The Phase IVd of Inactivated Enterovirus 71 Vaccine

Study Overview
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Brief Summary
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Enterovirus 71 (EV71), a major pathogen causing hand-foot-and-mouth disease (HFMD) worldwide, is a member of the Human Enterovirus species A, family Picornaviridae. Its infection occasionally leads to severe diseases and death, with central nervous system (CNS) damage. Recently, except of inactivated vaccine, several EV71 vaccine candidates have been evaluated in animals but no final results of clinical trials, such as attenuated vaccine, subunit vaccine. A formalin-inactivated EV71 vaccine (Human Diploid cell, KMB-17 Cell) has been finished phase I, II and III clinical trials and licensed by SFDA in China at Dec. 3, 2015. Based on the results of clinical trials, the protective efficacy of inactivated EV71 vaccine is 97% against HFMD caused by EV71. The phase IV clinical trial has been carried out from July 2016. The purpose of phase IVd is to evaluated the immunogenicity and safety of the inactive EV71 vaccine within two measles attenuated live vaccine and live attenuated Japanese encephalitis vaccine at the same time point in large scale population of Chinese children (8 months old) in Guangdong Province, China.

Detailed Description
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There are two parts of phase IVd clinical trials have been performed. First, to evaluate the immunogenicity of the inactive EV71 vaccine within two measles attenuated live vaccine and live attenuated Japanese encephalitis vaccine at the same time point in large scale population of Chinese children (8 months old), within 56-day-post-immunized. Second, to safety of the inactive EV71 vaccine within two measles attenuated live vaccine and live attenuated Japanese encephalitis vaccine at the same time point in large scale population of Chinese children (8 months old), within 56-day-post-immunized.

Official Title
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The Safety and Immunogenicity of Enterovirus Type 71 Inactivated Vaccine (Human Diploid Cell) With Two Measles Attenuated Live Vaccine and Live Attenuated Japanese Encephalitis Vaccine at the Same Time Point in Infants (8-month-old)

Conditions
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Hand, Foot and Mouth Disease (HFMD)

Intervention / Treatment
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* Biological: EV71 and two measles attenuated live vaccine
* Biological: EV71 and attenuated Japanese encephalitis vaccine
* Biological: two measles attenuated live vaccine
* Biological: live attenuated Japanese encephalitis vaccine
* Biological: EV71 vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy subjects (6-71 months old children) as established by medical history and clinical examination The subjects' legal guardian must be aware of this vaccines The subjects' legal guardian voluntarily participate in the study and signed Informed Consent Form Subjects with temperature ≤ 37.0 ℃ The subjects' legal guardian with the ability and objective to comply with the requirements of the protocol Persist for a 14-month visit (and receive blood, stool (or specimens by means of a swab) tests according to program requirements in immunogenicity observation group) Exclusion Criteria: Allergy or serious side-effects to a vaccine or any ingredient of vaccine Epilepsy, seizures, convulsions, neurological illness Congenital or hereditary immunodeficiency Autoimmune disease Asthma, thyroidectomy, angioneurotic edema, diabetes or cancer Asplenia, functional asplenia, and any circumstances leading to the asplenia or splenectomy Clinical diagnosis of coagulopathy (such as clotting factor deficiency, coagulation disorders, platelet abnormalities), significant bruising or blood clotting disorder Acute illness or acute exacerbation of chronic disease in last 7 days Any prior administration of immunodepressant or corticosteroids in last 6 months Any prior administration of blood products in last 3 months Any prior administration of live-attenuated vaccine in last 15 days Any prior administration of subunit or inactivated vaccines in last 7 days Fever before vaccination, axillary temperature ﹥37.0 ℃ The laboratory test abnormalities before vaccination, including blood tests (hemoglobin, total white blood cells, WBC, platelets), blood biochemistry tests (ALT, total bilirubin, direct bilirubin, Cr, BUN) and urine tests (urine protein, urine sugar, blood cells), etc. Hypertension or hypotension. Systolic blood pressure ﹥140 mmHg and/ or diastolic blood pressure ﹥90 mmHg; systolic blood pressure ﹤90 mmHg and/or diastolic blood pressure ﹤60 mmHg Any condition that in the opinion of the investigator, may interfere with the evaluation of study objectives take part into other vaccine or drug clinical trials in last half year

