A Phase II, Safety and Efficacy Study of Inactivated EV 71 Vaccine (Human Diploid Cell, KMB-17) in Chinese Infants

Study Overview
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Brief Summary
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Enterovirus 71 (EV71), a major pathogen that is responsible for causing hand-foot-and-mouth disease (HFMD) worldwide, is a member of the Human Enterovirus species A, family Picornaviridae. Since the late 1990s, a series of large HFMD epidemics caused by EV71 have been reported in the Asia-Pacific region. Notably, there is evidence that the most severe cases from these epidemic outbreaks are associated with neurological disorders with CNS involvement caused by EV71 infection. Because of these EV71 infection-related public health issues, the research and development of EV71 vaccine candidates have been heavily promoted. Recently, several EV71 vaccine candidates have been evaluated in animals but no final results of clinical trials, including inactivated vaccine, attenuated vaccine, subunit vaccine, DNA vaccine, epitope peptide vaccine, virus-like particles (VLPs). Basing on the previous studies of elicited protection in mice and rhesus monkeys, a formalin-inactivated EV71 vaccine (Human Diploid cell, KMB-17 Cell) has been licensed by SFDA in China, Dec. 2010. The phase I clinical trial was completed, during four months, in Guangxi Province, China. The phase II clinical trial has been carried out, from July 2011. The purpose of phase II is to evaluate the safety and efficacy of the formalin-inactivated EV71 vaccine in Chinese infants (from 6 to 36 months old).

Detailed Description
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Hand-foot-and-mouth disease (HFMD) is a significant cause of death, usually characterized by vesicular lesions on the skin and oral mucosa and high morbidity rates in children. Additionally, occasional fatal cases have been reported involving brainstem encephalitis and myelitis associated with cardiopulmonary collapse. Pulmonary edema/hemorrhage and respiratory failure are the major causes of death among children less than five years old. Enterovirus 71 (EV71), a major pathogen that is responsible for causing HFMD worldwide, is a member of the Human Enterovirus species A, family Picornaviridae. Since the late 1990s, a series of large HFMD epidemics caused by EV71 have been reported in the Asia-Pacific region. Notably, there is evidence that the most severe cases from these epidemic outbreaks are associated with neurological disorders with CNS involvement caused by EV71 infection. Because of these EV71 infection-related public health issues, the research and development of EV71 vaccine candidates have been heavily promoted. Recently, several EV71 vaccine candidates have been evaluated in animals but no final results of clinical trials, including heat-inactivated or formalin-inactivated vaccine, live-attenuated vaccine, recombinant viral protein 1 (VP1) vaccine, VP1 DNA vaccine, VP1 epitope peptide vaccine, EV71 virus-like particles (VLPs) and bacterial or viral vector expressing VP1. Overall, the inactivated whole-virus vaccines seem to be more immunogenic than recombinant VP1 and DNA vaccines. Basing on the previous studies of elicited protection in mice and rhesus monkeys (Ying Zhang, et al. Pathogenesis study of Enterovirus 71 Infection in Rhesus Monkeys. Lab Invest, 2011, doi:10.1038/labinest.2011.82; Longding Liu, et al. Neonatal Rhesus Monkey is a Potential Animal Model for Studying Pathogenesis of EV71 Infection. Virology, 2011, 412:91-100; Chenghong Dong, et al. Immunoprotection Elicited by an Enterovirus Type 71 Experimental Inactivated Vaccine in Mice and Rhesus Monkeys. Vaccine, 2011, doi: 10.1016/j.vaccine.2011.06.044.), a formalin-inactivated EV71 vaccine (Human Diploid cell, KMB-17 Cell) has been licensed by SFDA in China, Dec. 2010. The phase I clinical trial was completed, during four months, in Guangxi Province, China. The results showed that the formalin-inactivated EV71 vaccine (Human Diploid cell, KMB-17 Cell) was safety in Chinese adults (from 18 to 49 years old), children (from 3 to 11 years old) and infants (from 6 to 35 months old). This vaccine could induce specific cellular and humoral immune responses. The phase II clinical trial has been carried out, from July 2011. The purpose of phase II is to evaluate the safety and efficacy of the formalin-inactivated EV71 vaccine in Chinese infants (from 6 to 36 months old).

