Determining Safety and Efficacy of Japanese Encephalitis Vaccine When Given With Measles Vaccine

Study Overview
=================
Brief Summary
-----------------
This study will determine whether it is safe and effective to administer Japanese encephalitis (JE) live attenuated SA 14-14-2 vaccine at the same time as measles vaccine. If it is found to be safe, it will pave the way for use in routine vaccination programs. The hypothesis is that children who receive JE live attenuated SA 14-14-2 vaccine and measles vaccine at the same time are protected against these diseases at the same level as those who receive the vaccines at different intervals.

Detailed Description
-----------------
Japanese encephalitis is the leading cause of viral neurological disease and disability in Asia. The severity of sequelae, together with the volume of cases, make JE the most important cause of viral encephalitis in the world. Approximately 3 billion people-including 700 million children-live in Asian areas at risk for JE. JE most commonly infects children between the ages of 1 and 15 years, and can also infect adults in areas where the virus is newly introduced. More than 50,000 cases are reported annually and cause an estimated 10,000 to 15,000 deaths. This figure is believed to represent only a small proportion of the disease burden that actually exists. An effective vaccine has existed since 1941, but has not reached the poorest countries in Asia. During the 60 years that the vaccine has been available, JE has infected an estimated 10.5 million children, resulting in more than 3 million deaths and more than 4 million children living with long-term disabilities. Control of this disease has been limited due to poor disease surveillance, a limited and unstable vaccine supply, lack of guidance and programmatic support for immunization, and limited advocacy. A successful vaccine should be safe, efficacious, affordable, administered in a single dose, and easily incorporated into the routine Expanded Programmes on Immunization (EPI) programs. This study will help ensure the safety of SA 14-14-2 simultaneously administered with measles vaccine, paving the way for its use in routine EPI programs. If this candidate becomes widely available, it will drastically increase the feasibility of routine JE immunization in Asia, reducing the devastating death and disability caused by this disease. In addition to impacting low-income countries, the vaccine will allow countries that purchase vaccine-such as Thailand, Vietnam, Sri Lanka, and India-to recover health care dollars, improve their present programs, and address other unmet health care needs.

Official Title
-----------------
Assessment of the Non-Inferiority of the Concurrent Administration of Japanese Encephalitis Live Attenuated SA 14-14-2 Vaccine and Measles Vaccine Given Alone

Conditions
-----------------
Encephalitis, Japanese B

Intervention / Treatment
-----------------
* Biological: Live Japanese encephalitis vaccine SA 14-14-2 (LJEV)
* Biological: Measles Vaccine (MV)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant is healthy, aged between 8 months (± 2 weeks) at inclusion visit Subject is a full-term infant Subject's parents or legal guardian willing to provide signed informed consent. Children have completed 3 doses each of diphtheria, tetanus, pertussis (DTP) and oral polio vaccine (OPV). Exclusion Criteria: History of documented HIV. Known or suspected impairment of immunologic function. History of serious chronic disease Underlying medical condition such as inborn errors of metabolism, failure to thrive, bronchopulmonary dysplasia, or any major congenital abnormalities requiring surgery or chronic treatment. Acute medical illness with or without fever within the last 72 hours or an axillary temperature ≥ 37.5°C at the time of inclusion. History of documented suspected encephalitis, encephalopathy, or meningitis History of measles History of thrombocytopenic purpura. Received any JE or measles vaccine prior to enrollment. Received any vaccine, other than the study vaccines, within 2 weeks prior to or scheduled to receive a non-study vaccination during the conduct of this trial. Hypotonic - hyporesponsiveness, after the preceding vaccination. History of seizures, including history of febrile seizures, or any other neurologic disorder. Prior or anticipated receipt of immune globulin or other blood products, or injected or oral corticosteroids or other immune modulator therapy except routine vaccines within 6 weeks of administration of the study vaccines. Individuals on a tapering dose schedule of oral steroids lasting <7 days may be included in the trial as long as they have not received more than one course within the last 2 weeks prior to enrollment. Suspected or known hypersensitivity to any of the investigational or marketed vaccine components. Serious adverse event related to the vaccine (i.e., possible, probably, definite) Persistent inconsolable crying (>3 hours) observed after a previous dose. Unable to attend the scheduled visits or comply with the study procedures. Enrolled in another clinical trial involving any therapy. Any condition that in the opinion of the investigator, would pose a health risk to the participant, or interfere with the evaluation of the study objectives.

