline ................................................................................ 19 
7.4. 
Follow-up Visit 2 Days After Enrollment ................................................................. 20 

 
 
 
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7.4.1. Group 1 and Group 2 Visits to Assess Safety (D2+3) ................................ 20 
7.5. 
Follow-up Visit 14 Days After Enrollment ............................................................... 20 
7.5.1. Group 1 and Group 2 Visits to Assess Safety (D14+3) .............................. 20 
7.6. 
Follow-up Visit 28 Days After Enrollment ............................................................... 21 
7.6.1. Group 1 Visit to Assess Safety and Collect Serum (D28+7) ...................... 21 
7.6.2. Group 2 Visit to Assess Safety (D28+7) ..................................................... 21 
7.7. 
Follow-up 56 Days After Enrollment ....................................................................... 22 
7.7.1. Group 1 Visit to Collect Serum (D56+7) ..................................................... 22 
7.7.2. Group 2 Visit to Collect Serum and Provide CD-JEV (D56+7) ................... 22 
7.8. 
Follow-up visit 58 Days After Enrollment ............................................................... 23 
7.8.1. Group 2 Visit to Assess Safety 2 Days After CD-JEV (D58+3) .................. 23 
7.9. 
Follow-up Visit 70 days After Enrollment ............................................................... 23 
7.9.1. Group 2 Visit to Assess Safety 14 Days After CD-JEV (D70+3) ................ 23 
7.10. 
Follow-up 84 Days After Enrollment ....................................................................... 24 
7.10.1. Group 1 Follow-up Visit to Provide MMR (D84+7) ..................................... 24 
7.10.2. Group 2 Follow-up Visit (D84+7) ................................................................ 24 
7.11. 
Follow up 86 Days After Enrollment ....................................................................... 25 
7.11.1. Group 1 and Group 2 Visits to Assess Safety (D86+3) .............................. 25 
7.12. 
Follow-up Visit 98 Days After Enrollment ............................................................... 25 
7.12.1. Group 1 and Group 2 Visits to Assess Safety (D98+3) .............................. 25 
7.13. 
Final Study Visit 112 Days After Enrollment .......................................................... 26 
7.13.1. Group 1 and Group 2 Final Study Visit to Assess Safety (D112+7) ........... 26 
7.14. 
Allowable Schedule of Study Visits ........................................................................ 26 
 
Study Procedures/Evaluations ........................................................................................... 27 
8.1. 
Clinical Evaluations ................................................................................................ 27 
8.1.1. Medical History ........................................................................................... 27 
8.1.2. Physical Examination ................................................................................. 27 
8.1.3. Specific Clinical Signs and Symptoms of Interest ...................................... 28 
8.1.4. Illness Diagnosis and Treatment ................................................................ 29 
8.2. 
Laboratory Evaluations .......................................................................................... 29 
8.2.1. Clinical Laboratory Evaluations .................................................................. 29 
8.2.2. Serum Assays ............................................................................................ 29 
8.2.2.1. Anti-Japanese Encephalitis Immunogenicity Testing ..................... 29 
8.2.2.2. Measles .......................................................................................... 29 
8.2.2.3. Mumps ............................................................................................ 30 
8.2.2.4. Rubella ........................................................................................... 30 
8.2.3. Specimen Preparation, Handling, and Shipping ......................................... 30 
8.2.3.1. Specimen Collection ....................................................................... 30 
8.2.3.2. Specimen Preparation, Handling, and Storage .............................. 30 
8.2.3.3. Specimen Shipment ....................................................................... 31 
 
Assessment of Safety ........................................................................................................ 31 
9.1. 
Specification of Safety Parameters ........................................................................ 31 
9.2. 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters31 
9.2.1. Adverse Events .......................................................................................... 31 
9.2.2. Immediate Reactions .................................................................................. 32 
9.2.3. Reactogenicity ............................................................................................ 33 
9.2.3.1. Local and Systemic Signs and Symptoms ..................................... 33 
9.2.4. Serious Adverse Events ............................................................................. 35 
9.3. 
Reporting Procedures ............................................................................................ 35 
9.3.1. Serious Adverse Events ............................................................................. 35 
9.3.2. Regulatory Reporting ................................................................................. 36 
9.4. 
Type and Duration of Follow-up of Participants after Adverse Events ................... 36 

 
 
 
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9.5. 
Safety Oversight ..................................................................................................... 36 
9.5.1. SMC Roles and Responsibilities ................................................................ 36 
9.5.2. Study Materials for SMC Review ................................................................ 36 
9.5.3. Reports from the SMC ................................................................................ 37 
9.5.3.1. Review Report ................................................................................ 37 
9.5.3.2. Immediate Action Report ................................................................ 37 
9.6. 
Halting Rules .......................................................................................................... 37 
 
Clinical Monitoring.............................................................................................................. 37 
10.1. 
Site Monitoring Plan ............................................................................................... 37 
10.1.1. Site Initiation Visit ....................................................................................... 38 
10.1.2. Follow-up Visits .......................................................................................... 38 
10.1.3. Close-out Visit ............................................................................................ 38 
10.2. 
Audits and Inspections ........................................................................................... 39 
10.3. 
Archiving ................................................................................................................ 39 
 
Statistical Considerations .................................................................................................. 39 
11.1. 
Study Hypothesis ................................................................................................... 39 
11.2. 
Definition of Analysis Sets ...................................................................................... 39 
11.2.1. Intention-to-Treat Analysis Set ................................................................... 39 
11.2.2. Safety Analysis Set .................................................................................... 40 
11.2.3. Per-Protocol Analysis Set ........................................................................... 40 
11.2.3.1. Measles Per-Protocol Analysis Set (measles-PP) .......................... 40 
11.2.3.2. Mumps Per-Protocol Analysis set (mumps-PP) ............................. 40 
11.2.3.3. Rubella Per-Protocol Analysis Set (rubella-PP) ............................. 40 
11.2.3.4. JE Per-Protocol Analysis Set (JE-PP) ............................................ 41 
11.3. 
Analysis Plan.......................................................................................................... 41 
11.3.1. Immunogenicity .......................................................................................... 41 
11.3.1.1. Primary Hypotheses ....................................................................... 41 
11.3.2. Safety ......................................................................................................... 41 
11.3.3. Analysis and Reporting of Withdrawals ...................................................... 41 
11.4. 
Sample Size Considerations .................................................................................. 42 
11.5. 
Final Analysis Plan ................................................................................................. 42 
11.5.1. Primary Analyses ....................................................................................... 42 
11.5.2. Secondary Analyses ................................................................................... 42 
11.5.3. Exploratory Analyses .................................................................................. 43 
11.5.4. Timing of Analyses ..................................................................................... 43 
 
Source Documents and Access to Source Data/Documents ............................................. 43 
 
Quality Control and Quality Assurance .............................................................................. 43 
 
Ethics/Protection of Human Subjects ................................................................................. 44 
14.1. 
Ethical Standard ..................................................................................................... 44 
14.2. 
Institutional Review Board ...................................................................................... 44 
14.3. 
Independent Ethics Committee .............................................................................. 44 
14.4. 
Informed Consent Process ..................................................................................... 44 
14.5. 
Inclusion of Women and Children .......................................................................... 45 
14.6. 
Participant Confidentiality ....................................................................................... 45 
14.6.1. Confidentiality of Data ................................................................................ 45 
14.6.2. Confidentiality of Patient Records .............................................................. 46 
14.6.3. Notification of Primary Care Physician ....................................................... 46 
14.7. 
Study Discontinuation ............................................................................................ 46 
14.8. 
Future Use of Stored Specimens ........................................................................... 46 
 
Data Handling and Record Keeping .................................................................................. 47 
15.1. 
Data Management Responsibilities ........................................................................ 47 
15.2. 
Data Capture Methods ........................................................................................... 47 

 
 
 
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15.3. 
Types of Data ......................................................................................................... 47 
15.4. 
Timing/Reports ....................................................................................................... 47 
15.5. 
Study Records Retention ....................................................................................... 48 
15.6. 
Protocol Deviations ................................................................................................ 48 
 
Publication Policy ............................................................................................................... 48 
 
References ........................................................................................................................ 50 
 
 

 
 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
CDIBP 
Chengdu Institute of Biological Products 
CD-JEV 
prequalified live, attenuated SA-14-4-2 Japanese encephalitis vaccine  
CRF 
case report form 
CRO 
contract research organization 
CRS 
congenital rubella syndrome 
CSR 
Clinical Study Report 
DEN 
dengue 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EPI 
Expanded Programme on Immunization 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GMC 
geometric  mean concentration 
GMT 
geometric mean titer 
ICH 
International Conference on Harmonisation 
IEC 
Independent or Institutional Ethics Committee 
IgG 
Immunoglobulin G  
IgM 
Immunoglobulin M 
IRB 
Institutional Review Board 
ITT 
intent to treat analysis set 
JE 
Japanese encephalitis 
MCV 
measles containing vaccine 
MMR 
measles, mumps, rubella vaccine 
MR 
measles rubella vaccine 
RITM 
Research Institute for Tropical Medicine 
PHK 
primary hamster kidney 
PP 
per protocol analysis set 
PRNT 
plaque reduction neutralization test 
SAE 
serious adverse event 
SAGE 
WHO Strategic Advisory Group of Experts 
SAS 
safety analysis set 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
UNICEF 
United Nations Children’s Fund 
US 
United States 
WIRB 
Western Institutional Review Board 
WHO 
World Health Organization 
YF 
yellow fever 
 
 
 

 
 
 
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PROTOCOL SUMMARY 
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 
Study Code: 
JEV06 
Phase: 
Phase 4, randomized open label 
Population: 
628 healthy Filipino children aged 9 months at enrollment 
Study Site: 
Putatan Health Center and Bayanan Health Center located within the study area of 
the Research Institute for Tropical Medicine, Manila, Philippines  
Study Duration: 
7 to 8 months, dependent upon enrollment  
Participant 
Duration: 
4 months 
Agent Description: 
JE vaccine (CD-JEV): single 0.5 mL dose of World Health Organization (WHO) 
prequalified live, attenuated SA 14-14-2 JE vaccine manufactured by Chengdu Institute 
of Biological Products, Chengdu, China, administered by subcutaneous injection. 
Measles-mumps-rubella (MMR) vaccine: 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. 
Study Rationale: 
This non-inferiority study aims to provide evidence that co-administration of MMR and  
CD-JEV does not adversely affect safety or immunogenicity. With the use of MMR 
increasing, this study will provide critical data for policy makers considering the use of 
MMR and/or CD-JEV. 
Objectives and 
Outcome Measures: 
 
Primary Objectives and Outcome Measures:  
1. To demonstrate the non-inferiority of MMR vaccination in terms of measles 
immunogenicity when administered concomitantly to infants 9 months of age with  
CD-JEV compared to administration alone, as assessed by the rate of seropositivity 
56 days after vaccination. 
Measles immunogenicity will be assessed by the proportion (or percentage) of 
participants with demonstrated seropositivity for measles at 56 days post-
vaccination. Seropositivity will be 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).  
2. To demonstrate the non-inferiority of MMR vaccination in terms of rubella 
immunogenicity when administered to infants 9 months of age concomitantly with  
CD-JEV compared to administration alone, as assessed by the rate of seropositivity 
56 days after vaccination. 
Rubella immunogenicity will be assessed by the proportion (or percentage) of
participants with demonstrated seropositivity for rubella at 56 days post-vaccination
Seropositivity will be defined as anti-rubella Immunoglobulin G (IgG) concentration
of ≥10 IU/mL (corresponding to an optical density ratio ≥1.10) using a commercial

 
 
 
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IgG enzyme-linked immunosorbent assay (ELISA) manufactured by Wampole
Laboratories, Princeton, NJ. 
Secondary Objectives and Outcome Measures: 
1. To demonstrate the non-inferiority of MMR vaccination in terms of mumps 
immunogenicity when administered to infants 9 months of age concomitantly with 
CD-JEV compared to administration alone, as assessed by the rate of seropositivity 
56 days after vaccination.  
Mumps immunogenicity will be assessed by the proportion (or percentage) of 
participants with demonstrated seropositivity for mumps at 56 days post-
vaccination. Seropositivity will be defined as an optical density ratio ≥1.10 using a 
commercial ELISA manufactured by Zeus Scientific, Inc., Branchburg, NJ. 
2. To evaluate serum anti-measles geometric mean neutralizing antibody 
concentration (GMC) and anti-rubella IgG GMC at 56 days post-vaccination, 
comparing when MMR vaccine is co-administered with CD-JEV to when MMR 
vaccine is given alone. 
3. To evaluate anti-measles, anti-mumps, and anti-rubella seroconversion rates 56 
days after MMR vaccination, comparing when MMR vaccine is co-administered 
with CD-JEV to when MMR vaccine is given alone. For participants seronegative 
at baseline, seroconversion will be defined as a change to seropositive status (as 
defined above). For those participants seropositive for measles or rubella at 
baseline, seroconversion will be defined as a four-fold rise in concentration.  
4. To compare the anti-JE seropositivity rate 28 days after CD-JEV vaccination 
administered concurrently with MMR vaccine to CD-JEV administered alone. Anti-
JE seropositivity will be defined as an anti-JE serum neutralizing antibody titer of 
≥1:10, as measured by JE PRNT-50. 
5. To describe anti-JE neutralizing antibody geometric mean titers (GMTs) 28 days 
after CD-JEV vaccination when MMR vaccine is co-administered, compared to 
when CD-JEV is administered alone. 
6. To describe the safety profiles of CD-JEV and MMR vaccine when given 
concurrently and separately, as assessed by immediate reactions occurring within 
30 minutes, solicited injection site and systemic adverse reactions occurring within 
14 days, unsolicited adverse events (AEs) occurring within 28 days, and serious 
adverse events (SAEs) occurring throughout the study. Outcome measures for 
safety include: 
a. Frequency counts and percentage of participants reporting immediate reactions 
occurring within 30 minutes of each vaccination. 
b. Frequency counts and percentage of participants reporting solicited local and 
systemic AEs occurring within 14 days of each vaccination. 
c. Frequency counts and percentage of participants reporting unsolicited AEs 
occurring within 28 days of each vaccination. 
d. Frequency counts and percentage of participants reporting SAEs occurring 
throughout the study. 
 
 

 
 
 
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Exploratory Objective and Outcome Measure: 
1. To assess the effect of pre-existing anti-dengue antibody on CD-JEV 
immunogenicity 28 days following immunization. Pre-existing anti-dengue antibody 
will be measured first by the presence of anti-dengue IgG in ELISA and secondly 
by anti-dengue serotype 1-, 2-, 3-, and 4-specific serum neutralizing antibody titer 
of ≥1:10 as measured by dengue PRNT-50.  
 
Study Design: 
This study will be a phase 4 open-label trial in which 628 Philippine infants 9 months 
of age will be randomized 1:1 to one of two arms: 
 Group 1: 314 children 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 D84 (12 months of age). 
 Group 2: 314 children 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 D84 (12 months of age). 
Following receipt of study vaccine(s), infants will be monitored for immediate reactions 
during the first 30 minutes, solicited injection site and systemic adverse reactions for 
14 days, unsolicited adverse events for 28 days, and serious adverse events 
throughout the duration of the study. All safety events will be identified or observed by 
study staff and/or reported by a parent. Solicited adverse reactions will be recorded by 
the parent on diary cards or assessed during clinic visits. Study staff will make a follow-
up call to the participant’s parent 2(+3) days following vaccination to check on the 
welfare of the participant and ensure the diary card is being completed. The parent will 
return with the participant for a clinic visit 14(+3) days following vaccination for the 
study staff to review the diary card, conduct safety evaluations, and review any adverse 
events. Information regarding unsolicited AEs will be collected during any scheduled 
or unscheduled clinic visit. Events will be graded for severity and assessed for 
relatedness to vaccination by the study clinician.  
The study will be open-label; no placebo control will be employed. Due to the unequal 
number of injections per visit in each study arm, safety assessments will be unblinded. 
Blood samples for serologic testing will be collected on Day 0, Day 28(+7), and Day 
56(+7) for Group 1; and Day 0, Day 56(+7), and Day 84(+7) for Group 2.  
Baseline serologies will test for antibodies to JE, measles, mumps, rubella, and dengue 
virus. Antibody responses to CD-JEV will be tested 28 days after vaccination, while 
antibody responses to the first dose of MMR will be tested 56 days after vaccination. 
All laboratory testing will be conducted in a blinded fashion. 
 