Official Title
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A Phase II Clinical Trial for Inactivated Enterovirus Type 71 Vaccine (Human Diploid Cell, KMB-17 Cell) in Chinese Infants

Conditions
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The Study Focused on the Safety of Inactivated EV71 Vaccine (Human Diploid Cell) Against Hand, Foot and Mouth Disease in Chinese Children and Infants

Intervention / Treatment
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* Biological: 160Eu/0.5ml in infants (6-11 months old)
* Biological: 320Eu/0.5ml in infants (6-11 months old)
* Biological: 640Eu/0.5ml in infants (6-11 months old)
* Biological: 1280Eu/0.5ml (without adjuvant) in infants (6-11 months old)
* Biological: 0Eu/0.5ml in infants (6-11 months old)
* Biological: 160Eu/0.5ml in infants (12-23 months old)
* Biological: 320Eu/0.5ml in infants (12-23 months old)
* Biological: 640Eu/0.5ml in infants (12-23 months old)
* Biological: 1280Eu/0.5ml (without adjuvant) in infants (12-23 months old)
* Biological: 0Eu/0.5ml in infants (12-23 months old)
* Biological: 160Eu/0.5ml in children (24 months-5 years old)
* Biological: 320Eu/0.5ml in children (24 months-5 years old)
* Biological: 640Eu/0.5ml in children (24 months-5 years old)
* Biological: 1280Eu/0.5ml (without adjuvant) in children (24 months-5 years old)
* Biological: 0Eu/0.5ml in children (24 months-5 years old)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy subjects (6-35 months infants) as established by medical history and clinical examination Full-term (37-42 weeks), weight ≥ 2500 g when it was born 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 2-month visit and receive blood tests according to program requirements Exclusion Criteria: Subject who has a clinical diagnosis history of Hand, Foot and Mouth Disease (HFMD) 37 weeks gestation weight ≤ 2500 g when it was born Allergy or serious side-effects to a vaccine or any ingredient of vaccine Epilepsy, seizures, convulsions, neurological illness Congenital or hereditary immunodeficiency Autoimmune disease Severe malnutrition or dysgenopathy 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 28 days or 1 months Any prior administration of subunit or inactivated vaccines in last 14 days Under the anti-TB prevention or therapy 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 ﹥140mmHg and/or diastolic blood pressure ﹥90mmHg; systolic blood pressure ﹤90mmHg and/or diastolic blood pressure ﹤60mmHg Any condition that in the opinion of the investigator, may interfere with the evaluation of study objectives

