Seroprevalence of Neutralizing Antibodies Against Japanese Encephalitis Virus Among 6 Years Old Children With 5 Different Immunization Strategies in Zhejiang Province

Study Overview
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Brief Summary
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This study is to evaluate the seroprevalence of neutralizing antibodies against Japanese encephalitis (JE) virus in children aged 6 years who were previously administered with 5 different immunization strategies by JE attenuated live vaccine (JEV-L) or/and inactivated vaccine (JEV-I). The secondary objective is to evaluate the immunogenicity of the booster dose of JEV-I at 6 years old for those previously immunized with 3 doses of JEV-I or those sequential administered with 1 dose of JEV-L and another dose of JEV-I.

Detailed Description
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Based on the retrospective registry in Zhejiang Provincial Immunization Information System, healthy children aged 6 years from 5 cohorts were included according to their previous immunization schedules on JE: 3 doses of JEV-I (Group 1), JEV-L+ JEV-I (Group 2), JEV-L+ JEV-I + JEV-I (Group 3), JEV-I + JEV-I+ JEV-L (Group 4), and 2 doses of JEV-L (Group 5). According to immunization programs in China, a booster dose of JEV-I is needed at the age of 6 for Group 1 and Group 2. A pre-vaccination blood sample (2.5ml) will be collected to evaluate the proportions of seropositivity before the booster dose of JEV-I. A second blood sample will be collected 28-35 days after the booster dose. Immunogenicity of the booster dose will be assessed by seroconversion rates, proportions of seropositivity and GMTs for these two groups. In addition, safety will be assessed with the occurrence of adverse events reported in these two groups. For the rest three groups who have completed the immunization schedules on JE, only one blood sample will be taken at the age of 6 to evaluate the proportions of seropositivity and GMTs after 4 years post the complete immunization schedules. Plague reduction neutralization test (PRNT) against both vaccine strains (SA-14-14-2 strain for JEV-L and Beijing P3 strain for JEV-I) will be used to test neutralizing antibody titers, so as to avoid potential bias in favor of either vaccine. PRNT50 titers (the reciprocal of the serum dilution that reduced the virus plaque count by 50% compared with the virus-only controls) ≥ 1:10 are deemed as positive.

Official Title
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Seroprevalence of Neutralizing Antibodies Against Japanese Encephalitis Virus Among 6 Years Old Children With 5 Different Immunization Strategies in Zhejiang Province, China: An Open-labeled, Ambidirectional Cohort Study

Conditions
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Japanese Encephalitis, Vaccine Preventable Disease, Vaccine Reaction

Intervention / Treatment
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* Biological: Japanese Encephalitis Vaccine (Vero Cell), Inactivated;
* Other: No prospective interventions


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants aged ≥ 72 months to < 75 months. Participants have completed routine immunization schedules in time. Participants are healthy native residents. Parents/guardians can understand the protocol requirements, provide informed consent, accept all scheduled visits, and comply with all trial procedures. Exclusion Criteria: History of neurological diseases or related symptoms. An acute illness with fever (temperature ≥ 37.1℃) or any acute onset of chronic diseases. Known impairment of immunologic function, or receipt of immunosuppressive therapy or immunoglobulin in the past 3 months. Known allergy to any constituent of the vaccine. Have been injected with other vaccines or any clinical trial drugs in the past 4 weeks. Any condition which, in the opinion of the investigator, would pose a health risk to the subject or interfere with the vaccine.