Enrollment: 
3 to 4 months 
Study Population: 
Inclusion Criteria: 
Each participant receiving study vaccines must satisfy all of the following inclusion 
criteria at study entry: 
 
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. 

 
 
 
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 
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:  
No participant may have any of the following exclusion criteria at study entry: 
 
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 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.  
 
 

 
 
 
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Statistical Analysis: 
Populations for Analysis 
Intent-to-Treat Analysis Set (ITT): all participants who received a study vaccine. 
Participants in the ITT analysis set who have at least one post-vaccination serology 
result will be included in the immunogenicity analysis. 
Safety Analysis Set (SAS): all participants who received a study vaccine and have at 
least one safety measure post-vaccination. Participants in SAS will be analyzed based 
on the actual vaccine received rather than the group to which they have been 
randomized. 
Measles Per-Protocol Analysis Set (measles-PP): all participants who met eligibility 
criteria; received all study vaccines as planned within the specified time intervals; 
provided valid pre- and post-vaccination serum specimens for measles within the 
specified time intervals; did not receive restricted medications within 28 days post 
vaccination; and did not show seropositivity for measles at baseline.  
Mumps Per-Protocol Analysis Set (mumps-PP): all participants who met eligibility 
criteria; received all study vaccines as planned within the specified time intervals; 
provided valid pre- and post-vaccination serum specimens for mumps within the 
specified time intervals; did not receive restricted medications within 28 days post 
vaccination; and did not show seropositivity for mumps at baseline.  
Rubella Per-Protocol Analysis Set (rubella-PP): all participants who met eligibility 
criteria; received all study vaccines as planned within the specified time intervals; 
provided valid pre- and post-vaccination serum specimens for rubella within the 
specified time intervals; did not receive restricted medications within 28 days post 
vaccination; and did not show seropositivity for rubella at baseline.  
JE Per-Protocol Analysis Set (JE-PP): all participants who met eligibility criteria; 
received all study vaccines as planned within the specified time intervals; provided 
valid pre- and post-vaccination serum specimens for JE within the specified time 
intervals; did not receive restricted medications within 28 days post vaccination; and 
did not show seropositivity for JE at baseline. 
Safety analyses will be conducted on the ITT data set. Safety analyses will also be 
conducted on the SAS in the event participants received vaccine(s) to which they were 
not randomized. Immunogenicity analyses will be based on the ITT (with at least one 
post-vaccination serology result), measles-PP, mumps-PP, rubella-PP, and JE-PP. 
 
Primary Analyses: 
For each endpoint, non-inferiority will be demonstrated if the lower limit of the two-sided 
95% CI in the difference of the seropositivity rates between the two groups (concurrent 
administration minus separate administration) 56 days after vaccination is >-10%. The 
95% CI will be calculated using the Farrington-Manning score method.1  
 
Secondary Analyses: 
1. Non-inferiority for mumps will be demonstrated if the lower limit of the two-sided 
95% CI in the difference of the seropositivity rates between the two groups 
(concurrent administration minus separate administration) 56 days after 
vaccination is >-10%. The 95% CI will be calculated using the Farrington-Manning 
method. 

 
 
 
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2. The ratio of anti-measles and anti-rubella GMCs between both treatment groups 
with 95% CI obtained 56 days after vaccination (ratio of concurrent administration 
to separate administration) will be calculated using parametric models after log 
transformation of the concentrations and titers, where applicable.  
3. The difference with 95% CI between the anti-measles, anti-mumps, and anti-
rubella seroconversion rates 56 days after vaccination for the two groups 
(concurrent administration minus separate administration) will be calculated using 
the Farrington-Manning method. 
4. The difference with 95% CI between the anti-JE seropositivity rates 28 days after 
vaccination for the two groups (concurrent administration minus separate 
administration) will be calculated using the Farrington-Manning method.  
5. The ratio of anti-JE GMTs between both treatment groups with 95% CI obtained 
28 days after vaccination (ratio of concurrent administration to separate 
administration) will be calculated using parametric models after log transformation 
of the titers, where applicable. 
6. Safety endpoints will be descriptively summarized in terms of frequency counts 
and percentages by treatment group and severity, where applicable. Frequency 
counts and percentages will be provided along with 95% CI, where applicable.  The 
95% CI will be calculated based on the Exact test. 
 
Exploratory Analyses 
Post-vaccination serologic responses will be analyzed for any association between the 
baseline anti-dengue response and anti-JE antibody response 28 days after 
vaccination with CD-JEV.  
 
Sample Size and Power Estimation 
Enrollment size of 628 participants (314 per treatment group) was targeted to achieve 
an overall power of 90% (approximate individual power of 95% for each co-primary 
objective). This estimation is based upon a non-inferiority margin of 10%, a one-sided 
significance level of 2.5%, and assumed (based on historical data) a 95% seropositivity 
rate for measles vaccine, a 90% seropositivity rate for rubella vaccine, and a 20% non-
evaluable rate at 56 days post-vaccination. Individual sample size calculations were 
based on the Farrington-Manning score test. 

 
 
JEV06 Protocol v2.0 
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 KEY ROLES 
Institutions: 
Sponsor: 
PATH 
2201 Westlake Avenue, Suite 200 
Seattle, WA 98121, USA 
 
 
Research Institution: 
Research Institute for Tropical Medicine  
Filinvest Corporate City, Alabang, Muntinlupa City 
1781 Metro Manila, Philippines 
 
 
Vaccine Manufacturer: 
Chengdu Institute of Biological Products  
Baojiang Bridge 
Chengdu, 610023, Sichuan Province, People’s Republic of China 
 
 
GlaxoSmithKline, Inc. 
980 Great West Road,  
Brentford Middlesex,TW8 9GS, United Kingdom 
 
 
Monitoring and Pharmacovigilance: 
 
 
 
 
 
Data Management: 
 
 
 
 
 
Institutional Review Boards: 
Western Institutional Review Board 
1019 39th Avenue SE Suite 120 
Puyallup, WA 98374-2115 
   
 
 
Research Institute for Tropical Medicine  
Institutional Review Board 
Room 102 RITM Residence Hall 
Filinvest Corporate City, Alabang Muntinlupa City 
 
 
 
 
 
 
 
 

 
 
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National Ethics Board: 
Philippine Health Research Ethics Board 
c/o Philippine Council for Health Research and Development 
Department of Science and Technology 
3/F DOST Administrative Bldg., Gen. Santos Ave., Bicutan, Taguig City 
 
 
 
Individuals: 
RITM Investigator:  
 
  
 
 
 
RITM Clinical Operations: 
 
  
   
 
 
Immunological Laboratory Testing: 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
PATH Project Director: 
 
 
 
 
 
PATH Clinical Operations: 
 
 
 
 
 
 
 

 
 
JEV06 Protocol v2.0 
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 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1. Background Information 
2.1.1. Measles Virus and Vaccination 
Measles virus is an enveloped, single-stranded RNA virus affecting only humans.2 The virus causes 
high fever, cough, maculopapular rash, coryza, and conjunctivitis. Complications from the disease 
include otitis media, laryngo-tracheobronchitis, diarrhea, pneumonia, and in very severe cases, death.  
Measles is highly infectious through aerosolized respiratory droplets and by direct contact; in the 
prevaccine period, >90% of individuals were infected by 10 years of age. Before the introduction of 
measles vaccines, measles virus caused an estimated five to eight million deaths per year.3 Wide scale 
introduction of safe and effective measles vaccines has greatly reduced the burden of this disease—
from 2000 through 2011, the number of deaths from measles dropped from an estimated 548,000 to 
158,000 per year worldwide.4  
The recommended age for measles immunization in developing countries with ongoing transmission in 
which the risk of measles mortality among infants remains high is 9 months of age.5 In countries with 
low rates of measles transmission, the vaccine is recommended at 12 months of age to take advantage 
of the higher seroconversion rates achieved at this age. The proportion of children who develop 
protective antibody levels following measles immunization depends on the presence of inhibitory 
maternal antibodies and the immunologic maturity of the vaccine recipient. Approximately 85% of 
children develop protective antibody levels after one dose of measles at 9 months of age; this rate is 
much lower in children <9 months of age.3 Thus, routine immunization for measles is not given in 
children below 9 months.  
Since population immunity needs to be >90% in all districts to prevent measles epidemics, high 
immunization coverage is the cornerstone of effective measles control and the World Health 
Organization (WHO) now recommends two doses of measles vaccine for all children to ensure 
adequate immunity.6 WHO also recommends that countries take the opportunity offered by accelerated 
measles control and elimination activities to introduce rubella-containing vaccines.7 
2.1.2. Mumps Virus and Vaccination 
Mumps is an enveloped single-stranded RNA virus transmitted by direct contact or through contact with 
respiratory droplets or saliva.8 The virus causes respiratory problems with swelling of the salivary glands 
being the most common symptom. Early symptoms may include joint pain, lack of appetite, general 
discomfort, low grade fever, and vomiting. Mumps is typically a mild disease in children, but can cause 
more serious complications such as meningitis, encephalitis, and sensorineural deafness. With peaks 
every 2 to 5 years, the annual incidence ranges from 100 to 1,000 cases per 100,000 in non-immunized 
populations.9 While mumps vaccine is available as monovalent or bivalent product, the trivalent 
measles, mumps, and rubella (MMR) formulation is the most widely used product. 
2.1.3. Rubella Virus and Vaccination 
Rubella is an enveloped single-stranded RNA virus.10 Transmitted by the respiratory route, humans are 
the sole host of the virus. Rubella disease is a mild, self-limited illness that usually occurs during childhood. 
It may include a prodromal illness consisting of fever <39.0ºC, malaise, and mild conjunctivitis followed by 
postauricular, occipital, and posterior cervical lymphadenopathy and a maculopapular, erythematous and 
often pruritic rash. Post infectious encephalitis occurs in approximately 1/6000 rubella cases. Rubella 

 
 
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infection occurring just before conception and during early pregnancy may result in miscarriage, fetal 
death, or congenital defects (including congenital heart disease, cataracts, neurosensory deafness, 
mental retardation and intrauterine growth retardation) known as congenital rubella syndrome (CRS).11,12 
Rubella usually occurs in a seasonal pattern, with epidemics every 5-9 years.13 In countries that have not 
introduced rubella vaccine, the burden of CRS may be high; in 1996 an estimated 46,000 children were 
born with CRS in South-East Asia.14 High rubella vaccine coverage has significantly reduced or eliminated 
rubella and CRS in both developed and developing countries.15  
 
Since rubella is not as highly infectious as measles and because the effectiveness of one dose of a rubella 
containing vaccine is ≥95% when given at 9 months of age, only one dose of rubella vaccine is required 
to achieve rubella elimination if high coverage is achieved. However, the WHO Strategic Advisory Group 
of Experts (SAGE) Working Group on Measles and Rubella recently clarified its position through the 
following recommendation: 1) rubella-containing vaccine should be given in combination with measles-
containing vaccine (MCV) as measles-rubella (MR) or MMR and 2) in countries using rubella-containing 
vaccine in combination with MR or MMR, the same formulation should be used for both doses (either MR 
or MMR).7 
2.1.4. Clinical Aspects of Japanese Encephalitis (JE) 
With over three billion people living in 24 JE-endemic countries, Japanese encephalitis is the leading 
cause of viral neurological disease and disability in Asia (Figure 1).16-19 Children less than 15 years of 
age are at higher risk of JE than adults in 
most areas. More than 99 percent of JE 
infections are subclinical, so in areas with 
endemic transmission, naturally acquired 
infection at an early age results in immunity 
of greater than 80 percent of young adults.20 
However, clinical cases of JE can be very 
severe; some 70 percent of children with 
clinical JE either die or have severe, long-
term 
neurologic 
mental 
and 
physical 
disability. Nearly 70,000 cases are reported 
annually and cause approximately 10,000 to 
15,000 deaths, but because of limited 
surveillance and complexities in diagnosis, 
this is probably a substantial underestimate.21 
2.1.5. Epidemiological Profile of JE 
JE virus circulates in zoönotic cycles 
involving mosquitoes and several vertebrate 
species. Pigs and birds serve as amplifying 
and reservoir hosts, respectively, and are 
usually unaffected by infection.22-24 Pigs develop high viral loads after infection and can be key hosts for 
outbreaks by rapidly increasing the number of infectious mosquitoes in the environment through viral 
amplification. However, well-characterized outbreaks in regions without pigs are also recorded in the 
literature.25 In such cases, birds are thought to amplify the virus and result in human infections.26,27 JE 
virus cannot be transmitted person-to-person nor person-to-mosquito-to-person because the low-level 
viremia in humans cannot infect mosquitoes or contribute to the transmission cycle.  
 
Figure 1. Regions reported to have transmission of JE virus 
Source: Adapted from Halstead S, Tsai T. Japanese Encephalitis. In: 
Plotkin SA, Orenstein WA, eds. Vaccines. 4th edition. London, UK:  
W.B. Saunders Company; 2003:919–958. 

 
 
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JE is transmitted to humans by the bite of several mosquito species. The major mosquito vector of JE 
varies from region to region. Culex tritaeniorhynchus is the principal JE vector in Southeast Asia. Other 
ground pool and rice paddy breeding species, including C. vishnui, C. pseudovisnuri, C. gelidus, C. 
fuscocephala, C. bitaeniorhynchus, C. infula, C. whitmorei, and C. annulus, are also important.23,24  
2.1.6. Live, Attenuated SA 14-14-2 JE Vaccine 
Because of its zoönotic cycle, eradicating JE virus from the environment is unrealistic. Therefore, 
vaccination is the only way to protect children in JE-endemic countries from disease. For widespread 
use in developing countries, interest is focused on the WHO prequalified live, attenuated SA 14-14-2 
JE vaccine (hereafter referred to as CD-JEV), which is manufactured in China by the Chengdu Institute 
of Biological Products (CDIBP). CD-JEV is safe, effective, and the most affordable vaccine available 
that could be incorporated into routine immunization programs in endemic countries.  
 
CD-JEV has been used since 1988, with over 400 million doses administered in China and 
internationally. The vaccine is currently licensed in twelve countries, and, in 2013, vaccine produced at 
a new Good Manufacturing Practice-compliant production facility was prequalified by WHO. CD-JEV 
was also selected by UNICEF for use in 2015 Gavi-supported catch-up campaigns in children less than 
15 years old. 
 
Like other parenterally administered vaccines, immunization with CD-JEV vaccine may cause local and 
systematic side effects in some children. These include pain at the injection site for a short while after 
injection and swelling, redness, and tenderness at the injection site. Fever may occur and, in some 
cases, a rash may appear in the initial days following the vaccination. Because CD-JEV is a live- 
attenuated vaccine, there is a theoretical risk that systemic disease including encephalitis could occur 
if the vaccine strain replicates unchecked or if the vaccine strain reverts to neurovirulence. To date, only 
one case of encephalitis has been reported related to CD-JEV vaccination.28 No reports of severe 
allergic reactions or death have been associated with CD-JEV.  
 
In 2005 and 2006, WHO Global Advisory Committee on Vaccine Safety and the WHO SAGE on 
Immunization reviewed the safety of CD-JEV and other JE vaccines.7,29-31 These reviews stated that 
CD-JEV is well-tolerated across a wide age range and can safely be given to children as young as  
8 months of age. No serious adverse events (SAEs) were attributed to CD-JEV in 12 clinical studies 
conducted from 1992 through 2008 in China, India, the Philippines, South Korea, Sri Lanka, and 
Thailand.32-44 In 2013, the WHO Global Advisory Committee on Vaccine Safety reviewed the safety of 
CD-JEV again and concluded that it had an excellent safety profile.45  
 
Seroprotection rates following a single dose of CD-JEV (≥ 105.4 plaque-forming units) have been greater 
than 90% in most clinical trials. Several early Chinese studies have shown a dose-response gradient 
with 85% to 100% seroconversion after a single dose of CD-JEV vaccine was given to children  
1 to 12 years of age.32,35,36,41-43 In one of the first immunogenicity studies performed outside of China, 
95% of participants aged 9 to 15 months were seroprotected within 90 days after CD-JEV vaccination. 
A Korean study of 68 children 1 to 3 years of age showed high seroconversion rates of 96% four weeks 
after one dose of CD-JEV.38 Another long term study in Korea demonstrated that 90% of the study 
participants had a high level of neutralizing antibody four years after vaccination with a geometric mean 
titer (GMT) of 133 (range: 11-2991).46 
 
PATH, in partnership with CDIBP and others, has conducted Phase IIIb clinical trials evaluating the 
safety and immunogenicity of CD-JEV when co-administered with measles vaccine in healthy infants in 
the Philippines.33,39 These studies demonstrated the long-term immunogenicity and safety of  

 
 
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CD-JEV in infants as young as 8 months, continued seroprotection after three years in more than 80% 
of participants, and an acceptable safety profile. 
 