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 5 Years

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 160Eu/0.5ml in infants (6-11 months old)<br>inactivated EV71 vaccine (KMB-17) of 160Eu/0.5ml in 60 infants aged 6-11 months old on day 0, 28 | Biological: 160Eu/0.5ml in infants (6-11 months old)<br>* inactivated EV71 vaccine (KMB-17) of 160Eu/0.5ml in 60 infants aged 6-11 months old on day 0, 28<br>|
| Experimental: 320Eu/0.5ml in infants (6-11 months old)<br>inactivated EV71 vaccine (KMB-17) of 320Eu/0.5ml in 60 infants aged 6-11 months old on day 0, 28 | Biological: 320Eu/0.5ml in infants (6-11 months old)<br>* inactivated EV71 vaccine (KMB-17) of 320Eu/0.5ml in 60 infants aged 6-11 months old on day 0, 28<br>|
| Experimental: 640Eu/0.5ml in infants (6-11 months old)<br>inactivated EV71 vaccine (KMB-17) of 640Eu/0.5ml in 40 infants aged 6-11 months old on day 0, 28 | Biological: 640Eu/0.5ml in infants (6-11 months old)<br>* inactivated EV71 vaccine (KMB-17) of 640Eu/0.5ml in 40 infants aged 6-11 months old on day 0, 28<br>|
| Experimental: 1280Eu/0.5ml in infants (6-11 months old)<br>inactivated EV71 vaccine (KMB-17) of 1280Eu/0.5ml (without adjuvant) in 40 infants aged 6-11 months old on day 0, 28 | Biological: 1280Eu/0.5ml (without adjuvant) in infants (6-11 months old)<br>* inactivated EV71 vaccine (KMB-17) of 1280Eu/0.5ml (without adjuvant) in 40 infants aged 6-11 months old on day 0, 28<br>|
| Placebo Comparator: 0Eu/0.5ml in infants (6-11 months old)<br>0Eu/0.5ml placebo in 80 infants aged 6-11 months old on day 0, 28 | Biological: 0Eu/0.5ml in infants (6-11 months old)<br>* 0Eu/0.5ml placebo in 80 infants aged 6-11 months old on day 0, 28<br>|
| Experimental: 160Eu/0.5ml in infants (12-23 months old)<br>inactivated EV71 vaccine (KMB-17) of 160Eu/0.5ml in 30 infants aged 12-23 months old on day 0, 28 | Biological: 160Eu/0.5ml in infants (12-23 months old)<br>* inactivated EV71 vaccine (KMB-17) of 160Eu/0.5ml in 30 infants aged 12-23 months old on day 0, 28<br>|
| Experimental: 320Eu/0.5ml in infants (12-23 months old)<br>inactivated EV71 vaccine (KMB-17) of 320Eu/0.5ml in 30 infants aged 12-23 months old on day 0, 28 | Biological: 320Eu/0.5ml in infants (12-23 months old)<br>* inactivated EV71 vaccine (KMB-17) of 320Eu/0.5ml in 30 infants aged 12-23 months old on day 0, 28<br>|
| Experimental: 640Eu/0.5ml in infants (12-23 months old)<br>inactivated EV71 vaccine (KMB-17) of 640Eu/0.5ml in 40 infants aged 12-23 months old on day 0, 28 | Biological: 640Eu/0.5ml in infants (12-23 months old)<br>* inactivated EV71 vaccine (KMB-17) of 640Eu/0.5ml in 40 infants aged 12-23 months old on day 0, 28<br>|
| Experimental: 1280Eu/0.5ml in infants (12-23 months old)<br>inactivated EV71 vaccine (KMB-17) of 1280Eu/0.5ml (without adjuvant) in 40 infants aged 12-23 months old on day 0, 28 | Biological: 1280Eu/0.5ml (without adjuvant) in infants (12-23 months old)<br>* inactivated EV71 vaccine (KMB-17) of 1280Eu/0.5ml (without adjuvant) in 40 infants aged 12-23 months old on day 0, 28<br>|
| Placebo Comparator: 0Eu/0.5ml in infants (12-23 months old)<br>0Eu/0.5ml placebo in 50 infants aged 12-23 months old on day 0, 28 | Biological: 0Eu/0.5ml in infants (12-23 months old)<br>* 0Eu/0.5ml placebo in 50 infants aged 12-23 months old on day 0, 28<br>|
| Experimental: 160Eu/0.5ml in children (24 months-5 years old)<br>inactivated EV71 vaccine (KMB-17) of 160Eu/0.5ml in 30 children aged 24 months-5 years months old on day 0, 28 | Biological: 160Eu/0.5ml in children (24 months-5 years old)<br>* inactivated EV71 vaccine (KMB-17) of 160Eu/0.5ml in 30 children aged 24 months-5 years months old on day 0, 28<br>|
| Experimental: 320Eu/0.5ml in children (24 months-5 years old)<br>inactivated EV71 vaccine (KMB-17) of 320Eu/0.5ml in 30 children aged 24 months-5 years months old on day 0, 28 | Biological: 320Eu/0.5ml in children (24 months-5 years old)<br>* inactivated EV71 vaccine (KMB-17) of 320Eu/0.5ml in 30 children aged 24 months-5 years months old on day 0, 28<br>|
| Experimental: 640Eu/0.5ml in children (24 months-5 years old)<br>inactivated EV71 vaccine (KMB-17) of 640Eu/0.5ml in 40 children aged 24 months-5 years months old on day 0, 28 | Biological: 640Eu/0.5ml in children (24 months-5 years old)<br>* inactivated EV71 vaccine (KMB-17) of 640Eu/0.5ml in 40 children aged 24 months-5 years months old on day 0, 28<br>|
| Experimental: 1280Eu/0.5ml in children (24 months-5 years old)<br>inactivated EV71 vaccine (KMB-17) of 1280Eu/0.5ml (without adjuvant) in 40 children aged 24 months-5 years months old on day 0, 28 | Biological: 1280Eu/0.5ml (without adjuvant) in children (24 months-5 years old)<br>* inactivated EV71 vaccine (KMB-17) of 1280Eu/0.5ml in 40 children aged 24 months-5 years months old on day 0, 28<br>|
| Placebo Comparator: 0Eu/0.5ml in children (24 months-5 years old)<br>0Eu/0.5ml placebo in 50 children aged 24 months-5 years old on day 0, 28 | Biological: 0Eu/0.5ml in children (24 months-5 years old)<br>* 0Eu/0.5ml placebo in 50 children aged 24 months-5 years old on day 0, 28<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety of Inactivated EV 71 Vaccine (Human Diploid Cell, KMB-17) in Chinese Infants (from 6 to 11 months old) | Adverse reactions associated with vaccine were observed in Chinese Infants (from 6 to 11 months old) after the first vaccination. | within the first 28 days after the first vaccination | 