Ages Eligible for Study
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Minimum Age: 8 Months
Maximum Age: 9 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EV71 and two measles attenuated live vaccine<br>infants vaccinated with enterovirus type 71 inactivated vaccine (human diploid cell) and two measles attenuated live vaccine at 8 months old, and vaccinated with the second dose of enterovirus type 71 inactivated vaccine (human diploid cell) at 9 months old. | Biological: EV71 and two measles attenuated live vaccine<br>* infants vaccined with two dose (3.0 EU/dose) of inactivated enterovirus 71 vaccine (KMB-17) at 8 months old and 9 months old (namely interval one month). And meanwhile, they routine vaccined with two measles attenuated live vaccine at 8 months old.<br>|
| Experimental: EV71 and attenuated Japanese encephalitis vaccine<br>infants vaccinated with enterovirus type 71 inactivated vaccine (human diploid cell) and live attenuated Japanese encephalitis vaccine at 8 months old, and vaccinated with the second dose of enterovirus type 71 inactivated vaccine (human diploid cell) at 9 months old. | Biological: EV71 and attenuated Japanese encephalitis vaccine<br>* infants vaccined with two dose (3.0 EU/dose) of inactivated enterovirus 71 vaccine (KMB-17) at 8 months old and 9 months old (namely interval one month). And meanwhile, they routine vaccined with attenuated Japanese encephalitis vaccine at 8 months old.<br>|
| Active Comparator: two measles attenuated live vaccine<br>infants vaccinated with two measles attenuated live vaccine at 8 months old | Biological: two measles attenuated live vaccine<br>* infants vaccined with one dose two measles attenuated live vaccine at 8 months old.<br>|
| Active Comparator: live attenuated Japanese encephalitis vaccine<br>infants vaccinated with live attenuated Japanese encephalitis vaccine at 8 months old | Biological: live attenuated Japanese encephalitis vaccine<br>* infants vaccined with one dose attenuated Japanese encephalitis vaccine at 8 months old.<br>|
| Active Comparator: EV71 vaccine<br>infants vaccinated with enterovirus type 71 inactivated vaccine (human diploid cell) at 8 months old, and vaccinated with the second dose of enterovirus type 71 inactivated vaccine (human diploid cell) at 9 months old. | Biological: EV71 vaccine<br>* infants vaccined with two dose (3.0 EU/dose) of inactivated enterovirus 71 vaccine (KMB-17) at 8 months old and 9 months old (namely interval one month).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the seropositive rate of anti-EV71 antibodies in serum of children before first vaccination | Bloods were obtained before first vaccination. The antibody titers were tested in serum of children. | at 0 day before finishing 1st doses immunization | 
| Evaluate the seropositive rate of anti-EBV antibodies in serum of children before first vaccination | Bloods were obtained before first vaccination. The antibody titers were tested in serum of children. | at 0 day before finishing 1st doses immunization | 
| Evaluate the seropositive rate of anti-measles virus antibodies in serum of children before first vaccination | Bloods were obtained before first vaccination. The antibody titers were tested in serum of children. | at 0 day before finishing 1st doses immunization | 
| Evaluate the seropositive rate of anti-Rubella virus antibodies in serum of children before first vaccination | Bloods were obtained before first vaccination. The antibody titers were tested in serum of children. | at 0 day before finishing 1st doses immunization | 
| Evaluate the seroconversion rate of anti-EV71 antibodies in serum of children at 56 days after first vaccination | Bloods were obtained at 56 days after first vaccination. The antibody titers were tested in serum of children. | at 56 days after finishing 1st doses immunization | 
| Evaluate the seroconversion rate of anti-EBV antibodies in serum of children at 56 days after first vaccination | Bloods were obtained at 56 days after first vaccination. The antibody titers were tested in serum of children. | at 56 days after finishing 1st doses immunization | 
| Evaluate the seroconversion rate of anti-measles virus antibodies in serum of children at 56 days after first vaccination | Bloods were obtained at 56 days after first vaccination. The antibody titers were tested in serum of children. | at 56 days after finishing 1st doses immunization | 
| Evaluate the seroconversion rate of anti-Rubella virus antibodies in serum of children at 56 days after first vaccination | Bloods were obtained at 56 days after first vaccination. The antibody titers were tested in serum of children. | at 56 days after finishing 1st doses immunization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the antibody titers of anti-EV71 antibodies in serum of children | Bloods were obtained at 56 days after first vaccination. The antibody titers were tested in serum of children at 56 days. | at 56 days after finishing 1st doses immunization | 
| Evaluate the antibody titers of anti-EBV antibodies in serum of children | Bloods were obtained at 56 days after first vaccination. The antibody titers were tested in serum of children at 56 days. | at 56 days after finishing 1st doses immunization | 
| Evaluate the antibody titers of anti-measles virus antibodies in serum of children | Bloods were obtained at 56 days after first vaccination. The antibody titers were tested in serum of children at 56 days. | at 56 days after finishing 1st doses immunization | 
| Evaluate the antibody titers of anti-Rubella virus antibodies in serum of children | Bloods were obtained at 56 days after first vaccination. The antibody titers were tested in serum of children at 56 days. | at 56 days after finishing 1st doses immunization | 
| Incidence of treatment adverse events finishing 1st doses immunization | The adverse events were observed and recorded within 30 minutes post immunization (p.i.), within 0-1 days post immunization (d.p.i.), within 1-3 d.p.i. and within 28 d.p.i. after the 1st injection. | within 28 days after finishing 1st doses immunization | 
| Incidence of treatment adverse events finishing 2nd doses immunization | The adverse events were observed and recorded within 30 minutes post immunization (p.i.), within 0-1 days post immunization (d.p.i.), within 1-3 d.p.i. and within 28 d.p.i. after injection. | within 28 days after finishing 2nd doses immunization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hand, Foot and Mouth Disease (HFMD), immunogenicity, safety