Data from this trial showed that in one month following vaccine receipt, levels of neutralizing anti-JE 
antibody and anti-measles immunoglobulin G (IgG) in infants given CD-JEV and measles vaccine 
concurrently at 9 months of age were statistically non-inferior to levels in infants given the two vaccines 
separated by a month (Table 2).33,39   
 
Table 2. Seropositivity rates and anti-measles IgG geometric mean concentrations and anti-JE 
geometric mean titers in Philippine infants vaccinated with JE and measles vaccines. 
 
Seroresponse rates to CD-JEV may not be equal in all pediatric populations. A lot-to-lot consistency 
study conducted in 2012 among 10-month-old Bangladeshi infants in a rural area with a low incidence 
of JE demonstrated a seropositivity rate of only 82.3% (95% CI 79.0-85.2%) following a single vaccine 
dose.47 The reasons for this lower response rate are unclear, but may be related to the high rates of 
malnutrition found in the population or other population-specific causes. Nevertheless, these findings 
highlight the value of assessing the performance of the vaccine in other high-risk populations.  
 
In addition to the high seroprotection rates, CD-JEV is the only vaccine other than mouse-brain derived 
vaccine for which there is vaccine effectiveness data. A post-implementation case-control study from 
Nepal demonstrated an efficacy of 99.3% (95% CI 94.9–100) following administration of a single dose 
of live, attenuated SA 14-14-2 JE vaccine given within one week of an outbreak.48 A follow-up case-
control study reported that a protective efficacy rate of 96.2% (95% CI 73.1-99.9) was maintained five 
years later.49 CD-JEV vaccine has demonstrated high seroconversion rates after one or two doses in 
endemic areas of Nepal.48,50  
2.1.7. JE Disease in the Philippines 
While JE virus in the Philippines was isolated in horses in 1943, the first serologically confirmed case 
was not identified until 1956.51 In serological surveys that followed, anti-JE neutralization antibodies 
were found in 3% to 83% of children aged 6 months to 15 years living in three varied Philippine 
locations—an indication of widespread but variable JE transmission.52 Subsequent studies on clinical 
 
Group 1 (CD-JEV then MV) 
(N=88) 
Group 2 (concomitant) (N=219) 
Group 3 (MV then CD-JEV) 
(N=178) 
 
% seropositive 
(95% CI) 
GMC/GMT 
(95% CI) 
% seropositive 
(95% CI) 
GMC/GMT 
(95% CI) 
% seropositive 
(95% CI) 
GMC/GMT 
(95% CI) 
Measles vaccine 
response 
(anti-measles 
IgG) 
Day 0 
1.1 
(0.0-6.2) 
12.8a 
(10.2-16.2) 
0.0 
(0.0-1.7) 
7.4 
(6.3-8.8) 
0.0 
(0.0-2.1) 
7.0 
(5.8-8.5) 
Day 28 
88.6 
(80.1-94.4) 
318.9 
(273.0-372.6) 
91.8 
(87.3-95.1) 
301.9 
(269.0-338.9) 
86.5 
(80.6-91.2) 
262.5 
(222.2-310.2) 
JE vaccine 
response 
(anti-JE 
neutralizing 
ant body) 
Day 0 
3.4 
(0.7-9.6) 
5.7 
(4.9-6.5) 
5.4 
(2.8-9.3) 
5.7 
(5.2-6.1) 
6.1 
(3.1-10.7) 
5.9 
(5.3-6.6) 
Day 28 
92.1 
(84.3-96.7) 
202.8 
(140.5-292.9) 
90.5 
(85.9-94.1) 
155.0 
(123.5-194.5) 
90.6 
(85.3-94.4) 
139.4 
(109.5-177.5) 
Year 1 
90.2 
(82.2-95.4) 
106.8 
(71.5-159.4) 
84.0 
(78.3-88.6) 
80.7 
(62.4-104.3) 
85.9 
(80.5-90.3) 
74.9 
(59.2-94.9) 
Year 2 
81.7 
(72.4-89.0) 
68.8 
(47.3-100.1) 
83.0 
(77.3-87.8) 
61.6 
(49.1-77.4) 
81.7 
(75.8-86.6) 
70.1 
(54.6-90.1) 
Year 3 
79.6 
(70.0-87.2) 
49.9 
(36.5-68.3) 
81.9 
(75.9-86.8) 
45.7 
(37.2-56.3) 
82.6 
(76.8-87.4) 
59.3 
(47.1-74.8) 
CD-JEV: live, attenuated Japanese encephalitis SA 14-14-2 vaccine; MV: measles vaccine; N: number of infants in the per protocol analysis; CI: 
confidence interval; GMC: milli International Units per milliliter (mIU/mL), seroprotection defined as ≥120 mIU/mL; GMT: geometric mean titer, 
seroprotection defined as ≥1:10. 
a Although measles GMC/GMT at baseline were higher in Group 1, the GMC/GMT 28 days after vaccination were not significantly different. 
 

 
 
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cases from 1969 to 2006 suggest JE may account for 7% to 40% of all acute encephalitis syndrome 
(AES) cases.53  
 
In 2008, the Philippine Integrated Disease Surveillance and Response system began collecting data on 
all AES cases and in 2011 added sentinel surveillance for lab-confirmed JE. To understand the public 
health impact of JE disease, the Philippines Department of Health used the surveillance and response 
system to identify 1,032 AES cases from January 2011 through March 2013. Of 497 AES cases that 
underwent laboratory testing, 73 (15%) were positive for JE—of those positive, 55 (75%) were children 
under 15 years of age.54  
 
With AES and laboratory-confirmed JE cases reported from 84% of the provinces, JE disease in the 
Philippines is likely widespread.55 Recognizing the public health burden caused by JE, the Philippines 
Department of Health has planned the introduction of JE vaccination into the national immunization 
program in 2017. 
2.2. Scientific Rationale 
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. Based on the youngest age range evaluated in clinical development and to avoid the potential 
presence of maternal antibodies, the most logical time to administer CD-JEV is 9 to 12 months of age 
when MCVs are typically given in Asia. An increasing number of JE-endemic countries are introducing, 
or planning to introduce, MMR vaccine into the EPI. The UNICEF Supply Division expects demand for 
MMR to continue to increase in the long term. In 2014 demand for MMR reached 12.8 million doses, an 
increase of 100% above the previous year.56,57 Currently, measles vaccine is routinely offered at 9 months 
and MMR at 12 months in the Philippines. Like many countries, however, the Philippines Department of 
Health is considering moving to a two-dose MMR schedule by immunizing children with MMR at 9 and 
12 months.  
 
Although PATH-sponsored studies confirmed CD-JEV and measles vaccine could be administered 
concomitantly, no data currently exist on the simultaneous administration of CD-JEV and MMR vaccine. 
There is precedent in the yellow fever (YF) literature that suggests such a study is important. While 
several studies indicate that YF and measles vaccine can be simultaneously administered without any 
effects on safety and immunogenicity, a single study of simultaneous administration of YF and MMR 
vaccines in infants suggests that immunogenicity may be compromised for both YF vaccine and the 
rubella and mumps components of MMR vaccine.58 Separating MMR and YF vaccine administration by 
30 days mitigated the effect. These findings may have relevance for incorporating JE vaccine into 
routine immunization, as CD-JEV and YF vaccine are both live, attenuated flavivirus vaccines. 
 
This non-inferiority study aims to compare JE and MMR responses in a population of children in a 
country where MMR introduction is ongoing or planned. The proposed study design will be similar to 
that of previous PATH-sponsored co-administration CD-JEV trials.33,39 In addition, this information will 
help the Philippines Department of Health evaluate the addition of a second dose of MMR vaccine into 
routine EPI. 
 
The two-arm study has the advantage of allowing an evaluation of the non-inferiority of co-administration 
on the immune responses. Serum will be obtained at an optimal time to measure immunogenicity—28 
days post-CD-JEV immunization to estimate anti-JE seropositivity rates and GMTs and 56 days post-

 
 
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MMR vaccination to estimate anti-MMR seropositivity rates and geometric mean concentrations 
(GMCs).3,8,59,60 The primary outcome will be the non-inferiority of both measles and rubella seropositivity 
rates in the group given CD-JEV and MMR together versus that in the group given MMR alone (prior to 
receipt of CD-JEV). Such a study will require approximately 314 participants per primary comparison 
arm to provide at least 90 percent power to rule out a difference in seropositivity rates between groups 
of greater than 10 percent, depending on assumptions of seropositivity and retention rates.  
2.3. Potential Risks and Benefits 
2.3.1. Potential Risks 
Like any vaccine, vaccination with MMR and CD-JEV may cause side effects in some children. The 
side effects of vaccination may include pain at the injection site for a short while after injection and 
swelling, redness, and tenderness at the injection site. Fever may occur and in some cases a rash may 
appear in the initial days following the vaccination. Allergic reactions, febrile convulsions, encephalitis, 
and death, while rare, may also occur. 
 
The child may experience discomfort and pain from venipuncture for collection of 3-5 mL of blood. 
Venipuncture is sometimes associated with discomfort during phlebotomy, and rarely, an infection at 
the site of phlebotomy if improperly conducted. The child may experience discomfort, pain, redness, 
swelling, and/or local hardness at the injection site. 
 
A study clinician will be on-site during immunizations and will be available for any immediate and/or 
emergency care that may be needed. Research Institute for Tropical Medicine (RITM) is equipped to 
handle immediate care that may be needed in the case of an emergency following vaccination.  
 
Should any adverse events occur due to the study procedures, the investigator or a designee will be 
available to be reached 24 hours a day, via phone, by the participants. The investigator will be 
responsible for providing any treatment caused by procedures undertaken as part of the research study. 
If care is needed, parents will be sent to the clinic nearest them for care. If urgent care is needed, 
participants will be asked to visit RITM which is open 24 hours a day. The study will pay for any costs 
incurred for any unwanted reaction or other health problem resulting from participation in this clinical 
study.  
 
Participant personal identifiers, including name, birth date, and contact information (home address, 
phone number/email address) will be collected and recorded on enrollment logs; as a result, a potential 
risk for “loss of confidentiality” exists. To reduce this risk, participants will be assigned a unique study 
participant number that will be used to identify the participant and link an individual to his/her study data. 
The study participant number will be used on all study forms and in the study computer databases. 
Individual participants will not be identified in any study related reports, and all study results will be 
reported in aggregate only. 
2.3.2. Known Potential Benefits 
Although under consideration by the Philippines Department of Health, two doses of MMR vaccine are 
not routinely offered as part of the national immunization program. Likewise, JE vaccine has not been 
introduced into the national immunization program. By participating in this study, participants will benefit 
by receiving one dose of CD-JEV and two doses of MMR. Receipt of these vaccines may protect the 
participants against JE, measles, mumps, and rubella. The study clinician will check whether children 
have received all of their immunizations and counsel the parents on the importance of receiving all EPI 

 
 
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vaccines at the appropriate ages. They will also provide information to the parents on the EPI 
vaccination schedule. 
 
By participating in this study, the child and consenting parent will contribute greatly needed safety and 
immunogenicity information regarding the co-administration of these two vaccines. They will be 
significantly contributing to the advancement of a WHO-prequalified JE vaccine that if proven to be safe 
and efficacious given in conjunction with MMR vaccine, will be affordable and easily incorporated into 
routine EPI programs. By participating in this clinical trial they will help build the body of knowledge on 
CD-JEV and help ministries of health decide the best schedule for introducing CD-JEV to reduce and 
ultimately eliminate JE disease throughout Asia and the Western Pacific. 
 OBJECTIVES 
3.1. Study Objectives 
3.1.1. Primary Objectives 
1. To demonstrate the non-inferiority of MMR vaccination in terms of measles immunogenicity when 
administered concomitantly to infants 9 months of age with CD-JEV compared to administered 
alone, as assessed by the rate of seropositivity 56 days after vaccination. 
Measles vaccine immunogenicity will be evaluated by anti-measles neutralizing antibody titer. 
Seropositivity will be defined by a concentration of ≥120 mIU/mL, as measured by PRNT (dilution 
converted to concentration using the 3rd International Standard Reference serum).  
2. To demonstrate the non-inferiority of MMR vaccination in terms of rubella immunogenicity when 
administered to infants 9 months of age concomitantly with CD-JEV compared to administered 
alone, as assessed by the rate of seropositivity 56 days after vaccination. 
Rubella vaccine immunogenicity will be evaluated by presence of serum anti-rubella IgG antibody. 
Seropositivity will be defined as a concentration of ≥10 IU/mL corresponding to an optical density 
(OD) ratio ≥1.10 using a commercial IgG enzyme-linked immunosorbent assay (ELISA) 
manufactured by Wampole Laboratories, Princeton, NJ.  
3.1.2. Secondary Objectives 
1. To demonstrate the non-inferiority of MMR vaccination in terms of mumps immunogenicity when 
administered to infants 9 months of age concomitantly with CD-JEV compared to administered 
alone, as assessed by the rate of seropositivity 56 days after vaccination. 
Mumps vaccine immunogenicity will be evaluated by the presence of serum anti-mumps IgG antibody. 
Seropositivity will be defined as an OD ratio ≥1.10 using a commercial ELISA manufactured by Zeus 
Scientific, Inc., Branchburg, NJ 
2. To evaluate serum anti-measles geometric mean neutralizing antibody concentration (GMC) and 
anti-rubella IgG GMC at 56 days post-vaccination, comparing when MMR vaccine is co-
administered with CD-JEV to when MMR vaccine is given alone. 
3. To evaluate anti-measles, anti-mumps, and anti-rubella seroconversion rates 56 days after 
vaccination, comparing when MMR vaccine is co-administered with CD-JEV to when MMR vaccine 
is given alone. For participants seronegative at baseline, seroconversion will be defined as a change 

 
 
JEV06 Protocol v2.0 
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to seropositive status (as defined above). For participants seropositive for measles or rubella at 
baseline, seroconversion will be defined as a four-fold rise in concentration. 
4. To compare the anti-JE seropositivity rate 28 days after CD-JEV vaccination administered 
concurrently with MMR vaccine to CD-JEV administered alone. Anti-JE seropositivity will be defined 
as an anti-JE serum neutralizing antibody titer of ≥1:10, as measured by JE PRNT-50. 
5. To describe anti-JE neutralizing antibody GMTs 28 days after CD-JEV vaccination when MMR 
vaccine is co-administered compared to when CD-JEV is administered alone. 
6. To describe the safety profiles of CD-JEV and MMR vaccine when given concurrently and 
separately, as assessed by immediate reactions occurring within 30 minutes, solicited injection site 
and systemic adverse reactions occurring within 14 days, unsolicited adverse events (AEs) 
occurring within 28 days, and SAEs throughout the course of the study. 
3.1.3. Exploratory Objectives 
1. To assess the effect of pre-existing anti-dengue antibody on CD-JEV immunogenicity. Pre-existing 
anti-dengue antibody will be measured first by the presence of anti-dengue IgG in ELISA and secondly 
by anti-dengue serum neutralizing antibody titer of ≥1:10 as measured by dengue PRNT-50. 
3.2. Study Outcome Measures 
3.2.1. Primary Outcome Measures 
1. Measles immunogenicity will be assessed by the proportion (or percentage) of participants with 
demonstrated seropositivity for MMR at 56 days post-vaccination. Seropositivity will be defined as 
a post-vaccination concentration of ≥120mIU/mL, as measured by PRNT (using the 3rd International 
Standard Reference serum to convert dilutions to concentrations). 
2. Rubella immunogenicity will be assessed by the proportion (or percentage) of participants with 
demonstrated seropositivity for rubella at 56 days post-vaccination. Seropositivity will be defined as a 
post-vaccination concentration of ≥10 IU/mL (corresponding to an OD ratio ≥1.10 using a commercial 
ELISA manufactured by Wampole Laboratories, Princeton, NJ. 
For each endpoint, non-inferiority will be demonstrated if the lower limit of the two-sided 95% CI of the 
difference of the seropositivity rates between the two groups (concurrent administration and separate 
administration) 56 days after vaccination is >-10%. 
3.2.2. Secondary Outcome Measures 
1. Mumps immunogenicity will be assessed by the proportion (or percentage) of participants with 
demonstrated seropositivity for mumps at 56 days post-vaccination. Seropositivity will be defined 
as an OD ratio ≥1.10 using a commercial ELISA manufactured by Zeus Scientific, Inc, Branchburg, 
NJ. 
2. Measles and rubella antibody levels will be assessed by the GMC of serum measles neutralizing 
antibody and the GMC of serum anti-rubella IgG antibody.  
3. Measles, mumps, and rubella seroconversion rates will be defined as the proportions 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 or rubella at baseline.  