| Evaluate the safety of Inactivated EV 71 Vaccine (Human Diploid Cell, KMB-17) in Chinese Infants (from 12 to 23 months old) | Adverse reactions associated with vaccine were observed in Chinese Infants (from 12 to 23 months old) after the first vaccination | within the first 28 days after the first vaccination | 
| Evaluate the safety of Inactivated EV 71 Vaccine (Human Diploid Cell, KMB-17) in Chinese children (from 24 months to 5 years old) | Adverse reactions associated with vaccine were observed in Chinese children (from 24 months to 5 years old) after the first vaccination | within the first 28 days after the first vaccination | 
| Evaluate the safety of Inactivated EV 71 Vaccine (Human Diploid Cell, KMB-17) in Chinese Infants (from 6 to 11 months old) | Adverse reactions associated with vaccine were observed in Chinese Infants (from 6 to 11 months old) after the second vaccination | within the first 56 days after the second vaccination | 
| Evaluate the safety of Inactivated EV 71 Vaccine (Human Diploid Cell, KMB-17) in Chinese Infants (from 12 to 23 months old) | Adverse reactions associated with vaccine were observed in Chinese Infants (from 12 to 23 months old) after the second vaccination | within the first 56 days after the second vaccination | 
| Evaluate the safety of Inactivated EV 71 Vaccine (Human Diploid Cell, KMB-17) in Chinese children (from 24 months to 5 years old) | Adverse reactions associated with vaccine were observed in Chinese children (from 24 months to 5 years old) after the second vaccination | within the first 56 days after the second vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the seroconversion rate of anti-EV71 antibodies in serum of children and infant, after first vaccination | The seroconversion rate of anti-EV71 antibodies was evaluated in serum of children and infant, at the 28 day after the first vaccination | at the 28 day after the first vaccination | 
| Evaluate the seroconversion rate of anti-EV71 antibodies in serum of children and infant, after second vaccination | The seroconversion rate of anti-EV71 antibodies was evaluated in serum of children and infant, at the 28 or 56 days after the second vaccination | at the 28 or 56 days after the second vaccination | 
| Evaluate the seroconversion rate of antinuclear antibodies in serum of children and infant, after first vaccination | The seroconversion rate of antinuclear antibodies was evaluated in serum of children and infant, at the 28 day after the first vaccination | at the 28 day after the first vaccination | 
| Evaluate the seroconversion rate of antinuclear antibodies in serum of children and infant, after second vaccination | The seroconversion rate of antinuclear antibodies was evaluated in serum of children and infant, the 28 or 56 days after the second vaccination | at the 28 or 56 days after the second vaccination | 
| Evaluate the abnormity change of live and kidney function indexes in serum of children and infant, after first vaccination | The abnormity change of live and kidney function indexes were evaluated in serum of children and infant, at the 28 days after the first vaccination | at the 28 days after the first vaccination | 
| Evaluate the abnormity change of live and kidney function indexes in serum of children and infant, after second vaccination | The abnormity change of live and kidney function indexes were evaluated in serum of children and infant, the 28 or 56 days after the second vaccination | at the 28 or 56 days after the second vaccination | 
| Evaluate the abnormity change of body temperature of children and infant, after first vaccination | The abnormity change of body temperature of children and infant were evaluated, at the 28 days after the first vaccination | within the first 28 days after the first vaccination | 
| Evaluate the abnormity change of body temperature of children and infant, after second vaccination | The abnormity change of body temperature of children and infant were evaluated, within the first 56 days after the second vaccination | within the first 56 days after the second vaccination | 
| Evaluate the vaccine-induced cellular immune responses in children and infant after first vaccination | The vaccine-induced cellular immune responses were evaluated in serum of children and infant, at the 28 day after the first vaccination | at the 28 day after the first vaccination | 
| Evaluate the vaccine-induced cellular immune responses in children and infant after second vaccination | The vaccine-induced cellular immune responses were evaluated in serum of children and infant, at the 28 or 56 days after the second vaccination | at the 28 or 56 days after the second vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human Enterovirus 71 (EV71), Hand, Foot and Mouth Disease, Inactivated Vaccine, Human Diploid cell, Safety, Immunogenicity, Adverse reactions associated with vaccine