Ages Eligible for Study
-----------------
Minimum Age: 8 Months
Maximum Age: 11 Months

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LJEV then MV<br>Received one dose of Live Japanese encephalitis vaccine SA 14-14-2 (LJEV) at 8 months of age, and one dose of measles vaccine (MV) one month later. | Biological: Live Japanese encephalitis vaccine SA 14-14-2 (LJEV)<br>* Live Japanese encephalitis vaccine SA 14-14-2 (LJEV) is lyophilized powder that looks like a milky-white crisp cake. After reconstitution, it turns into a transparent orange red liquid. Its container is a vial. It is stored and transported between 2°C to 8°C and protected from light. Each single human dose is 0.5 ml containing not less than 5.4 log particle flux unit (PFU) of live Japanese Encephalitis (JE) virus. The 0.5ml injection is delivered subcutaneously via auto-disable syringe. Lot number 200411129-3 manufactured by Chengdu Institute of Biological Products (CDIBP), Chengdu, China.<br>Biological: Measles Vaccine (MV)<br>* The Serum Institute of India (SII) measles vaccine provided routinely in the Expanded Program on Immunization (EPI) of the Philippines was the measles vaccine provided to the study participants. The vaccine met the requirements of the World Health Organization (WHO). SII measles vaccine contained live attenuated (freeze-dried) Edmonston-Zagreb strain measles virus propagated on human diploid cells (HDC). Each single human dose when reconstituted in a volume of 0.5 ml contains no less than 1000 Cell culture infectious dose 50% (CCID50) of live virus particles. SII measles vaccine is presented as a yellowish-white dry cake. The vaccine should be reconstituted with the diluent supplied (sterile water for injection). A sterile disposable syringe and needle are supplied separately. The 0.5ml injection is delivered subcutaneously via auto-disable syringe. Lot number 2979.<br>|
| Experimental: LJEV and MV<br>Received one dose of Live Japanese encephalitis vaccine SA 14-14-2 (LJEV) concurrently with one dose of measles vaccine (MV) at 9 months of age. | Biological: Live Japanese encephalitis vaccine SA 14-14-2 (LJEV)<br>* Live Japanese encephalitis vaccine SA 14-14-2 (LJEV) is lyophilized powder that looks like a milky-white crisp cake. After reconstitution, it turns into a transparent orange red liquid. Its container is a vial. It is stored and transported between 2°C to 8°C and protected from light. Each single human dose is 0.5 ml containing not less than 5.4 log particle flux unit (PFU) of live Japanese Encephalitis (JE) virus. The 0.5ml injection is delivered subcutaneously via auto-disable syringe. Lot number 200411129-3 manufactured by Chengdu Institute of Biological Products (CDIBP), Chengdu, China.<br>Biological: Measles Vaccine (MV)<br>* The Serum Institute of India (SII) measles vaccine provided routinely in the Expanded Program on Immunization (EPI) of the Philippines was the measles vaccine provided to the study participants. The vaccine met the requirements of the World Health Organization (WHO). SII measles vaccine contained live attenuated (freeze-dried) Edmonston-Zagreb strain measles virus propagated on human diploid cells (HDC). Each single human dose when reconstituted in a volume of 0.5 ml contains no less than 1000 Cell culture infectious dose 50% (CCID50) of live virus particles. SII measles vaccine is presented as a yellowish-white dry cake. The vaccine should be reconstituted with the diluent supplied (sterile water for injection). A sterile disposable syringe and needle are supplied separately. The 0.5ml injection is delivered subcutaneously via auto-disable syringe. Lot number 2979.<br>|