 
 
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4. JE immunogenicity will be assessed by the proportion of participants with demonstrated 
seropositivity for JE at 28 days post vaccination with CD-JEV. Seropositivity will be defined as a JE 
serum neutralizing antibody titer of ≥1:10 as measured by JE PRNT-50. 
5. JE antibody levels will be assessed by the GMT of serum neutralizing antibody to JE virus at 28 
days post vaccination with CD-JEV.  
6. Study vaccine safety profiles will be assessed by the proportion of participants experiencing specific 
adverse events categorized into one of the following categories: 
a. Immediate reactions occurring within 30 minutes of each vaccination, measured as observed 
by study staff or reported by the parent to study staff. 
b. Solicited signs and symptoms occurring within 14 days of each vaccination, measured as 
observed by parent on diary card or reported to study staff.  
c. All other adverse events occurring within 28 days of each vaccination, measured as 
observed by study staff or reported by the parent to study staff. 
d. All SAEs occurring throughout the course of the study. 
 STUDY DESIGN 
This study will be a phase 4 open-label trial in which 628 Philippine infants 9 months of age will be 
randomized 1:1 to one of two arms: 
 
Group 1: 314 children receiving one dose of CD-JEV vaccine and one dose of MMR vaccine 
concurrently at enrollment; Group 1 will also receive a second dose of MMR per the routine 
immunization schedule at D84 (12 months of age). 
 
 
Group 2: 314 children receiving one dose of MMR vaccine at enrollment and one dose of  
CD-JEV 56 days later. Group 2 will receive a second dose of MMR per the routine immunization 
schedule at D84 (12 months of age). 
 
Following receipt of study vaccine, infants will be monitored for immediate reactions during the first 30 
minutes, solicited injection site and systemic adverse reactions for 14 days, unsolicited adverse events 
for 28 days, and serious adverse events throughout the duration of the study. All safety events will be 
identified or observed by study staff and/or reported by a parent. Solicited adverse reactions will be 
recorded by the parent on diary cards or assessed during clinic visits. Study staff will make a follow-up 
call to the participant’s parent/guardian 2 days post vaccination (+3 days) to check on the welfare of the 
participant and ensure the diary card is being completed. The parent will return for a clinic visit 14 days 
post vaccination (+3 days) for the study staff to review the diary card, conduct safety evaluations, and 
review any adverse events. Information regarding unsolicited AEs will be collected during any 
scheduled or unscheduled clinic visit. Events will be graded for severity and assessed for relatedness 
to vaccination by the study clinician. 
 
The study will be open-label; no placebo control will be employed. Due to the unequal number of 
injections per visit in each study arm, safety assessments will be unblinded. 
 
Blood samples for serologic testing will be collected on Day 0, Day 28(+7), and Day 56(+7) for  
Group 1; and Day 0, Day 56(+7), Day 84(+7) for Group 2.  
 
Baseline serologies will test for antibodies to JE, measles, mumps, rubella, and dengue virus. Antibody 
responses to CD-JEV will be tested 28(+7) days after vaccination, while antibody responses to the first 
dose of MMR will be tested 56(+7) days after vaccination. All laboratory testing will be conducted in a 
blinded fashion. 

 
 
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4.1. Study Site 
The study will be conducted at RITM, Filinvest Corporate City, Alabang, Muntinlupa City, Philippines. 
Established to spearhead the planning and implementing of research programs for infectious and/or 
tropical diseases, RITM’s core research facilities are equipped with ample technical support for the 
conduct of valid and reliable scientific investigations. With a 35-bed research hospital consisting of an 
intensive care unit, wards, and isolation room, the hospital provides care of patients needing tertiary 
management of infectious and/or tropical diseases. The research hospital has a clinical and a blood-
banking laboratory.  
 
Recruitment of study participants will be conducted at the Putatan Health Center and Bayanan Health 
Center, two barangay health centers located near RITM. A barangay is the smallest local government 
unit in the Philippines and is very similar to a village or town. Each barangay health center is headed 
by a physician and is supported by health workers composed of nurses, midwives, and dentists. RITM 
will provide medical care in collaboration with the participating clinics or through its medical facility free 
of cost. All the participants will be encouraged to seek care at the local clinic or RITM for any medical 
problems, whether minor illness or urgent care. Both health clinics are within 5 kilometers of RITM, 
which is equipped to handle any care that may be needed in the case of an emergency. 
 STUDY ENROLLMENT AND WITHDRAWAL 
5.1. Participant Inclusion Criteria 
Each participant receiving study vaccines must satisfy all of the following inclusion criteria at study entry: 
 
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 of the investigator. 
 
A parent or guardian is willing to attend all planned study visits and allow home visits and phone 
contacts, as required by the protocol. 
5.2. Participant Exclusion Criteria 
No participant receiving study vaccines may have any of the following exclusion criteria at study entry: 
 
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 

 
 
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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 for 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 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 in the opinion of 
the study physician, might interfere with the study objectives. 
 
Severely malnourished infants as measured by the 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 
5.3. Treatment Assignment Procedures 
5.3.1. Randomization Procedures 
This is an unblinded, individually randomized study. Enrolled children will be randomized in a 1:1 ratio 
to one of two arms:  
 
Group 1: 314 children receiving one dose of CD-JEV vaccine and one dose of MMR vaccine 
concurrently at enrollment;  
 
Group 2: 314 children receiving one dose of MMR vaccine at enrollment and one dose of  
CD-JEV 56 days later.  
A detailed randomization standard operating procedure (SOP) will be developed and executed prior to 
study initiation to generate the allocation sequence. The study will use a random permuted block design 
to assure as close to 1:1 group balance is maintained.  
PATH will maintain all electronic documents generated as part of the randomization in a secure location 
not accessible to other study staff involved in the trial.  
 
 

 
 
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5.3.2. Allocation and Masking Procedures 
A detailed allocation SOP will be developed in cooperation with the investigator. This allocation SOP 
will specify how enrolled participants must be allocated to study Group 1 (CD-JEV and MMR 
concurrently) or Group 2 (MMR alone and CD-JEV 56 days later). 
 
Commercial presentations of MMR and CD-JEV will be used in this study. MMR will be procured from 
the Philippine distributor for MMR vaccine and CD-JEV will be donated by CDIBP. Since this is an open-
label trial with licensed vaccines, parents of participants will know whether their child is in the 
experimental group receiving MMR and CD-JEV concurrently. While study vaccines will not be masked, 
they will be labeled for clinical trial use per section 6.1.4.  
 
Laboratory staff performing serologic tests will remain masked to individual group assignments during 
the study period until database lock is performed. Study statisticians will be unmasked to study group 
identification for the purposes of performing statistical analyses. 
5.3.3. Adherence to Randomization 
The investigator or designee will document adherence to the allocation SOP. Additionally, specific study 
vaccines given to each individual participant will be documented.  
5.3.4. Reasons for Withdrawal 
After enrollment, a participant might be withdrawn from participation for several reasons: 
 
The investigator requests withdrawal of the participant because the child is not eligible or is no 
longer eligible, because he/she has developed an AE requiring withdrawal, or because the 
participant is non-compliant; 
 
A participant voluntarily withdraws at his/her own request; 
 
A participant is lost to follow-up; 
 
The trial is terminated prematurely by the sponsor, institutional or ethical review committees, or 
the regulatory agency; or 
 
Death of the participant. 
5.3.5. Handling of Withdrawals 
In case of premature withdrawal for any reason, the investigator should exert her best effort to: 
 
Conduct an interview to determine if the participant has had any reaction or AE (serious or non-
serious) that has led to the withdrawal during the 28-day period after any study vaccination. 
Where possible, the investigator should visibly or physically assess any reported adverse 
reaction or AE. 
 
Attempt to complete all scheduled procedures and evaluations planned for the next study visit. 
 
Document the reason for premature withdrawal. 
 
Complete the end of the study record. 
Withdrawal of a participant by the investigator may occur only if the child is identified to have one of the 
listed exclusion criteria or if continued participation threatens the child’s well-being or the integrity of the 

 
 
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study. If the participant develops a reaction to study vaccine which the investigator believes threatens 
the child’s well-being, the withdrawn participant must be treated or transferred to a treatment facility. 
If premature withdrawal is initiated by the parent or investigator, PATH must be informed within 48 hours 
about all instances (excluding lost to follow-up).  
5.3.6. Suspension or Termination of Study  
The trial might be suspended at any time by PATH or by any ethical review committee overseeing this 
study for any safety concern. This includes, for example, and without limitation, an SAE resulting in 
death that is viewed to be related to receipt of study vaccine or an unusually high rate of SAEs. PATH 
may suspend the study in the event that study conduct is found to be below Good Clinical Practice 
(GCP) standards. 
In the event of the appearance of new data that indicate an increased level of risk to study participants, 
the clinical trial will be suspended until PATH and all ethical review committees have reviewed relevant 
data and agreed that the trial may proceed. 
 STUDY VACCINES 
6.1. Study Vaccine Descriptions 
6.1.1. Live, Attenuated SA 14-14-2 JE Vaccine 
The derivation of the live, attenuated Japanese encephalitis virus strain, SA 14-14-2, was through an 
empirical process of serial passage, principally in PHK cells.61 The live, attenuated SA 14-14-2 JE virus 
genome has 57 nucleotide changes from that of wild-type JE virus, resulting in 24 amino acid changes. 
Eight amino acid changes in the E protein gene, which is strongly associated with neurovirulence, result 
in attenuation. These eight critical amino acid changes have been shown to be genetically quite stable. 
 
The WHO prequalified live, attenuated SA 14-14-2 JE vaccine manufactured by CDIBP and marketed 
as CD-JEVAX™ or RS.JEV™ is a preparation of live, attenuated JE virus (strain SA 14-14-2) grown in 
culture on a monolayer of PHK cells. After cultivation and harvest, an appropriate stabilizer is added in 
the virus suspension, which is then lyophilized. Live, attenuated JE virus (strain SA 14-14-2), minimum 
essential medium, and human serum albumin are the major components of the final vaccine. 
6.1.2. Measles, Mumps, Rubella Vaccine 
The MMR vaccine manufactured by GlaxoSmithKline, Inc., and licensed as Priorix® in the Philippines 
is a lyophilized vaccine containing live, attenuated Schwarz measles virus produced in chick embryo 
cells, RIT 4385 mumps (derived from Jeryl Lynn strain) produced in chick embryo cells, and Wistar RA 
27/3 rubella virus propagated on human diploid cells. Each single human dose when reconstituted in a 
volume of 0.5 mL contains not less than 1000 CCID50 of measles virus, 5012 CCID50 of mumps virus, 
and 1000 CCID50 of rubella virus. The vaccine meets the requirements of WHO Technical Report Series 
840 (1994). 
 
 

 
 
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6.1.3. Acquisition  
RITM will be responsible for vaccine receipt and management of the vaccine. Appropriate vaccine 
acquisition and handling SOPs will be developed in collaboration with the investigator. Extra doses of 
both vaccines will be provided and shall be used when the initially allocated dose is broken, damaged, 
or unusable. For CD-JEV, the manufacturer will donate these vaccines free of charge; whereas, MMR 
vaccine will be procured. Vaccine accountability practices will be established to ensure receipt, storage, 
administration, and disposal are documented and monitored. The investigator and their institution will 
receive no monetary compensation from the manufacturers for their participation in this study. 
6.1.4. Packaging and Labeling 
Both study vaccines will be provided in their commercial presentation, containing their package insert. 
The commercial vial labels for these vaccines should remain intact. Study products will be labeled in 
compliance with any applicable national regulations. At a minimum, an additional label will be affixed to 
each box and will bear the following information: 
 
Study number 
 
Legal information: “For Clinical Trial Use Only” 
6.1.5. Product Storage and Stability 
CD-JEV and MMR vaccine should be stored in a refrigerator or cold box at a temperature ranging from 
+2°C to +8°C and protected from light. Storage temperature should be monitored and documented on 
an appropriate form during the entire trial. 
 
The vaccines should never be frozen. In case of deep freezing or accidental disruption of the cold chain, 
the vaccine should not be administered and the investigator or the responsible person should contact 
PATH to receive further instructions. 
6.2. Dosage, Preparation, and Administration of Study Vaccines 
The vaccines in general should be gently shaken prior to administration to assure homogenous 
suspension. CD-JEV will be administered subcutaneously into the anterolateral aspect of the right upper 
thigh. MMR vaccine will be administered subcutaneously into the anterolateral aspect of the left upper 
thigh.  
 
CD-JEV will be supplied in 5-dose vials as a lyophilized powder that looks like a milky-white crisp cake. 
After reconstitution, it turns into a transparent orange-red liquid. Each 0.5 mL human dose for 
subcutaneous injection contains not less than 5.4 log PFU of live JE virus. A single dose of 0.5 mL 
should be administered by subcutaneous injection with the rest of the vial contents discarded. 
 
Measles-mumps-rubella vaccine appears as a white to slightly pink dry cake. It will be supplied in its 
monodose commercial presentation. The vaccine should be reconstituted only with the diluent supplied 
(sterile water for injection). A single dose of 0.5 mL should be administered by subcutaneous injection. 
 
Standard immunization practices will be observed and care will be taken to administer the injections. 
As with all injectable vaccines, appropriate medical treatment, staff, and supervision will be readily 
available in case of rare anaphylactic reactions following administration of the study vaccine and 
epinephrine 1:1000 will be available in case of any anaphylactic reactions. 

 
 
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6.3. Accountability Procedures for the Study Vaccines 
Study vaccine must be kept in a secure place. The investigator or the person in charge of vaccine 
management will maintain records of the vaccine's delivery to the trial site, the inventory at the site, the 
dose(s) given to each participant, and the return of unused doses to the sponsor. Appropriate vaccine 
accountability SOPs will be developed in collaboration with the investigator. 
 
If the investigator runs out of vaccine during the trial, she should alert PATH, who will undertake the 
necessary steps to provide extra doses. 
6.4. Concomitant Medications/Treatments 
All medications administered must be checked against the inclusion/exclusion criteria. All medications 
used between enrollment and 28 days post-vaccination, except for topical treatment or vitamins, will be 
reported, including the following details: international non-proprietary name, dose, frequency, route, 
duration (start and end date), and indication for the treatment. The parents will be requested not to give 
the child preemptive analgesic or antipyretic drugs, as they may change the reactogenicity profile of the 
vaccine. 
 
Injection of immunoglobulin, use of a systemic corticosteroid therapy for more than one week (inhalation 
will not be considered as systemic treatment) within 14 days before or after vaccination, or 
administration of any other immunomodulating agent, except the vaccines anticipated in the protocol, 
during the study period will lead to exclusion of the participant from the per-protocol statistical analysis. 
 STUDY SCHEDULE 
7.1. Screening  
1. Study staff in charge of recruitment will make sure that the infant will be between 9 months to <10 
months of age at the time of enrollment. 
7.2. Consent 
1. If the child is eligible for the study based on the screening process, the study staff will review the 
informed consent process with the parent or guardian. 
2. The investigator, or a person designated by the investigator, will fully inform the participant’s 
parent(s)/legal guardian(s) of all pertinent aspects of the study, and individual consent will be 
documented by a signature and/or signature of an impartial literate witness on the consent form. 
3. Following confirmation of consent, the child will be given a unique screening number and undergo 
assessment of eligibility, enrollment, and baseline activities as described below. 
 
