A Clinical Trial to Assess the Efficacy and Safety of an Inactivated Vaccine (Vero Cell) Against EV71 in Chinese Children Aged 6-35 Months

A Multiple-center Randomized Double-blind Placebo-controlled Phase 3 Clinical Trial to Assess the Efficacy and Safety of an Inactivated Vaccine (Vero Cell) Against EV71 in Chinese Children Aged 6-35 Months

Since its discovery in 1969, enterovirus 71 (EV71) has been recognised as a frequent cause of epidemics of hand-foot-mouth disease (HFMD) associated with severe neurological sequelae in a small proportion of cases. There has been a significant increase in EV71 epidemic activity throughout the Asia-Pacific region since 1997. Recent HFMD epidemics in this region have heen associated with a severe from of brainstem encephalitis associated with pulmonary oedema and high case-fatality rates.

The data from the phase 1 and 2 trials suggested that the inactivated EV71 vaccine had a clinically acceptable safety and good immunogenicity for healthy Chinese children and infants. According to the immunogenicity and safety results, the 320U with adjuvant with immunizing schedule of two doses (per 28 day) will be applied in phase 3 clinical trial.

Study Overview

• Status: Completed
• Conditions: Hand, Foot and Mouth Disease; Herpangina; Other EV71-associated Diseases
• Intervention / Treatment: Biological: inactivated vaccine (Vero Cell) against EV71; Biological: 0/0.5ml placebo

• Study Type: Interventional
• Enrollment (Actual): 10245
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Chaoyang Distinct Center for Disease Control and Prevention
  • Jiangsu
    • Lianyungang, Jiangsu, China
      • Donghai County Center for Disease Control and Prevention
    • Xuzhou, Jiangsu, China
      • Pizhou County-Level City Center for Disease Control and Prevention
    • Yangzhou, Jiangsu, China
      • Baoying County Center for Disease Control and Prevention

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 2 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Only subjects fulfilling all of the following criteria will be eligible for the study:

• Healthy children aged from 6 to 35 months old
• General good health as established by medical history and physical examination
• The subjects' guardians are able to understand and sign the informed consent
• Had never received the vaccine against EV71
• The subjects' guardians allow to comply with the requirements of the protocol
• Available for all visits scheduled in this study
• Subjects with temperature <=37.0°C on axillary setting

Exclusion Criteria:

Subjects will not be eligible for the study if any of the following criteria is met:

• Subject who has a medical history of HFMD
• Subject that has a medical history of any of the following: allergic history, or allergic to any ingredient of vaccine
• Family history of seizures or progressive neurological disease
• Family history of congenital or hereditary immunodeficiency
• Severe malnutrition or hypogenesis
• Major congenital defects or serious chronic illness, including perinatal brain damage
• Autoimmune disease
• Bleeding disorder diagnosed by a doctor or significant bruising or bleeding difficulties with IM injections or blood draws
• Asplenia, functional asplenia, or splenic excision
• History of asthma, angioneurotic edema, diabetes or malignant tumour
• History of thyroidectomy, or thyroid disease in last 12 months
• Any acute infections 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 other research vaccines or medicines in last 1 month
• Any prior administration of attenuated live vaccine in last 15 days
• Any prior administration of subunit or inactivated vaccines in last 7 days
• Under the anti-TB prevention or therapy
• Subjects with temperature >37.0°C on axillary setting
• Any condition that in the opinion of the investigator, may interfere with the evaluation of study objectives

Exclusion Criteria for the second dose:

Subjects will not be eligible for the second dose if any of following adverse events happened after the first dose. They can continue other process of the study without the second dose vaccination according to the opinion of the investigator.

• Had any serious adverse events related to the first dose of inactivated vaccine (vero cell) against EV71 within 7 days
• Hypersensitivity reactions after vaccination (including urticaria/rashes that occur within 30 minutes after inoculation)
• Anaphylaxis after vaccination
• Any confirmed or suspected autoimmune disease or immune deficiency diseases, including human immunodeficiency virus (HIV) infection
• Any condition that in the opinion of the investigator, or IRB

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: vaccine against EV71; Inactivated vaccine (Vero Cell) against EV71 of 320U /0.5ml in 5000 children aged 6-35 months on day0, 28	Biological: inactivated vaccine (Vero Cell) against EV71; inactivated vaccine (vero cell) against EV71, 320U /0.5ml, two doses, on day0, 28
Placebo Comparator: placebo; 0/0.5ml placebo in 5000 children aged 6-35 months on day0, 28	Biological: 0/0.5ml placebo; 0/0.5ml placebo, two doses, on day0, 28