| Experimental: MV then LJEV<br>Received one dose of measles vaccine (MV) at 9 months of age, followed by one dose of Live Japanese encephalitis vaccine SA 14-14-2 (LJEV) one month later. | Biological: Live Japanese encephalitis vaccine SA 14-14-2 (LJEV)<br>* Live Japanese encephalitis vaccine SA 14-14-2 (LJEV) is lyophilized powder that looks like a milky-white crisp cake. After reconstitution, it turns into a transparent orange red liquid. Its container is a vial. It is stored and transported between 2°C to 8°C and protected from light. Each single human dose is 0.5 ml containing not less than 5.4 log particle flux unit (PFU) of live Japanese Encephalitis (JE) virus. The 0.5ml injection is delivered subcutaneously via auto-disable syringe. Lot number 200411129-3 manufactured by Chengdu Institute of Biological Products (CDIBP), Chengdu, China.<br>Biological: Measles Vaccine (MV)<br>* The Serum Institute of India (SII) measles vaccine provided routinely in the Expanded Program on Immunization (EPI) of the Philippines was the measles vaccine provided to the study participants. The vaccine met the requirements of the World Health Organization (WHO). SII measles vaccine contained live attenuated (freeze-dried) Edmonston-Zagreb strain measles virus propagated on human diploid cells (HDC). Each single human dose when reconstituted in a volume of 0.5 ml contains no less than 1000 Cell culture infectious dose 50% (CCID50) of live virus particles. SII measles vaccine is presented as a yellowish-white dry cake. The vaccine should be reconstituted with the diluent supplied (sterile water for injection). A sterile disposable syringe and needle are supplied separately. The 0.5ml injection is delivered subcutaneously via auto-disable syringe. Lot number 2979.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Seroprotection for Measles 4 Weeks After Vaccination | Seroprotection after measles vaccination was defined as a measles antibody titer ≥ 120 mIU/mL. Measles immunoglobulin G (IgG) antibody was determined using the Enzygnost® Anti-Measles Virus/IgG enzyme-linked immunosorbent assay(ELISA) assay from Siemens, Marburg, Germany. | Day 0 (before vaccination) and Day 28 (4 weeks after measles vaccination) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Seroprotection for Japanese Encephalitis 4 Weeks After Vaccination | Seroprotection after LJEV was defined as at least 1:10 dilution as recommended by the World Health Organization (WHO). JE antibody titers were determined by a plaque reduction neutralization test (PRNT). | Day 0 (before vaccination) and Day 28 (4 weeks after LJEV vaccination) | 
| Geometric Mean Concentration (GMC) of Measles Antibodies After Vaccination | Measured using the Enzygnost® Anti-Measles Virus/IgG ELISA assay from Siemens, Marburg, Germany. | Day 0 (before vaccination) and Day 28 (4 weeks after measles vaccination) | 
| Geometric Mean Titer (GMT) of Japanese Encephalitis Antibodies After Vaccination | Assayed by plaque reduction neutralization test (PRNT). | Day 0 (before vaccination) and Day 28 (4 weeks after LJEV vaccination) | 
| Number of Participants Experiencing Local and Systemic Reactogenicity After Receiving Live Attenuated Japanese Encephalitis Vaccine (LJEV) | Local reactions included erythema, pain, swelling, or induration. Systemic reactions included loss of appetite, crying, diarrhea, drowsiness, insomnia, irritability, vomiting, or fever. The parents of the participants recorded all local reactions and systemic events on an individual safety diary form. | Up to 7 days after LJEV administration | 
| Number of Participants Experiencing Local and Systemic Reactogenicity After Receiving Measles Vaccine | Local reactions included erythema, pain, swelling, and induration. Systemic reactions included loss of appetite, crying, diarrhea, drowsiness, insomnia, irritability, and vomiting. The parents of the participants recorded all local reactions and systemic events on an individual safety diary form. | Up to 7 days after measles vaccination | 
| Number of Participants Experiencing Unsolicited Adverse Events (AE) |  | Up to 7 days post-vaccination | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Japanese Encephalitis, Japanese B Encephalitis, Japanese B Viral Encephalitis, Viral Encephalitis, Japanese B