 

 
 
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7.3. Eligibility/Enrollment/Baseline  
For participants in the two groups, the following activities will occur at the time of eligibility assessment 
(Eligibility Assessment/Enrollment/Allocation/Blood Sample/Vaccine Administration):   
1. At the designated location for vaccination, the parent will be interviewed to collect baseline 
information including demographic (age and gender) and health (known medical conditions and 
allergies including medications taken) information in order to confirm eligibility. 
2. Qualified study staff will perform a physical examination of the child. Results will be reviewed by 
study staff and with the participant’s parents to confirm eligibility prior to conduct of further 
procedures.  
3. Based on collected information, inclusion/exclusion criteria will be verified and eligibility confirmed. 
4. If eligible, the participant will be allocated into Group 1 or 2 according to the allocation process and 
given a unique participant ID number. 
5. Prior to administration of the vaccine, a specimen of 3-5 mL of blood will be collected for baseline 
testing.  
6. Study vaccine will be allocated to the participant per the allocation sequence and the child will 
receive the assigned study vaccination into the anterolateral aspect of the upper thigh. 
a. Group 1 will receive MMR vaccine subcutaneously into the anterolateral aspect of the left 
upper thigh and CD-JEV subcutaneously into the anterolateral aspect of the right upper 
thigh. 
b. Group 2 will receive MMR vaccine subcutaneously into the anterolateral aspect of the left 
upper thigh. 
7. The parents will be asked to wait with the child in the clinic for 30 minutes after the vaccination(s), 
so that the study staff can observe for immediate reactions. If the child experiences an adverse 
reaction or an SAE during this time period, he/she will be treated or referred as appropriate, and the 
event will be recorded. 
8. The parents will be given a study identification card that indicates that the child has been enrolled 
in a research study. The card will contain the following information: 
 
Name, address, and contact phone numbers of the investigator and local study staff.  
 
Child’s unique study participant number. 
 
Indication that the child is in a vaccine trial and a request that medical personnel who provide 
care to the child report any suspected adverse events and any abnormal or unusual clinical 
findings to the investigator. 
9. The parents will be given a diary card and trained on how to record solicited and unsolicited adverse 
events occurring within 14 days post vaccination.  
10. Parents will be informed that they will be contacted in 2 days (+3 days) in order to check on the 
welfare of the participant, answer any questions about the diary card, and assess the occurrence of 
any local or systemic reactions. 

 
 
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11. An appointment will be made to visit the clinic 14 days after vaccination (+3 days) for a follow-up 
visit. 
12. Parents will be reminded to seek medical care as appropriate and inform the study clinician as soon 
as possible in the event of an adverse reaction or SAE. If the child visits a health care provider, the 
parents should be sure to inform him/her of the child’s participation in the study and present the 
provider with contact information for the study staff as indicated on the study identification card. 
Additionally, the parents will be reminded to inform the study clinician that the child has visited a 
health care provider.  
7.4. Follow-up Visit 2 Days After Enrollment 
7.4.1. Group 1 and Group 2 Visits to Assess Safety (D2+3) 
1. The parents will be called to check on the welfare of the child and ensure the diary card is being 
completed. 
2. The parents will be asked if the child experienced any other adverse reaction or SAE and/or sought 
medical care. 
3. The parents will be reminded of their appointment to visit the clinic 14 days after vaccination  
(+3 days) for a follow-up visit. 
4. Parents will be reminded to seek medical care as appropriate and inform the study clinician as soon 
as possible in the event of an adverse reaction or SAE. If the child visits a health care provider, the 
parents should be sure to inform him/her of the child’s participation in the study and present the 
provider with contact information for the investigator as indicated on the study identification card. 
Additionally, the parents will be reminded to inform the study clinician that the child has visited a 
health care provider. 
7.5. Follow-up Visit 14 Days After Enrollment 
7.5.1. Group 1 and Group 2 Visits to Assess Safety (D14+3) 
1. The parents will visit the clinic for a follow-up visit in which the diary card will be reviewed and 
collected. Parents will be asked whether the child experienced any local and systemic reactions 
during the 14 days after vaccination. 
2. The parents will be asked if the child experienced any other adverse reaction or SAE and/or sought 
medical care. 
3. Concomitant therapies since the last visit will be reviewed.  
4. Parents will receive an appointment to return to the designated location with their child 28 days after 
vaccination (+7 days) for a follow-up visit. 
5. Parents will be reminded to seek medical care as appropriate and inform the study clinician as soon 
as possible in the event of an adverse reaction or SAE. If the child visits a health care provider, the 
parents should be sure to inform him/her of the child’s participation in the study and present the 
provider with contact information for the study staff as indicated on the study identification card. 

 
 
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Additionally, the parents will be reminded to inform the study clinician that the child has visited a 
health care provider. 
7.6. Follow-up Visit 28 Days After Enrollment 
7.6.1. Group 1 Visit to Assess Safety and Collect Serum (D28+7) 
1. At the designated location for vaccinations/blood draws, the participant’s identity will be confirmed. 
2. Study staff will review interim medical histories and concomitant medications with the participant 
since the last visit to the study clinic. 
3. Qualified study staff will perform a physical examination of the child. Results will be reviewed by 
study staff and with the participant’s parents. 
4. The parents will be asked if the child experienced any adverse reaction or SAE and/or sought 
medical care since the last visit. 
5. A specimen of 3-5 mL of blood will be collected for anti-JE antibody testing.  
6. Parents will be reminded to seek medical care as appropriate and inform the study clinician as 
soon as possible in the event of an adverse reaction or SAE. If the child visits a health care 
provider, the parents should be sure to inform him/her of the child’s participation in the study and 
present the provider with contact information for the study staff as indicated on the study 
identification card. Additionally, the parents will be reminded to inform the study clinician that the 
child has visited a health care provider. 
7. An appointment will be made with the parent to return with the child 56 days (+7 days) after 
vaccination for a follow-up visit.  
7.6.2. Group 2 Visit to Assess Safety (D28+7) 
1. At the designated location for vaccinations/blood draws, the participant’s identity will be confirmed. 
2. Study staff will review interim medical histories and concomitant medications with the participant 
since the last visit to the study clinic. 
3. Qualified study staff will perform a physical examination of the child. Results will be reviewed by 
study staff and with the participant’s parents. 
4. The parents will be asked if the child experienced any adverse reaction or SAE and/or sought 
medical care since the last visit. 
5. Parents will be reminded to seek medical care as appropriate and inform the study clinician as 
soon as possible in the event of an adverse reaction or SAE. If the child visits a health care 
provider, the parents should be sure to inform him/her of the child’s participation in the study and 
present the provider with contact information for the study staff as indicated on the study 
identification card. Additionally, the parents will be reminded to inform the study clinician that the 
child has visited a health care provider. 
6. An appointment will be made with the parent to return with the child 56 days (+7 days) after 
vaccination for a follow-up visit. 

 
 
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18 January 2017 
7.7. Follow-up 56 Days After Enrollment 
7.7.1. Group 1 Visit to Collect Serum (D56+7) 
1. At the designated location for vaccinations/blood draws, the participant’s identity will be confirmed. 
2. Study staff will review interim medical histories and concomitant medications with the participant 
since the last visit to the study clinic. 
3. Qualified study staff will perform a physical examination of the child. Results will be reviewed by 
study staff and with the participant’s parents. 
4. The parents will be asked if the child experienced any adverse reaction or SAE and/or sought 
medical care since the last visit. 
5. A specimen of 3-5 mL of blood will be collected for anti-measles, anti-mumps, and anti-rubella 
testing.  
6. An appointment will be made with the parent to return with the child 84 days (+7 days) after 
vaccination for a follow-up visit to receive the second dose of MMR vaccine. 
7.7.2. Group 2 Visit to Collect Serum and Provide CD-JEV (D56+7) 
1. At the designated location for vaccinations/blood draws, the participant’s identity will be confirmed. 
2. Study staff will review interim medical histories and concomitant medications with the participant 
since the last visit to the study clinic. 
3. Qualified study staff will perform a physical examination of the child. Results will be reviewed by 
study staff and with the participant’s parents. 
4. The parents will be asked if the child experienced any adverse reaction or SAE and/or sought 
medical care since the last visit. 
7. Before administration of vaccine, a specimen of 3-5 mL of blood will be collected for anti-measles, 
anti-mumps, anti-rubella, anti-JE testing, and anti-dengue.  
5. The child will receive CD-JEV into the anterolateral aspect of the right upper thigh. 
6. The parents will be asked to wait with the child in the clinic for 30 minutes after the vaccination, so 
that the physician can observe for immediate reactions. If the child experiences an adverse reaction 
or an SAE immediately following the vaccination, he/she will be treated or referred as appropriate. 
7. Parents will be informed that they will be contacted in 2 days (+3 days) in order to check on the 
welfare of the participant, answer any questions about the diary card, and assess the occurrence of 
any local or systemic reactions. 
8. The parents will be given a diary card and trained on how to record solicited and unsolicited adverse 
events occurring within 14 days post vaccination.  
9. An appointment will be made to visit the clinic 14 days after vaccination (+3 days) for a follow-up 
visit. 

 
 
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10. Parents will be reminded to seek medical care as appropriate and inform the study clinician as soon 
as possible in the event of an adverse reaction or SAE. If the child visits a health care provider, the 
parents should be sure to inform him/her of the child’s participation in the study and present the 
provider with contact information for the investigator as indicated on the study identification card. 
Additionally, the parents will be reminded to inform the study clinician that the child has visited a 
health care provider 
7.8. Follow-up visit 58 Days After Enrollment 
7.8.1. Group 2 Visit to Assess Safety 2 Days After CD-JEV (D58+3) 
1. The parents will be called to check on the welfare of the child and ensure the diary card is being 
completed. 
2. The parents will be asked if the child experienced any other adverse reaction or SAE and/or sought 
medical care. 
3. The parents will be reminded of their appointment to visit the clinic 14 days after vaccination  
(+3 days) for a follow-up visit. 
4. Parents will be reminded to seek medical care as appropriate and inform the study clinician as soon 
as possible in the event of an adverse reaction or SAE. If the child visits a health care provider, the 
parents should be sure to inform him/her of the child’s participation in the study and present the 
provider with contact information for the investigator as indicated on the study identification card. 
Additionally, the parents will be reminded to inform the study clinician that the child has visited a 
health care provider. 
7.9. Follow-up Visit 70 days After Enrollment 
7.9.1. Group 2 Visit to Assess Safety 14 Days After CD-JEV (D70+3) 
1. The parents will visit the clinic for a follow-up visit in which the diary card will be reviewed and 
collected. Parents will be asked whether the child experienced any local and systemic reactions 
during the 14 days after vaccination. 
2. The parents will be asked if the child experienced any other adverse reaction or SAE and/or sought 
medical care. 
3. Concomitant therapies since the last visit will be reviewed.  
4. Parents will receive an appointment to return to the designated location with their child 28 days after 
receipt of CD-JEV (+7 days) for a follow-up visit to receive the second dose of MMR. 
5. Parents will be reminded to seek medical care as appropriate and inform the study clinician as soon 
as possible in the event of an adverse reaction or SAE. If the child visits a health care provider, the 
parents should be sure to inform him/her of the child’s participation in the study and present the 
provider with contact information for the study staff as indicated on the study identification card. 
Additionally, the parents will be reminded to inform the study clinician that the child has visited a 
health care provider. 
 
 

 
 
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7.10. Follow-up 84 Days After Enrollment 
7.10.1. 
Group 1 Follow-up Visit to Provide MMR (D84+7) 
1. At the designated location for vaccinations/blood draws, the participant’s identity will be confirmed. 
2. Study staff will review interim medical histories and concomitant medications with the participant 
since the last visit to the study clinic. 
3. Qualified study staff will perform a physical examination of the child. Results will be reviewed by 
study staff and with the participant’s parents. 
4. The parents will be asked if the child experienced any adverse reaction or SAE and/or sought 
medical care since the last visit. 
5. The child will receive MMR subcutaneously into the anterolateral aspect of the left upper thigh. 
6. The parents will be asked to wait with the child in the clinic for 30 minutes after the vaccination, so 
that the physician can observe for immediate reactions. If the child experiences an adverse reaction 
or an SAE immediately following the vaccination, he/she will be treated or referred as appropriate. 
7. Parents will be informed that they will be contacted in 2 days (+3 days) in order to check on the 
welfare of the participant, answer any questions about the diary card, and assess the occurrence of 
any local or systemic reactions. 
8. The parents will be given a diary card and trained on how to record solicited and unsolicited adverse 
events occurring within 14 days post vaccination.  
9. An appointment will be made to visit the clinic 14 days after vaccination (+3 days) for a follow-up 
visit. 
10. Parents will be reminded to seek medical care as appropriate and inform the study clinician as 
soon as possible in the event of an adverse reaction or SAE. If the child visits a health care 
provider, the parents should be sure to inform him/her of the child’s participation in the study and 
present the provider with contact information for the study staff as indicated on the study 
identification card. Additionally, the parents will be reminded to inform the study clinician that the 
child has visited a health care provider. 
7.10.2. 
Group 2 Follow-up Visit to Assess Safety, Collect Serum, and Provide MMR (D84+7) 
1. At the designated location for vaccinations/blood draws, the participant’s identity will be confirmed. 
2. Study staff will review interim medical histories and concomitant medications with the participant 
since the last visit to the study clinic. 
3. Qualified study staff will perform a physical examination of the child. Results will be reviewed by 
study staff and with the participant’s parents. 
4. The parents will be asked if the child experienced any adverse reaction or SAE and/or sought 
medical care since the last visit. 
5. A specimen of 3-5 mL of blood will be collected for anti-JE antibody testing.  
6. The child will receive a second dose of MMR vaccine subcutaneously into the anterolateral aspect 
of the left upper thigh. 

 
 
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7.  The parents will be asked to wait with the child in the clinic for 30 minutes after the vaccination, so 
that the physician can observe for immediate reactions. If the child experiences an adverse reaction 
or an SAE immediately following the vaccination, he/she will be treated or referred as appropriate. 
8. Parents will be informed that they will be contacted in 2 days (+3 days) in order to check on the 
welfare of the participant, answer any questions about the diary card, and assess the occurrence of 
any local or systemic reactions. 
9. The parents will be given a diary card and trained on how to record solicited and unsolicited adverse 
events occurring within 14 days post vaccination.  
10. An appointment will be made to visit the clinic 14 days after vaccination (+3 days) for a follow-up 
visit. 
11. Parents will be reminded to seek medical care as appropriate and inform the study clinician as soon 
as possible in the event of an adverse reaction or SAE. If the child visits a health care provider, the 
parents should be sure to inform him/her of the child’s participation in the study and present the 
provider with contact information for the investigator as indicated on the study identification card. 
Additionally, the parents will be reminded to inform the study clinician that the child has visited a 
health care provider. 
7.11. Follow up 86 Days After Enrollment 
7.11.1. 
Group 1 and Group 2 Visits to Assess Safety (D86+3) 
1. The parents will be called to check on the welfare of the child and ensure the diary card is being 
completed. 
2. The parents will be asked if the child experienced any other adverse reaction or SAE and/or sought 
medical care. 
3. The parents will be reminded of their appointment to visit the clinic 14 days after vaccination  
(+3 days) for a follow-up visit. 
4. Parents will be reminded to seek medical care as appropriate and inform the study clinician as soon 
as possible in the event of an adverse reaction or SAE. If the child visits a health care provider, the 
parents should be sure to inform him/her of the child’s participation in the study and present the 
provider with contact information for the investigator as indicated on the study identification card. 
Additionally, the parents will be reminded to inform the study clinician that the child has visited a 
health care provider. 
7.12. Follow-up Visit 98 Days After Enrollment 
7.12.1. 
Group 1 and Group 2 Visits to Assess Safety (D98+3) 
1. The parents will visit the clinic for a follow-up visit in which the diary card will be reviewed and 
collected. Parents will be asked whether the child experienced any local and systemic reactions 
during the 14 days after vaccination. 
2. The parents will be asked if the child experienced any other adverse reaction or SAE and/or sought 
medical care. 
3. Concomitant therapies since the last visit will be reviewed.  