Ages Eligible for Study
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Minimum Age: 72 Months
Maximum Age: 75 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 3JEV-I (Group 1)<br>Retrospective: 3 doses of JE vaccines. 2 doses of Inactivated JE Vaccine (JEV-I, 7-10 days apart) at 8 months of age and 1 dose of JEV-I at 2 years old. Prospective: 1 booster dose of JEV-I at 6 years old. | Biological: Japanese Encephalitis Vaccine (Vero Cell), Inactivated;<br>* The investigators recruit 6 years old children who have been vaccinated by 2-3 doses of JE vaccines with different immunization strategies. For participants from Group 1 and Group 2 who haven't completed the JE immunization schedules, a booster dose of JEV-I will be administered at 6 years old.<br>|
| Experimental: JEV-L+JEV-I (Group 2)<br>Retrospective: 2 doses of JE vaccines. 1 dose of JE attenuated live vaccine (JEV-L) at 8 months of age and 1 dose of JEV-I at 2 years old. Prospective: 1 booster dose of JEV-I at 6 years old. | Biological: Japanese Encephalitis Vaccine (Vero Cell), Inactivated;<br>* The investigators recruit 6 years old children who have been vaccinated by 2-3 doses of JE vaccines with different immunization strategies. For participants from Group 1 and Group 2 who haven't completed the JE immunization schedules, a booster dose of JEV-I will be administered at 6 years old.<br>|
| Experimental: JEV-L+2JEV-I (Group 3)<br>Retrospective: 3 doses of JE vaccines. 1 dose of JEV-L at 8 months of age and 2 dose (7-10 days apart) of JEV-I at 2 years old. | Other: No prospective interventions<br>* The investigators recruit 6 years old children who have been vaccinated by 2-3 doses of JE vaccines with different immunization strategies. Participants from Group 3-5 have completed the JE immunization schedules with JEV-I or/and JEV-L. No prospective intervention will be given.<br>|
| Experimental: 2JEV-I+JEV-L (Group 4)<br>Retrospective: 3 doses of JE vaccines. 2 doses of JEV-I (7-10 days apart) at 8 months of age and 1 dose of JEV-L at 2 years old. | Other: No prospective interventions<br>* The investigators recruit 6 years old children who have been vaccinated by 2-3 doses of JE vaccines with different immunization strategies. Participants from Group 3-5 have completed the JE immunization schedules with JEV-I or/and JEV-L. No prospective intervention will be given.<br>|
| Experimental: 2JEV-L (Group 5)<br>Retrospective: 2 doses of JE vaccines. 2 doses of JEV-L respectively administered at 8 months of age and 2 years old. | Other: No prospective interventions<br>* The investigators recruit 6 years old children who have been vaccinated by 2-3 doses of JE vaccines with different immunization strategies. Participants from Group 3-5 have completed the JE immunization schedules with JEV-I or/and JEV-L. No prospective intervention will be given.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportions of seropositivity of neutralizing antibodies against JE at the age of 6 | Defined as any positive antibody (neutralizing antibody titers ≥1:10) response in children aged 6. | At the age of 6. Test immediately after enrollment by a dose of blood sample. | 
| Geometric Mean Titers (GMTs) or Median antibody titers for children aged 6 years | Neutralizing antibody titers by plaque-reduction neutralization tests (PRNT). | At the age of 6. Test immediately after enrollment by a dose of blood sample. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Seroconversion rates of the booster dose of JEV-I for Group 1 and Group 2 | Defined as any positive antibody (neutralizing antibody titers ≥1:10) response in children who were seronegative prior to the booster dose, or at least a four-fold increase for children who had pre-existing positive antibodies. | before and 28-35 days after the booster dose. | 
| Proportion of seropositivity of neutralizing antibodies against JE after the booster dose for Group 1 and Group 2. | Defined as any positive antibody (neutralizing antibody titers ≥1:10) response after the booster dose. | 28-35 days after the booster dose. | 
| Geometric Mean Titers (GMTs) or Median antibody titers after the booster dose for Group 1 and Group 2. | Neutralizing antibody titers by PRNT. | 28-35 days after the booster dose. | 
| Safety of the booster dose for Group 1 and Group 2 | The occurrence of adverse events for the booster dose | From inoculation to 30 days after the inoculation. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Japanese Encephalitis, Seroprevalence, Immunogenicity, Immunization schedule, Safety