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

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

• Live attenuated SA 14-14-2 Japanese Encephalitis vaccine (Biological), also known as CD-JEV, CD.JEVAX®, RS.JEV®: Single 0.5 mL dose of World Health Organization prequalified live, attenuated SA 14-14-2 JE vaccine manufactured by Chengdu Institute of Biological Products, Chengdu, China, administered by subcutaneous injection
• Measles, mumps, rubella vaccine (Biological), also known as MMR, Priorix®: 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.

Primary outcomes

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

Secondary outcomes

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

Sex: All, ages: 9 Months to 9 Months, accepts healthy volunteers

Inclusion Criteria:

* Age 9 months to < 10 months at the time of enrollment.
* Residence in the study area.
* At least one parent or guardian willing to provide written informed consent.
* Generally healthy and free of obvious health problems as established by medical history, physical examination, and clinical judgment.
* A parent or guardian is willing to attend all planned study visits and allow home visits and phone contacts, as required by the protocol.

Exclusion Criteria:

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

Participant flow

Outcome results

• Percentage of Participants With Measles Seropositivity 56 Days Post-vaccination (Primary), Number, percentage of participants: Group 1: MMR and CD-JEV 98.1 (95.8 to 99.3); Group 2: MMR Then CD-JEV 98.0 (95.8 to 99.3)
• Percentage of Participants With Rubella Seropositivity 56 Days Post-vaccination (Primary), Number, percentage of participants: Group 1: MMR and CD-JEV 100.0 (98.7 to 100.0); Group 2: MMR Then CD-JEV 99.7 (98.1 to 100.0)
• Percentage of Participants With Mumps Seropositivity 56 Days Post-vaccination (Secondary), Number, percentage of participants: Group 1: MMR and CD-JEV 98.5 (96.3 to 99.6); Group 2: MMR Then CD-JEV 98.5 (96.2 to 99.6)
• Geometric Mean Concentration (GMC) for Anti-measles Neutralizing Antibody Concentration at 56 Days Post-vaccination (Secondary), Geometric mean, mIU/mL: Group 1: MMR and CD-JEV 1964.4 (1769.3 to 2181.0); Group 2: MMR Then CD-JEV 1866.3 (1649.1 to 2112.0)
• GMC for Anti-rubella IgG Antibody Concentration at 56 Days Post-vaccination (Secondary), Geometric mean, IU/mL: Group 1: MMR and CD-JEV 230.8 (214.4 to 248.5); Group 2: MMR Then CD-JEV 229.8 (210.0 to 251.3)
• Seroconversion Rate for Measles 56 Days Post-vaccination (Secondary), Number, percentage of participants: Group 1: MMR and CD-JEV 98.1 (95.8 to 99.3); Group 2: MMR Then CD-JEV 98.0 (95.8 to 99.3)
• Seroconversion Rate for Mumps 56 Days Post-vaccination (Secondary), Number, percentage of participants: Group 1: MMR and CD-JEV 96.7 (93.8 to 98.5); Group 2: MMR Then CD-JEV 95.1 (91.8 to 97.4)
• Seroconversion Rate for Rubella 56 Days Post-vaccination (Secondary), Number, percentage of participants: Group 1: MMR and CD-JEV 100.0 (98.7 to 100.0); Group 2: MMR Then CD-JEV 99.7 (98.1 to 100.0)
• Percentage of Participants With Japanese Encephalitis Seropositivity 28 Days Post-vaccination (Secondary), Number, percentage of participants: Group 1: MMR and CD-JEV 72.3 (67.0 to 77.2); Group 2: MMR Then CD-JEV 68.2 (62.6 to 73.4)
• Geometric Mean Titer (GMT) for Serum Neutralizing Antibody Titer to JE Virus at 28 Days Post-vaccination (Secondary), Geometric mean, titer: Group 1 - MMR and CD-JEV 24.0 (20.8 to 27.6); Group 2 - MMR Then CD-JEV 20.3 (17.8 to 23.1)
• Number of Participants With Immediate Reactions Within 30 Minutes of Each Vaccination (Secondary), Count of participants, Participants: Group 1: MMR Dose 1 + CD-JEV 6; Group 2: MMR Dose 1 3; Group 2: CD-JEV 5; Group 1: MMR Dose 2 5; Group 2: MMR Dose 2 3
• Number of Participants With Solicited Local and Systemic Reactions Within 14 Days of Each Vaccination (Secondary), Count of participants, Participants: Group 1: MMR Dose 1 + CD-JEV 35; Group 2: MMR Dose 1 31; Group 2: CD-JEV ; Group 1: MMR Dose 2 12; Group 2: MMR Dose 2 9
• Number of Participants With Solicited Local Reactions Within 14 Days of Each Vaccination by Maximum Severity (Secondary), Count of participants, Participants: Group 1: MMR Dose 1 6; Group 1: CD-JEV 6; Group 2: MMR Dose 1 10; Group 2: CD-JEV 3; Group 1: MMR Dose 2 0; Group 2: MMR Dose 2 5
• Number of Participants With Systemic Reactions Within 14 Days of Each Vaccination by Maximum Severity (Secondary), Count of participants, Participants: Group 1: MMR Dose 1 + CD-JEV 135; Group 2: MMR Dose 1 119; Group 2: CD-JEV 87; Group 1: MMR Dose 2 79; Group 2: MMR Dose 2 84
• Number of Participants With Unsolicited Adverse Events Within 28 Days of Each Vaccination (Secondary), Count of participants, Participants: Group 1: MMR Dose 1 + CD-JEV 207; Group 2: MMR Dose 1 211; Group 2: CD-JEV 164; Group 1: MMR Dose 2 110; Group 2: MMR Dose 2 148
• Number of Participants With Serious Adverse Events Throughout the Study (Secondary), Count of participants, Participants: Group 1: MMR and CD-JEV 8; Group 2: MMR Then CD-JEV 15

Adverse events

Time frame: Mortality and serious adverse events were collected through the end of study, up to 112 days. Non-serious adverse events were collected through 28 days after each vaccination.

Serious adverse events by term

Other adverse events by term

25 more terms not shown.

• Study Protocol (PDF, 2017-01-18)
• Statistical Analysis Plan (PDF, 2017-06-06)

• Maria Rosario Capeding, MD, Principal investigator, Research Institute for Tropical Medicine