 
 
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4. Parents will receive an appointment to return to the designated location with their child 28 days after 
vaccination (+7 days) for a follow-up visit. 
5. Parents will be reminded to seek medical care as appropriate and inform the study clinician as soon 
as possible in the event of an adverse reaction or SAE. If the child visits a health care provider, the 
parents should be sure to inform him/her of the child’s participation in the study and present the 
provider with contact information for the study staff as indicated on the study identification card. 
Additionally, the parents will be reminded to inform the study clinician that the child has visited a 
health care provider. 
7.13. Final Study Visit 112 Days After Enrollment 
7.13.1. 
Group 1 and Group 2 Final Study Visit to Assess Safety (D112+7) 
1. At the designated location for vaccinations/blood draws, the participant’s identity will be confirmed. 
2. Study staff will review interim medical histories and concomitant medications with the participant 
since the last visit to the study clinic. 
3. Qualified study staff will perform a physical examination of the child. Results will be reviewed by 
study staff and with the participant’s parents. 
4. The parents will be asked if the child experienced any adverse reaction or SAE and/or sought 
medical care since the last visit. 
5. The final study record will be completed and participant will be exited from the study. 
7.14. Allowable Schedule of Study Visits 
For clarity, per-protocol timing of key study visits is provided below. No child should be dropped from 
the study solely on the basis of a visit falling outside of an allowable time-frame for that visit if there is 
good faith attempt by study staff and the participant’s parent(s)/guardian(s) to adhere to the protocol. 
Table 3. Group 1 Allowable Schedule 
Study Visit 
Should occur 
May occur 
Visit 0 (screening and consent) 
On or before D0 
Within 2 weeks of Visit 1 
Visit 1 (eligibility, blood draw, MMR/CD-JEV vaccination) 
Day 0 
 on Day 0 
Visit 2 (MMR/CD-JEV follow-up) 
Day 2 
2 to 5 days after MMR/CD-JEV vaccination 
Visit 3 (MMR/CD-JEV follow-up) 
Day 14 
14 to 17 days after MMR/CD-JEV vaccination 
Visit 4 (MMR/CD-JEV follow-up, CD-JEV blood draw) 
Day 28 
28 to 35 days after MMR/CD-JEV vaccination 
Visit 5 (MMR blood draw) 
Day 56 
56 to 63 days after MMR/CD-JEV vaccination 
Visit 6 (MMR vaccination) 
Day 84 
84 to 91 days after MMR/CD-JEV vaccination 
Visit 7 (MMR follow-up) 
Day 86 
2 to 4 days after MMR vaccination 
Visit 8 (MMR follow-up) 
Day 98 
14 to 17 days after MMR vaccination 
Visit 9 (final assessment) 
Day 112 
28 to 35 days after MMR vaccination 

 
 
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Table 4. Group 2 Allowable Schedule 
Study Visit 
Should occur 
May occur 
Visit 0 (screening and consent) 
On or before D0 
Within 2 weeks of visit 1 
Visit 1 (eligibility, blood draw, MMR vaccination) 
Day 0 
 on Day 0 
Visit 2 (MMR follow-up) 
Day 2 
2 to 5 days after MMR vaccination 
Visit 3 (MMR follow-up) 
Day 14 
14 to 17 days after MMR vaccination 
Visit 4 (MMR follow-up) 
Day 28 
28 to 35 days after MMR vaccination 
Visit 5 (MMR blood draw, CD-JEV vaccination) 
Day 56 
56 to 63 days after MMR vaccination 
Visit 6 (CD-JEV follow-up) 
Day 58 
2 to 5 day after CD-JEV vaccination  
Visit 7 (CD-JEV follow-up) 
Day 70 
14 to 17 days after CD-JEV vaccination 
Visit 8 (CD-JEV blood draw, MMR vaccination) 
Day 84 
28 to 35 days after CD-JEV vaccination  
Visit 9 (MMR follow-up) 
Day 86 
2 to 5 days after MMR vaccination 
Visit 10 (MMR follow-up) 
Day 98 
14 to 17 days after MMR vaccination 
Visit 11 (final assessment) 
Day 112 
28 to 35 days after MMR vaccination 
 
 STUDY PROCEDURES/EVALUATIONS 
8.1. Clinical Evaluations 
A key objective of this study is to describe the safety profile of the study vaccines. AEs and SAEs are 
defined in Section 9. Included below are brief listings of clinical parameters to be measured and used in 
evaluation of the general health of the child and in describing safety of study vaccines. 
8.1.1. Medical History 
At enrollment, medical histories will be reviewed through interview with the participant and his/her 
parent/legal guardian. The following medical conditions, especially, will be assessed: 
 
Current or recent febrile illness 
 
Recent vaccination history 
 
Hypersensitivity of any kind 
 
Any chronic disease (cardiac, renal, neurologic, metabolic, or rheumatologic) 
 
Seizures, including history of febrile seizures, or any other neurologic disorder 
8.1.2. Physical Examination 
Qualified study staff will collect general information on the participant including:   
 
Recording of general participant appearance 
 
Measurement of height and weight 
 
Measurement of the following vital signs: 
o Body temperature (and body location of measurement) 
o Respiratory rate 
o Pulse rate/heart rate 
 

 
 
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Qualified study staff will conduct a physical examination of all participants. This physical examination 
will include the following:  
 
Physical examination of all organ systems. This includes, without limitation, the following: 
o Chest auscultation 
o Heart auscultation 
o Abdomen palpation 
8.1.3. Specific Clinical Signs and Symptoms of Interest 
During follow-up, all clinical signs and symptoms must be documented. However, the following signs 
and symptoms and date of onset/occurrence and resolution will be solicited and recorded for all 
participants from 30 minutes until 14 days post vaccination per section 9.2.3.1. Signs and symptoms to 
be solicited will be those commonly reported in the large cumulative experience of CD-JEV and MMR in 
children. 
Local Signs/Symptoms at the Injection Site: 
 
Ecchymosis (bruising) 
 
Erythema (redness) 
 
Edema (swelling) 
 
Induration (hardness) 
 
Pain/tenderness 
General Signs/Symptoms: 
 
Fever 
 
Rash 
 
Cough 
 
Runny nose 
 
Change in eating habits 
 
Diarrhea 
 
Sleepiness 
 
Irritability 
 
Unusual crying 
 
Vomiting 
In addition, a standardized clinical assessment including history and physical examination will be 
conducted by all clinicians per routine community practice. Evaluation of the above solicited 
signs/symptoms and unsolicited adverse events will include assessment of severity per Section 9.2.1.   
Reported symptoms and clinical signs will be recorded in a daily diary by parent/guardian. Evaluations 
will be made by qualified study staff on each day of visit to the study clinic (Group 1: Days 0, 14, 28, 56, 
84, 98, 112; Group 2: Days 0, 14, 28, 56, 70, 84, 98, 112) and at any time a participant is seen by a 
clinician.  
Parents will be instructed to complete a daily diary of the above Specific Clinical Signs and Symptoms 
of Interest to the best of their ability. Parents will be instructed to contact a study clinician in the event of 
illness that may require urgent care to facilitate a rapid assessment of danger signs and assist in 
arranging transportation by the study to the health center or local hospital, as required. While the event 
may or may not be attributable to the study vaccines, study staff will follow the ethical imperative of 

 
 
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assisting ill participants once aware of severe illness. After referral, it will be the responsibility of a study 
clinician to assess and document all signs and symptoms. 
8.1.4. Illness Diagnosis and Treatment 
Participants will be instructed to seek care at the study sites and referred to RITM when necessary. The 
care provided to study participants presenting for outpatient consultation services at the sites will be 
recorded directly to the subject medical record. For participants visiting sites during non-working RITM 
hours, hospitalized at RITM, or visiting another facility, the study team will request the medical abstract. 
In the event this information cannot be obtained from the facility, as much information as possible will be 
obtained from the family of the participant. If the event is classified as an SAE, medical records regarding 
the event must be obtained. 
 
While parents will be encouraged to seek care for their child at the sites or RITM, for participants 
presenting to a health center or transported to a health center or hospital other than RITM, a clinical 
assessment will be performed by a non-study health practitioner per routine community practice. Data 
on participant illness history, physical examination, diagnosis, and treatment will be documented. If 
necessary, staff will assist in arranging transportation for higher level care if necessary in their clinical 
judgment.  
8.2. Laboratory Evaluations 
8.2.1. Clinical Laboratory Evaluations 
There will be no clinical (safety) laboratory evaluations scheduled in this study. However, laboratory 
testing will be provided if required for the assessment of an AE. Laboratory assays specified in Section 
8.2.2. are for research purposes only and are not to be used for clinical diagnosis. 
8.2.2. Serum Assays 
8.2.2.1. 
Anti-Japanese Encephalitis Immunogenicity Testing 
JE vaccine immunogenicity will be assessed by measurement of serum anti-JE neutralizing antibody. 
Testing will be performed at the Department of Virology, Armed Forces Research Institute of Medical 
Sciences in Bangkok, Thailand. A 50% PRNT will be used to measure neutralizing antibodies for JE. 
Seroprotection will be defined as a serum JE PRNT titer of ≥1:10.62  
8.2.2.2. 
Measles 
Measles vaccine immunogenicity will be assessed by measurement of serum anti-measles neutralizing 
antibody. Testing will be performed at the Laboratory of Pediatric and Respiratory Viral Diseases,  
US FDA, in Silver Spring, MD. A 50% PRNT will be used to measure neutralizing antibodies for measles 
virus. Seroprotection will be defined as a serum measles plaque reduction neutralization concentration 
of ≥120 mIU/mL, as measured by the PRNT (dilution converted to concentration using the 3rd 
International Standard Reference serum). 
 
 

 
 
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8.2.2.3. 
Mumps 
Mumps vaccine immunogenicity will be assessed by the presence of serum anti-mumps IgG antibody. 
Testing will be performed at the Laboratory of Pediatric and Respiratory Viral Diseases, US FDA, in 
Silver Spring, MD. A commercial IgG ELISA will be used to measure anti-mumps IgG antibody. 
Seroprotection will be defined as a serum anti-mumps IgG OD ratio ≥1.10 per the package insert. 
8.2.2.4. 
Rubella  
Rubella vaccine immunogenicity will be assessed by measurement of serum anti-rubella IgG 
concentration. Testing will be performed at the Laboratory of Pediatric and Respiratory Viral Diseases, 
US FDA, in Silver Spring, MD. A commercial IgG ELISA will be used to measure anti-rubella antibody 
concentration. Seroprotection will be defined as a serum anti-rubella IgG concentration corresponding 
to ≥10 IU/mL per the package insert. 
8.2.3. Specimen Preparation, Handling, and Shipping 
8.2.3.1. 
Specimen Collection 
Blood draws of 3-5 mL will be collected during study visits as outlined in Section 7. The identity of the 
child will be verified immediately prior to the blood draw using the child’s study participant number. 
Aliquot labels will be generated that indicate the participant ID, a designation for the type of test required 
(MMR and/or JE), and timepoint of collection (pre or post). One label will be affixed onto the vacutainer 
tube immediately following the blood sample drawing. 
 
After collection, blood samples must clot for 60 minutes to 2 hours at room temperature. Samples will 
be maintained at 2°C to 8°C until processed in the site laboratory. 
8.2.3.2. 
Specimen Preparation, Handling, and Storage 
After centrifugation, the serum will be aliquoted. To ensure that samples are not mixed or inaccurately 
labelled, the child’s study participant number, date of blood collection, number of aliquots obtained, and 
the date and time of aliquoting will be specified on the sample identification log. Comments may be made 
on the quality of samples (e.g., hemolyzed, contaminated). A label will be affixed onto each of the 
aliquots to indicate participant ID, a designation for the type of test required (MMR or JE), and timepoint 
of collection (pre or post). 
 
All serum aliquots will be kept under appropriate conditions at the local study site. Study staff will monitor 
and record temperature on the appropriate form during the entire trial. For anti-JE testing, serum aliquots 
collected on D0 and D28 for Group 1 and D56 and D84 for Group 2 will be shipped to the Department 
of Virology, Armed Forces Research Institute of Medical Sciences in Bangkok, Thailand. For anti-
measles, anti-mumps, and anti-rubella testing, serum aliquots obtained on D0 and D56 for both groups 
will be shipped to the Laboratory of Pediatric and Respiratory Viral Diseases, US FDA, in Silver Spring, 
MD. A backup aliquot from each timepoint of collection will be retained for five years following study 
completion. Only authorized study staff will have access to the samples.  
 
 

 
 
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8.2.3.3. 
Specimen Shipment 
Specimens will be shipped according to the International Air Transport Association regulations. 
Following the testing of specimens, all remaining back-up specimens will be stored for five years at a 
location designated by the sponsor following study completion. 
 ASSESSMENT OF SAFETY 
9.1. Specification of Safety Parameters 
Study vaccine safety profiles will be parameterized as the proportion of participants experiencing specific 
adverse events categorized into one of the following categories:  
 
Immediate reactions occurring within 30 minutes of administration of each study vaccine, as 
observed by study staff or reported by the participant to study staff. 
 
Solicited signs and symptoms occurring greater than 30 minutes after administration of each 
study vaccine through 14 days following vaccination, as observed by the parent/guardian and 
indicated on the diary card or observed by study staff. 
 
All other adverse events occurring within 28 days of receipt of each study vaccine, as observed 
by study staff or reported by the participant’s parents to study staff. 
 
All SAEs occurring during the course of the study, as observed by study staff or reported by the 
participant’s parents to study staff. 
9.2. Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
9.2.1. Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation 
participant administered a pharmaceutical product, which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. The occurrence of an AE may come 
to the attention of study personnel during study visits and interviews of a study participant presenting for 
medical care. 
 
Information to be collected on adverse events includes event description, date of onset, clinician’s 
assessment of severity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis), and date of resolution/stabilization of the event. 
 
Any medical condition that was present at the time that the patient was enrolled should not be reported 
as an AE. However, if it deteriorates during the study safety recording periods, it should be recorded as 
an AE. 
 
AEs should be graded for severity and relationship to vaccine. 

 
 
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18 January 2017 
9.2.3. Reactogenicity 
Reactogenicity post-vaccination will be assessed from 30 minutes through 14 days following vaccination. 
All solicited local and systemic signs recorded from 30 minutes through 14 days post vaccination will be 
considered “related” to study vaccination. The parent will use a structured reactogenicity diary card for 
recording solicited (pre-listed) and unsolicited reactogenicity. Any reactogenicity continuing beyond 14 
days will be documented as an adverse event and followed until resolution. 
 
Any reactogenicity will be managed in accordance with good medical practices by the clinical study site 
team who will assess and treat or refer the child for medical care as appropriate. If needed to monitor or 
treat reactogenicity, additional study visits may be conducted. If any acute treatment or medical care is 
required as a result of harm caused by the study vaccine or study procedure, this care will be provided 
by the site free of charge. All children reporting reactogenicity will be followed clinically until the condition 
resolves (returns to baseline) or stabilizes. Conditions likely to be related to the product, whether serious 
or not, which persist at the end of the trial will be followed up by the study clinician until resolution or 
stabilization.  
 