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the incidence density of the EV71-associated diseases in the vaccine group and placebo group.	compare the incidence density of the EV71-associated diseases between the vaccine group and placebo group in Chinese children aged 6-35 months.	begin at day 56 up to 14 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the frequency of all the adverse events in vaccine group and placebo group.	compare frequency of all the solicited events, unsolicited adverse events and serious adverse events between vaccine group and placebo group.	up to 14 months
Seropositive rate of the vaccine group	calculate the seropositive rate of the vaccine group in Chinese children aged 6-35 months at month 8 after first vaccination.	8 months after first vaccination
Seroconversion rate of the vaccine group	calculate the seroconversion rate of the vaccine group in Chinese children aged 6-35 months at month 8 after first vaccination.	8 months after first vaccination
GMT of the vaccine group	calculate the geometric mean titre (GMT) of the vaccine group in Chinese children aged 6-35 months at month 8 after first vaccination.	8 months after first vaccination
Seropositive rate of the vaccine group	calculate the seropositive rate of the vaccine group in Chinese children aged 6-35 months at month 14 after first vaccination.	14 months after first vaccination
Seroconversion rate of the vaccine group	calculate the seroconversion rate of the vaccine group in Chinese children aged 6-35 months at month 14 after first vaccination.	14 months after first vaccination
GMT of the vaccine group	calculate the geometric mean titre (GMT) of the vaccine group in Chinese children aged 6-35 months at month 14 after first vaccination.	14 months after first vaccination
Seropositive rate of the vaccine group and placebo group	compare the seropositive rate of the vaccine group and placebo group in healthy children aged 6-35 months.	28 days after the second vaccination
Seroconversion rate of the vaccine group and placebo group	compare the Seroconversion rate of the vaccine group and placebo group in healthy children aged 6-35 months.	28 days after the second vaccination
GMT of the vaccine group and placebo group	compare the geometric mean titre (GMT) of the vaccine group and placebo group in healthy children aged 6-35 months.	28 days after the second vaccination
GMI of the vaccine group and placebo group	compare the geometric mean fold increase (GMFI) of the vaccine group and placebo group in healthy children aged 6-35 months.	28 days after the second vaccination

Collaborators and Investigators

• Sponsor: Jiangsu Province Centers for Disease Control and Prevention
• Collaborators: Bejing Vigoo Biological Co., LTD

Publications and helpful links

General Publications

• Zhu W, Jin P, Li JX, Zhu FC, Liu P. Correlates of protection for inactivated enterovirus 71 vaccine: the analysis of immunological surrogate endpoints. Expert Rev Vaccines. 2017 Sep;16(9):945-949. doi: 10.1080/14760584.2017.1335603. Epub 2017 Jun 12.
• Wei M, Meng F, Wang S, Li J, Zhang Y, Mao Q, Hu Y, Liu P, Shi N, Tao H, Chu K, Wang Y, Liang Z, Li X, Zhu F. 2-Year Efficacy, Immunogenicity, and Safety of Vigoo Enterovirus 71 Vaccine in Healthy Chinese Children: A Randomized Open-Label Study. J Infect Dis. 2017 Jan 1;215(1):56-63. doi: 10.1093/infdis/jiw502. Epub 2016 Oct 17.
• Zhu FC, Meng FY, Li JX, Li XL, Mao QY, Tao H, Zhang YT, Yao X, Chu K, Chen QH, Hu YM, Wu X, Liu P, Zhu LY, Gao F, Jin H, Chen YJ, Dong YY, Liang YC, Shi NM, Ge HM, Liu L, Chen SG, Ai X, Zhang ZY, Ji YG, Luo FJ, Chen XQ, Zhang Y, Zhu LW, Liang ZL, Shen XL. Efficacy, safety, and immunology of an inactivated alum-adjuvant enterovirus 71 vaccine in children in China: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2013 Jun 8;381(9882):2024-32. doi: 10.1016/S0140-6736(13)61049-1. Epub 2013 May 29.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: January 4, 2012
• First Submitted That Met QC Criteria: January 10, 2012
• First Posted (Estimate): January 11, 2012

Study Record Updates

• Last Update Posted (Estimate): March 29, 2013
• Last Update Submitted That Met QC Criteria: March 27, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: safety; efficacy; inactivated vaccine (Vero Cell) against EV71; EV71-associated diseases
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Stomatognathic Diseases; Enterovirus Infections; Picornaviridae Infections; Coxsackievirus Infections; Echovirus Infections; Mouth Diseases; Foot-and-Mouth Disease; Hand, Foot and Mouth Disease; Herpangina
• Other Study ID Numbers: JSVCT010