The parents of infants enrolled in this study will be instructed to contact the study site staff to report any 
reactogenicity of concern that their child experiences. In the case of a life-threatening event, they will be 
instructed to seek immediate emergency care. Where feasible and medically appropriate, parents will 
be encouraged to seek medical care for the child at the RITM clinic, and to request that the study 
physician be contacted upon their arrival. 
9.2.3.1. 
Local and Systemic Signs and Symptoms 
All participants will be monitored at home for assessment of local and systemic signs and symptoms 
occurring from 30 minutes through 14 days following receipt of study vaccines. Parents will be instructed 
to record reactogenicity on diary cards. Study staff will call parents 2 days following vaccination to check 
on the participant and ensure the parent is completing the diary card.  
Using a standardized data collection instrument, the following local and systemic signs and symptoms 
will be documented and graded on predefined scales based on functional assessment or magnitude of 
reaction64: 
Local reactions (at injection site): 
 
Ecchymosis (bruising) 
 
Erythema (redness) 
 
Edema (swelling) 
 
Induration (hardness) 
 
Pain/tenderness  
 
 

 
 
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Local ecchymosis, erythema, edema, and induration, if present, will be 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 (upper arm 
or thigh). 
Grade 3:  ≥50% surface area of extremity segment involved (upper arm or thigh) OR ulceration 
OR secondary infection OR phlebitis OR sterile abscess OR drainage. 
Grade 4:  potentially life-threatening consequences (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), 
if present, will be graded as follows:  
Grade 1:  pain or tenderness causing no or minimal limitation of use of limb. 
Grade 2:  pain or tenderness causing greater than minimal limitation of use of limb. 
Grade 3:  pain or tenderness causing inability to perform usual social and functional activities. 
Grade 4:  pain or tenderness causing inability to perform basic self-care function OR 
hospitalization indicated. 
Systemic reactions: 
General Signs/Symptoms: 
 
Fever 
 
Rash 
 
Cough 
 
Runny nose 
 
Change in eating habits 
 
Diarrhea 
 
Sleepiness 
 
Irritability 
 
Unusual crying 
 
Vomiting 
Fever if present will be 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 
 
 

 
 
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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 will be 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. 
9.2.4. Serious Adverse Events 
An SAE is defined as an AE that meets one of the following conditions: 
 
Death. 
 
Life threatening (participant at immediate risk of death) (The term “life-threatening” in the definition 
of “serious” refers to an event in which the patient was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it were more severe). 
 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
 
Results in a persistent or significant disability or incapacity. 
 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
may jeopardize the participant and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Medical and scientific judgment should be exercised in 
deciding whether reporting is appropriate. 
All SAEs occurring at any time during the study must be reviewed and evaluated by a study clinician 
(SAE relationship to study vaccine must be evaluated as outlined in Section 9.2.1) and recorded on an 
SAE form and reported (as specified in Section 9.3). All SAEs should be followed until satisfactory 
resolution or until the study clinician deems the event to be chronic or the patient to be stable. 
9.3. Reporting Procedures 
9.3.1. Serious Adverse Events 
All SAEs occurring at any time during the study must be reported, even if the investigator considers that 
the SAE is not related to treatment. The study clinician will complete a Serious Adverse Event Form and 
send it to the medical monitor with copy to the Sponsor and CRO within 24 hours of site awareness, as 
outlined in a reporting SOP. 
 
 

 
 
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9.3.2. Regulatory Reporting  
Collected SAEs will be reported to responsible ethical review committees according to requested 
timelines. Collected local and systemic reactions and adverse events not meeting the criteria of an SAE 
will be summarized at the end of the study, and a summary report will be sent to responsible ethical 
review committees and CDIBP. 
9.4. Type and Duration of Follow-up of Participants after Adverse Events 
Serious adverse events occurring throughout the study will be recorded. Adverse events likely to be 
related to the product, whether serious or not, which persist at the end of the trial will be followed up by 
the study clinician until resolution. The study clinician will document the date of final disappearance of 
the adverse event on a data clarification form. However, any AE not resolved at the time of data lock will 
be classified as “unresolved” for data cleaning and locking purposes. 
9.5. Safety Oversight 
Additional safety oversight will be conducted by a Safety Monitoring Committee (SMC). The SMC will 
operate under rules of an SMC-approved charter that will be finalized at the organizing meeting of the 
SMC (first meeting). PATH will draft this charter, and the SMC will approve it, after any modification by 
the SMC. The draft charter will embody the elements of the following sections.  
9.5.1. SMC Roles and Responsibilities 
An SMC will be constituted for independent safety review of this trial. The SMC will review individual and 
cumulative participant safety data when making recommendations regarding the safe continuation of the 
study. SMC members will not participate in the study, nor will they fall under the direct supervision of 
any investigator participating in the study. 
 
PATH will, prior to any review of data, confirm that no conflicts of interest exist with any SMC member. 
Interests that might create a potential conflict of interest should be disclosed to PATH prior to any review 
of safety data. PATH will determine if the relationship is in conflict or gives the appearance of a conflict 
such that the individual should not serve on the SMC. PATH will determine how to handle such potential 
conflicts. PATH might dismiss an SMC member in the event of an unmanageable potential conflict. 
9.5.2. Study Materials for SMC Review 
The primary focus of the SMC will be to independently review all SAEs and items that PATH refers to it. 
The SMC will accomplish this by evaluating all such events against the known or expected safety profile 
of the study vaccine. Clinical and laboratory data, clinical records, and other study-related records will 
be made available for the SMC, as appropriate and available. If necessary, special reports will be 
prepared by the investigator or PATH. 
 
It is the responsibility of the investigator and PATH to ensure that the SMC is apprised of all new safety 
information relevant to the study vaccines and the study. Summary safety and enrollment data will be 
forwarded periodically to the SMC. The SMC will receive all protocol revisions and might receive other 
documents related to the study. 
 
 

 
 
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9.5.3. Reports from the SMC 
9.5.3.1. 
Review Report 
According to pre-specified criteria agreed upon by PATH, the SMC will communicate in writing its 
findings and any concerns and recommendations to PATH. Unless otherwise specified, the written report 
will then be forwarded to the investigator, who may, in turn, submit the report as per local independent 
ethics committee (IEC) policy. 
9.5.3.2. 
Immediate Action Report 
The SMC will notify PATH of any findings of a serious and immediate nature including any 
recommendations to discontinue all or part of the trial. In addition to any verbal communications, 
recommendations to discontinue or substantially modify the design or conduct of a study must be 
conveyed in writing on the day of the SMC review. This written, confidential report may contain 
unmasked supporting data and include the SMC’s rationale for the recommendations. 
9.6. Halting Rules 
Given the experience with CD-JEV and MMR vaccine, no safety issues are anticipated which would 
result in the suspension of enrollment in the study. However, the trial might be suspended at any time 
by PATH or any ethical review committee overseeing this study for any safety concern. This includes, 
for example, and without limitation, an SAE resulting in death, an unexpectedly high number of persons 
experiencing a similar event after receipt of any dose, or an unusually high rate of SAEs. PATH may 
suspend the study in the event that study conduct is found to be below GCP standards. 
Should an SAE occur which is likely related to administration of study vaccine, the decision whether the 
study should continue per protocol, proceed with caution, be suspended pending further investigation, 
be discontinued, or be modified and then proceed will be made by PATH in consultation with the 
investigator, the SMC, the RITM institutional review board (IRB), and/or Western IRB (WIRB). However, 
no rules will be pre-specified to define these conditions.  
If the study is halted, participants will be contacted immediately explaining why the study has been halted 
and the implications for their medical well-being. 
In the event of the appearance of new data that indicate an increased level of risk to study participants, 
the clinical trial will be suspended until PATH, the SMC, and all ethical review committees have reviewed 
relevant data and agreed that the trial may proceed. 
 
CLINICAL MONITORING 
10.1. Site Monitoring Plan 
Qualified and appropriately trained individuals will carefully monitor the study. The study monitor will 
periodically contact the site and perform on-site visits. The extent, nature, and frequency of site visits 
will be based on such considerations as study objectives, study design and complexity, and enrollment 
rate; periodicity and nature of monitoring activities will be described in the Monitoring Plan. PATH may 

 
 
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also include representatives of the Bill & Melinda Gates Foundation (the Foundation) in site contacts 
and visits, as appropriate, and will keep the Foundation program officer apprised of study progress. 
10.1.1. 
Site Initiation Visit 
Prior to study start, the monitor or PATH representative will ensure specific regulatory documents are 
available, such as IEC approvals, other IRB required approvals, and curriculum vitae for investigator and 
study staff. PATH will inform the investigator which documents need to be provided according to the 
applicable regulatory requirements. Prior to initiating recruitment, obtaining informed consent, and 
enrolling participants, the monitor or PATH representative will visit the site to train site personnel on the 
protocol and data collection procedures and to ensure the site meets all requirements for study start. 
10.1.2. 
Follow-up Visits 
Monitoring will be conducted according to PATH’s requirements. The individuals responsible for 
monitoring the study will periodically review the progress of the study and should have access to all 
records necessary to ensure the ethical and safe conduct of the study and the integrity/validity of the 
recorded data. 
During site visits and contacts, the monitor will: 
 
Check and assess the progress of the study. 
 
Review study data collected. 
 
Perform source data verification. 
 
Review regulatory files. 
 
Evaluate adherence to standard operating procedures. 
 
Identify any issues and address their resolution. 
 
This will be done in order to verify that: 
 
The data are authentic, accurate, and complete. 
 
The safety and rights of participants are being protected. 
 
The study is conducted in accordance with the approved protocol (and any subsequent 
amendment) and all applicable regulatory requirements. 
As part of study conduct, the investigator agrees to allow the monitor or PATH representative direct 
access to all relevant documents and to allocate time and the time of staff to discuss findings and any 
relevant issues. The investigator also agrees to allow representatives of the Foundation, authorized by 
PATH, to occasionally accompany the monitor or PATH representative during site visits. 
10.1.3. 
Close-out Visit 
Upon completion of the study, the study monitor or PATH representative and the investigator will conduct 
the following activities: 
 
Data clarification and/or resolution. 
 
Accounting, reconciliation, and destruction at sites of used and unused vaccines. 
 
Review of site study records for completeness. 
PATH and any regulatory body retain the right to temporarily suspend or prematurely discontinue this 
study at any time related to safety. If the study is stopped or suspended prematurely, PATH will inform 
the investigator as well as regulatory authorities about the decision and the reasons for termination or 

 
 
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suspension. If such action is taken, all efforts must be made to ensure the safety of the participants 
enrolled in the study. The investigator will inform the responsible IEC and provide the reason for the 
suspension or termination. In case of premature study or study site closure, the monitor or PATH 
representative will conduct all activities as indicated above. 
10.2. Audits and Inspections 
For the purpose of compliance with applicable regulatory guidelines it may be necessary for PATH or 
national or foreign regulatory authorities to conduct a site audit. This may occur at any time from start to 
after conclusion of the study. 
 
The investigator agrees to allow the auditor direct access to all relevant documents and to allocate her 
time and the time of her staff to the auditor to discuss findings and any relevant issues. 
 
National and foreign regulatory authorities may conduct a regulatory inspection of this study. If a 
regulatory authority requests an inspection, the investigator must inform PATH immediately about this 
request. The investigator agrees to allow the inspector(s) direct access to all relevant documents and to 
allocate her time and the time of her staff to discuss findings and any relevant issues. 
10.3. Archiving 
In accordance with applicable regulatory requirements, following closure of the study, the 
investigator/institution will maintain a copy of study documents in a secure and designated location at 
the study site. Essential documents shall be retained for at least five years after the completion or 
discontinuation of the study. 
 
STATISTICAL CONSIDERATIONS 
11.1. Study Hypothesis 
The primary study hypotheses are to prove that CD-JEV does not interfere with the immune response 
to measles and rubella antigens contained in the MMR vaccine. 
11.2. Definition of Analysis Sets 
All immunogenicity analyses and summaries will be performed on a per-protocol basis which will be 
considered as the primary approach to immunogenicity analyses. Supportive intention-to-treat 
immunogenicity analyses will also be conducted on all enrolled participants who received at least one 
dose of study vaccines and have at least one post-vaccination serology result. Safety analyses will be 
conducted on an intention-to-treat basis. In the event that there are participants who do not receive the 
vaccine(s) to which they were randomized, safety analyses will be performed on the safety analysis set 
as well. Analyses set definitions are provided below. 
11.2.1. 
Intention-to-Treat Analysis Set 
The Intention-To-Treat (ITT) set will include all participants who received a study vaccine. Participants 
in the ITT data set will be analyzed in the group to which participants have been assigned (not based on 

 
 
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the actual vaccine received). Participants who withdraw or are terminated from the study will be included 
in the ITT data set until the time of withdrawal or termination. Participants in the ITT analysis set who 
have at least one post-vaccination serology result will be included in the supportive immunogenicity 
analysis. 
11.2.2. 
Safety Analysis Set 
The Safety Analysis Set (SAS) will include all participants who received a study vaccine and have at 
least one post-vaccination safety result. Participants in the safety data set will be analyzed based on the 
actual vaccine received rather than the group to which they have been randomized. 
11.2.3. 
Per-Protocol Analysis Set 
The Per-Protocol (PP) sets will include the participants in the ITT set who are compliant with the protocol. 
This data set will be used for immunogenicity analysis only. 
11.2.3.1. Measles Per-Protocol Analysis Set (measles-PP)  
The measles-PP analysis set will be based on participants that meet all of the following criteria: 
 
Fulfilled the eligibility (inclusion/exclusion) criteria set forth in Sections 5.1. and 5.2. 
 
Received all study vaccines as assigned. 
 
Provided a valid measles serology laboratory result at baseline and at 56 days post-vaccination 
with MMR vaccine, with specimens taken within the windows prescribed by Section 7.14.  
 
Did not take any prohibited concomitant medication within 28 days post-vaccination. 
 
Did not show seropositivity for measles at baseline.   
11.2.3.2. Mumps Per-Protocol Analysis set (mumps-PP) 
The mumps-PP analysis set will be based on participants that meet all of the following criteria: 
 
Fulfilled the eligibility (inclusion/exclusion) criteria set forth in Sections 5.1. and 5.2. 
 
Received all study vaccines as assigned. 
 
Provided a valid mumps serology laboratory result at baseline and at 56 days post-vaccination 
with MMR vaccine, with specimens taken within the windows prescribed by Section 7.14.  
 
Did not take any prohibited concomitant medication within 28 days post-vaccination. 
 
Did not show seropositivity for mumps at baseline. 
11.2.3.3. Rubella Per-Protocol Analysis Set (rubella-PP) 
The rubella-PP analysis set will be based on participants that meet all of the following criteria: 
 
Fulfilled the eligibility (inclusion/exclusion) criteria set forth in Sections 5.1. and 5.2. 
 
Received all study vaccines as assigned. 
 
Provided a valid rubella serology laboratory result at baseline and at 56 days post-vaccination 
with MMR vaccine, with specimens taken within the windows prescribed by Section 7.14.  
 
Did not take any prohibited concomitant medication within 28 days post-vaccination. 
 
Did not show seropositivity for rubella at baseline. 
 
 

 
 
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11.2.3.4. JE Per-Protocol Analysis Set (JE-PP) 
The JE-PP analysis set will be based on participants that meet all of the following criteria: 
 
Fulfilled the eligibility (inclusion/exclusion) criteria set forth in Sections 5.1. and 5.2. 
 
Received all study vaccines as assigned. 
 
Provided a valid JE serology laboratory result at baseline and at 28 days post-vaccination with 
CD-JEV vaccine, with specimens taken within the windows prescribed by Section 7.14.  
 
Did not take any prohibited concomitant medication within 28 days post-vaccination. 
 
Did not show seropositivity for JE at baseline. 
11.3. Analysis Plan 
A full and final Statistical Analysis Plan will be specified prior to the first participant first visit and finalized 
before locking of the database. 
11.3.1. 
Immunogenicity 
11.3.1.1. Primary Hypotheses 
Non-inferiority of the concomitant administration of MMR and CD-JEV vaccines (Group 1) to MMR and 
CD-JEV vaccines given 2 months apart (Group 2) in children 9 months of age at 56 days is established in 
terms of percentage (or proportions) of participants achieving seropositivity to measles and rubella 
assuming a non-inferiority margin of 10%. 
The following co-primary hypotheses will be tested:  
 
H0M: (P(M1) minus P(M2)) ≤ –10% 
H1M: (P(M1) minus P(M2)) > –10% 
and 
H0R: (P(R1) minus P(R2)) ≤ –10% 
H1R: (P(R1) minus P(R2)) > –10% 
 
where P(M1) refers to the percentage of participants seroconverting to measles in Group 1 and P(M2) refers 
to the percentage of participants seroconverting to measles in Group 2 and where P(R1) refers to the 
percentage of participants seroconverting to rubella in Group 1 and P(R2) refers to the percentage of 
participants seroconverting to rubella in Group 2.  
11.3.2. 
Safety 
To evaluate safety, proportions of participants experiencing any category of adverse event will be 
calculated with corresponding 95% confidence intervals using the Exact test. 
11.3.3. 
Analysis and Reporting of Withdrawals 
Participants may withdraw from the study at any time and for any reason. The investigator may withdraw 
participants from the study for various reasons. These reasons and how to handle withdrawals are 
detailed in Section 5.3. Regardless of reason for withdrawal, it is the obligation of the investigator and 
sponsor to report these withdrawals as part of the analyses, the clinical study report, and peer-reviewed 

 
 
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publication(s) summarizing study results. Withdrawals will be summarized with their reasons in these 
reports. 
11.4. Sample Size Considerations 
An enrollment size of 628 participants (314 per treatment group) was targeted to achieve an overall 
power of 90% (approximate individual power of 95% for each co-primary objective). This estimation is 
based upon a non-inferiority margin of 10% and a one-sided type-one error rate of 2.5% or less, and 
assumes (based on historical data) a 95% seropositivity rate for measles vaccine, a 90% seropositivity 
rate for rubella vaccine, and approximately 20% non-evaluable rate (exclusion for baseline seropositivity 
and loss to follow-up) at 56 days post-vaccination. Individual sample size calculations were based on 
Farrington-Manning score test. 
11.5. Final Analysis Plan 
11.5.1. 
Primary Analyses 
Non-inferiority will be achieved when both H0M and H0R are rejected, that is, if the lower limit of the 95% 
CI for the differences in percentage of the participants achieving seropositivity between Group 1 and 
Group 2 >–10% for both measles and rubella outcomes. The 95% CI will be calculated using the 
Farrington-Manning method. Within-group exact 95% binomial confidence intervals for the proportion (or 
percentage) of seropositivity will be calculated. 
11.5.2. 
Secondary Analyses 
1. Non-inferiority of the concomitant administration of MMR and CD-JEV vaccines (Group 1) to MMR 
and CD-JEV vaccines given 2 months apart (Group 2) is established in terms of percentage (or 
proportions) of participants achieving seropositivity to mumps 56 days after vaccination, assuming a 
non-inferiority margin of 10%. The 95% CI will be calculated using the Farrington-Manning method. 
Within-group exact 95% binomial confidence intervals for the proportion (or percentage) of 
seropositivity will be calculated. 
2. The ratio of anti-measles and anti-rubella GMCs between both treatment groups with 95% CI 
obtained 56 days after vaccination (ratio of concurrent administration to separate administration) will 
be calculated using parametric models after log transformation of the concentrations where 
applicable. 
3. The difference with 95% CI between the anti-measles, anti-mumps, and anti-rubella seroconversion 
rates 56 days after vaccination for the two groups (concurrent administration minus separate 
administration) will be calculated using the Farrington-Manning method. 
4. The difference with 95% CI between the anti-JE seropositivity rates 28 days after vaccination for the 
two groups (concurrent administration minus separate administration) will be calculated using the 
Farrington-Manning method.   
5. The ratio of anti-JE GMTs between both treatment groups with 95% CI obtained 28 days after 
vaccination (ratio of concurrent administration to separate administration) will be calculated using 
parametric models after log transformation of the titers where applicable.  

 
 
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6. Safety endpoints will be descriptively summarized in terms of frequency counts and percentages by 
treatment group, where applicable.  
11.5.3. 
Exploratory Analyses 
Post-vaccination serologic responses will be analyzed for any association between the baseline anti-
dengue antibody response and the anti-JE antibody response 28 days after vaccination with CD-JEV.  
 
11.5.4. 
Timing of Analyses 
Due to an expected delay in MMR testing, JE testing will be completed first. According to this order of 
available serology testing results, two independent final analyses will be conducted stepwise as follows: 
 
 
The first final analysis will include all safety data and JE immunogenicity results. The estimates 
of the JE immunogenicity endpoints and safety endpoints and statistical tests associated with 
relevant secondary objectives and exploratory objective will be provided. This analysis will be 
performed after anti-JE antibody results are available and database is cleaned and locked at the 
end of the study. 
 
 
The second final analysis will include all MMR immunogenicity results. The estimates of the 
MMR-related immunogenicity endpoints and statistical tests associated with primary and relevant 
secondary objectives will be presented. This analysis will be performed as soon as MMR results 
are available, cleaned, and locked. 
 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Prior to the start of the trial it will be determined and documented which documents or data fields 
completed by the investigative team will be considered source documents. Only authorized study staff 
and representatives of PATH and authorized regulatory agencies may have direct access to source 
documents containing study data. Participant identification will be revealed to authorized representatives 
of these organizations only when necessary. 
 
 
QUALITY CONTROL AND QUALITY ASSURANCE 
The study will be conducted in accordance with procedures identified in the protocol and staff will be 
guided by procedural activities detailed in the SOP.  
Site monitoring will be conducted to ensure that human subject protection, study procedures, laboratory 
procedures, study intervention administration, and data collection processes are of high quality and meet 
International Conference on Harmonisation Good Clinical Practice (ICH-GCP), sponsor standards, and 
regulatory guidelines, and that the study is conducted in accordance with the protocol and sponsor 
SOPs. 

 
 
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All site staff will be required to have had training in GCP, informed consent, and protocol implementation 
prior to work on the project. All study staff, including temporary staff such as nurses, phlebotomists, and 
interviewers will attend mandatory training prior to participant enrollment.  
 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1. Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the current revision of the 
Declaration of Helsinki, ICH-GCP, and/or with local regulatory requirements, whichever affords the 
greater protection to the participant. 
14.2. Institutional Review Board 
The protocol will be reviewed and approved by all of the following bodies before recruitment begins: 
1. Western Institutional Review Board (WIRB). PATH subcontracts its ethical review for clinical trials 
to WIRB.  
2. The RITM Institutional Ethical Review Board.  
 
The investigator, with the help of PATH and the CRO, shall be responsible for obtaining IRB and ethics 
committee(s) approval of the protocol and any subsequent amendments in compliance with local law 
before the start of the trial. The investigator must forward copies of these approvals to PATH with the 
composition (names and qualification of the members) of the ethics committee. 
 
In addition, the protocol will be reviewed and approved by the FDA Research Involving Human Subject 
Committee before samples are sent to the FDA laboratory for testing. 
14.3. Independent Ethics Committee 
Per the Philippines Food & Drug Circular 2012-07, the protocol and other pertinent documents will be 
reviewed and approved by an Ethical Review Board/Committee selected by the Philippine Health Research 
Ethics Board. 
 
The CRO, with the help of PATH, shall be responsible for obtaining independent ethics committee(s) 
approval of the protocol and any subsequent amendments in compliance with local law before the start 
of the trial. The CRO must forward copies of these approvals to PATH with the composition (names and 
qualification of the members) of the ethics committee. 
14.4. Informed Consent Process 
Prior to receipt of study vaccine, written informed consent will be obtained from a parent/guardian for all 
participants. Informed consent documents will embody the elements of consent as described in the 
Declaration of Helsinki and the ICH Harmonised Tripartite Guidelines for Good Clinical Practice. 

 
 
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Original Informed Consent Forms must be kept on file by the investigator for possible inspection by 
regulatory authorities and PATH. The participant or the participant’s legally acceptable representative 
must receive a copy of the signed and dated Informed Consent Form(s), and any subsequent updates 
or amendments. 
The study monitor shall check the documentation of the individual Informed Consent Form(s) during 
each monitoring visit. 
Monetary incentives will not be provided to participants or their parent(s)/guardian(s) in exchange for 
participation. However, parents/guardians of participants will be paid 1,000 to 1,500 pesos per scheduled 
clinic visits after Day 0 to reimburse for transport costs and loss of wages. The scheduled clinic visits 
will require the parent/guardian to attend the vaccination clinic for specific follow-up procedures. To 
ensure that compensation does not risk becoming an inducement for participation, the parent/guardian 
will not be compensated for the study visit to the clinic at Day 0 for study enrollment. 
Given the local social structure, information about the study and informed consent process will be 
conducted via a series of procedures: 1) consent forms will be in the local language and written within 
the eighth grade reading level or lower; 2) meetings will be scheduled with the community and 
government leaders and the study will be explained in detail by trained study staff fluent in the local 
language; 3) after the community leaders provide approval for conduct of the study, 4) the investigator, 
or a person designated by the investigator, will fully inform the participant’s parent(s) of all pertinent 
aspects of the study and direct interested persons to the vaccination sites; and 5) individual consent will 
be documented by a signature and/or signature of an impartial literate witness of the consent form. 
14.5. Inclusion of Women and Children 
Children of any race/ethnicity and residing in the study area will be recruited for participation in the study. 
No special recruitment methods will be used to ensure certain levels of participation by any specific 
minorities residing in the source population. The investigator will emphasize during information sessions 
that girls and boys are at equal risk of JE and its complications. 
14.6. Participant Confidentiality 
14.6.1. 
Confidentiality of Data 
By signing the protocol, the investigator agrees that the study protocol, documentation, data, and all 
other information generated regarding the vaccines will be held in strict confidence. The investigator may 
divulge such information within regulatory restrictions and ethical considerations only to ethical review 
committees or similar expert boards or committees, and their affiliated institutions and employees, only 
under an appropriate understanding of confidentiality with such board or committee, and their affiliated 
institutions and employees. No information concerning the study or the data may be released to any 
unauthorized third party without prior written approval of PATH. The investigator will ensure that all 
employees involved in the study respect the same rules.  
Documents and data pertaining to the study will be kept in a locked cabinet under the responsibility of 
the investigator. PATH will conduct periodic monitoring visits to ensure that the data is safe and stored 
in this secure place and that only those authorized study staff have access to the data. Study data will 
be kept for five years after completion of the study. 

 
 
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Study participants will not be reported by name in any report or publication resulting from data collected 
in this study. 
14.6.2. 
Confidentiality of Patient Records 
Participant confidentiality is strictly held in trust by the participating investigator, her staff, and the 
sponsor(s) and their agents. This confidentiality pertains to a participant’s personal and health 
information and extends to information on any biological specimen of the participant. Medical information 
about individual participants obtained during the course of this study is confidential and may not be 
disclosed to third parties, except authorized monitors, sponsors, auditors, or inspectors. Confidentiality 
will be ensured by the use of participant numbers coding for the identification of each participant’s 
personal, health, and specimen information. Access to this linkage and other confidential data will be 
strictly controlled. 
The investigator will keep individual results confidential to the extent permitted by law. Information will 
not be released to anyone other than the participant, their parent or their medical provider, unless 
required to do so by law. 
14.6.3. 
Notification of Primary Care Physician 
If agreed by the participant’s legally acceptable representative, the study staff shall notify the participant’s 
primary clinician, if applicable, of child’s participation in the study. Participation in the study and study 
team contact numbers will be reported on the participant’s study identification card as applicable. 
14.7. Study Discontinuation 
Study discontinuation is not expected to occur. However, if the study is discontinued for safety reasons, 
parents of participants will be informed of the reasons for discontinuation and of the implications/potential 
consequences for the child. 
14.8. Future Use of Stored Specimens 
Aliquots of participant’s back-up serum specimens will be maintained for five years after the completion 
of the study. This is to allow the samples to be stored long enough to support any requests for additional 
information from WHO or other agencies. Following completion of this period, all samples will be 
destroyed. No personal identifying information associated with the study will be stored on site with the 
specimens. After the data analysis for the study is complete, the master linking document will be 
destroyed, thus removing the possibility of identifying the individual from whom the data and sample 
were collected. Samples will not be used for unrelated, future studies without appropriate ethics 
committee approvals and consent from participants (if deemed required by ethics committees and the 
master linking document with identifiers has not yet been destroyed). 
 
 

 
 
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DATA HANDLING AND RECORD KEEPING 
15.1. Data Management Responsibilities 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness of the data 
reported. Data collection is the responsibility of the clinical study staff at the site under the supervision of 
the investigator. 
Adverse events must be graded, assessed for severity and causality, and reviewed by the investigator 
or designee. 
15.2. Data Capture Methods 
Clinical data and laboratory data will be recorded. All children will be assigned a unique study participant 
number at study enrollment; this study participant number will be included on all forms and in the 
computer database and will serve to link study data to specific individuals. Data forms will be verified for 
accuracy, linked by study participant number, and managed using database management software. 
The study will utilize DataFax software, an electronic data capture (EDC) system uniquely suited for 
international clinical research developed by DF/Net Research. Site staff will use the EDC tool to securely 
enter data into electronic case report forms (eCRFs) from source documents, or from medical or clinical 
records, directly into the database. The software utilizes workflows and specifically programmed edit 
checks to ensure that data is entered correctly and on time within expected parameters. The data 
validation process continues with routine batch edit checks initiated at the data management center to 
detect data issues. 
The EDC system will distribute data entry and validation tasks to the research sites to optimize quality 
data collection at the point of entry. It will encompass an extensive edit check language to enforce legal 
ranges, field requirements, and other per-field attributes as well as higher-level concepts such as visit 
and form timing, conditional data, and data consistency across visits and forms. The data management 
system is ISO 9001:2008 certified and is routinely audited. It includes a 21 CRF Part 11-compliant audit 
trail and is implemented in accordance with Good Clinical Data Management Practices, all applicable 
regulations, and recognized best practices.  
15.3. Types of Data 
Data for this study will include biographical, medical history, clinical (signs, symptoms, prescription and non-
prescription medical treatments, and non-study vaccinations), safety data, and immunologic laboratory data. 
15.4. Timing/Reports 
No interim analysis are planned. SMC reports will be completed within two weeks of each SMC meeting. 
The full Clinical Study Report (CSR) will be completed approximately six months after the completion of 
the analyses. 
 
 

 
 
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15.5. Study Records Retention 
It is planned that the study data will be kept for five years after completion of the study. No records will be 
destroyed without the written consent of PATH. It is the responsibility of PATH to inform the investigator 
when these documents no longer need to be retained. 
15.6. Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol, GCP, or the site manual of 
procedures. The noncompliance may be either on the part of the participant, the investigator, or the 
study site staff. As a result of any deviations, corrective actions are to be developed by the site and 
implemented promptly. Examples of protocol deviations include the following: 
 
Non-adherence to inclusion and/or exclusion criteria. 
 
Irregular or improper implementation of the trial product. 
 
Unnecessary repeated performance of any planned procedures or tests. 
 
Changing the interval between two visits or procedures more than allowed by the protocol. 
 
Incorrect or careless documentation of study procedures on primary documents or required 
logs. 
 
Premature withdrawal of a participant for any reason, even if withdrawal is in the best interest 
of the well-being of the participant. 
Trial procedures shall not be changed without the consent of PATH. Insignificant violations of the protocol 
will be examined on an individual basis taking into account information documenting the reason(s) that 
the deviation occurred. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations to PATH in 
a timely manner after identification. Reports of protocol deviations must be sent to WIRB and the RITM 
IRB, as required per their respective guidelines. The investigator and study staff are responsible for 
knowing and adhering to IRB and IEC requirements. PATH will assist the investigator in all reporting to 
WIRB or file reports on behalf of the investigator. 
 
PUBLICATION POLICY 
A CSR comprised of text and results tables reflecting all safety and immunogenicity data will be generated. 
The CSR will be reviewed, approved, and signed by the investigator. The CSR will be compliant with ICH 
guidelines. 
All data, documents, any recordings and information transferred by PATH to any contractor or obtained 
or prepared by any contractor, his/her consultants or persons associated by contractual relationships 
with any contractor during the trials, belong to PATH. 
All confidential information communicated to the investigator by PATH shall be kept strictly confidential 
by her or any other person connected with the study and shall not be disclosed, either orally or in written 
form, to any third party without prior written consent of the organization of which the information is the 
exclusive property. 

 
 
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Following completion of the CSR, the investigator, working with PATH representatives, is expected to 
publish the results of this research in peer-reviewed scientific journal(s). In no way may anyone or any 
organization prohibit the public dissemination of valid results of this trial. 
The International Committee of Medical Journal Editors’ member journals have adopted a trials-
registration policy as a condition for publication. This policy requires that all clinical trials be registered 
in a public trials registry. It will be the responsibility of PATH representatives to register this trial in an 
acceptable registry preferably before enrollment but no later than 30 days following the enrollment of the 
first participant. Likewise, all clinical trials are required to be uploaded in the Philippine Clinical Trial 
Registry. It is the responsibility of the study sponsor to upload information related to the clinical trial to 
the registry (http://registry.healthresearch.ph) 30 days after the application to conduct the clinical trial 
has been granted. International Committee of Medical Journal Editors’ authorship criteria will be strictly 
followed for publication of any manuscript(s) arising from this trial. 
 
 

 
 
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