Clinical trial NCT01014845: Clinical Trial of Recombinant Hepatitis E Vaccine
Official title: A Phase 3, Randomized, Double-blind, Placebo (Hepatitis B Vaccine) Controlled Clinical Trial of Recombinant (E. Coli) Hepatitis E Vaccine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatitis E
Keywords: hepatitis E
vaccine
efficacy
Lead sponsor: Xiamen University
Sponsor class: OTHER
Collaborators: name: Xiamen Innovax Biotech Co., Ltd
name: Beijing Wantai Biological Pharmacy Enterprise Co., Ltd.
name: National Institute of Diagnostics and Vaccine Development in infectious disease
name: Jiangsu Provincial Center for Disease Control and Prevention
First posted: 2009-11-17
Enrollment: 112604
Sex: ALL
Minimum age (years): 16
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The primary purpose of this study is to determine whether the preventive hepatitis E are effective in the prevention of hepatitis E occurring at least 30 days after the administration of the third dose of vaccine.

The secondary purpose of this study is to to evaluate the safety and immunogenicity and immunopersistence of the study vaccine.

The initial study is planed to be ended on month 19 and the results were analysed and used for registration purpose. The extended study will be continued to assess the long-term efficacy, immunogenicity and safety.

Detailed description: Participants were randomly allocated into two groups, one received Hepatitis E vaccine and the other received hepatitis B vaccine. The study was carried out with two stages. In the first stage (phase 3a), 2 645 subjects was enrolled and actively monitored for solicited adverse events for 1 month after each injection. Serum samples from all the subjects were collected on day 0, 7m, 13m, 19m and timely after then to evaluate the immunogenicity and immuno-persistency. In the second stage (phase 3b), another 109 959 subjects was enrolled and monitored for solicited adverse events for 1 month after each injection. Serum samples from 9764 subjects among the phase 3b participants were collected on day 0, 7m, 19m and timely after then to evaluate the immunogenicity and immuno-persistency. Serious adverse events during the trial were followed up.

Suspected hepatitis cases were identified through an established active hepatitis surveillance system. The sentinels of the system comprised all the healthcare facilities in the field. Suspected hepatitis was defined as when patients presented with systemic symptoms such as fatigue and/or loss of appetite for more than 3 days with alanine aminotransferase (ALT) exceeding 2.5 fold upper limit of normal range (ULN). Paired sera were obtained from these patients at the time of presentation and 2-6 weeks later. Sera were tested for the HEV antibodies and HEV-RNA.

Eligibility criteria: Inclusion Criteria:

* Healthy people aged from 16 years to 65 years old at the time of the first vaccination, normal intelligence and agree to sign the informed consent form.
* Subjects will reside in the study region in the next 19 months.
* Free of history of hepatitis B or hepatitis E.
* Can comply with the request of study.
* Axillary temperature is below 37 degree centigrade.

Exclusion Criteria:

For dose 1:

* Having other vaccine or immunoglobulin within two weeks;
* Having allergic history to vaccine and medicine
* Eclampsia, epilepsy, encephalopathy and history of mental disease or family;
* Thrombocytopenia or other disturbance of blood coagulation which would lead to muscle injection taboo;
* Fixed or suspected deficiency of immunologic function, containing immunosuppressant treatment(radiation therapy, chemical treatment, steroid hormone, antimetabolites, cytotoxic drugs), genetic defect(e.g. fabism), HIV or other factors;
* congenital malformation, eccyliosis or severe chronic disease(e.g. Down Syndrome, diabetes, sickle cell anemia or mental disease);
* fixed or suspected other disease including fever, active infection, liver and kidney disease, angiocardiopathy, malignancy, acute and chronic disease;
* joining other clinical study undergoing;
* women pregnant or in lactation.

For dose 2 or 3:

* Severe allergy for dose 1 or 2;
* Severe adverse reaction associated with last vaccination;
* New occurrence of symptoms meet dose 1 exclusion criteria after the first dose.

Primary outcomes:
measure: Rate of confirmed hepatitis E cases
timeFrame: One year since one month post the third injection
Secondary outcomes:
measure: IgG anti-HEV seroconversion rate
timeFrame: On one month post the third injection
measure: Persistency of IgG anti-HEV
timeFrame: One year
Other outcomes:
Locations:
city: Dongtai
country: China
facility: Dongtai Center for Disease Control and Prevention
state: Jiangsu
Study officials:
affiliation: National Institute of Diagnostics and Vaccine Development in infectious disease, Xiamen University
name: Jun Zhang, M.D.
role: STUDY_DIRECTOR
affiliation: Jiangsu Provincial Center for Disease Control and Prevention, China
name: Feng-Cai Zhu, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zhang J, Liu CB, Li RC, Li YM, Zheng YJ, Li YP, Luo D, Pan BB, Nong Y, Ge SX, Xiong JH, Shih JW, Ng MH, Xia NS. Randomized-controlled phase II clinical trial of a bacterially expressed recombinant hepatitis E vaccine. Vaccine. 2009 Mar 13;27(12):1869-74. doi: 10.1016/j.vaccine.2008.12.061. Epub 2009 Jan 23.
citation: Li S, Tang X, Seetharaman J, Yang C, Gu Y, Zhang J, Du H, Shih JW, Hew CL, Sivaraman J, Xia N. Dimerization of hepatitis E virus capsid protein E2s domain is essential for virus-host interaction. PLoS Pathog. 2009 Aug;5(8):e1000537. doi: 10.1371/journal.ppat.1000537. Epub 2009 Aug 7.
citation: He S, Miao J, Zheng Z, Wu T, Xie M, Tang M, Zhang J, Ng MH, Xia N. Putative receptor-binding sites of hepatitis E virus. J Gen Virol. 2008 Jan;89(Pt 1):245-249. doi: 10.1099/vir.0.83308-0.
citation: Li SW, Zhang J, Li YM, Ou SH, Huang GY, He ZQ, Ge SX, Xian YL, Pang SQ, Ng MH, Xia NS. A bacterially expressed particulate hepatitis E vaccine: antigenicity, immunogenicity and protectivity on primates. Vaccine. 2005 Apr 22;23(22):2893-901. doi: 10.1016/j.vaccine.2004.11.064.
citation: Zhang J, Gu Y, Ge SX, Li SW, He ZQ, Huang GY, Zhuang H, Ng MH, Xia NS. Analysis of hepatitis E virus neutralization sites using monoclonal antibodies directed against a virus capsid protein. Vaccine. 2005 Apr 22;23(22):2881-92. doi: 10.1016/j.vaccine.2004.11.065.
citation: Li SW, Zhang J, He ZQ, Gu Y, Liu RS, Lin J, Chen YX, Ng MH, Xia NS. Mutational analysis of essential interactions involved in the assembly of hepatitis E virus capsid. J Biol Chem. 2005 Feb 4;280(5):3400-6. doi: 10.1074/jbc.M410361200. Epub 2004 Nov 22.
citation: Zhu FC, Zhang J, Zhang XF, Zhou C, Wang ZZ, Huang SJ, Wang H, Yang CL, Jiang HM, Cai JP, Wang YJ, Ai X, Hu YM, Tang Q, Yao X, Yan Q, Xian YL, Wu T, Li YM, Miao J, Ng MH, Shih JW, Xia NS. Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial. Lancet. 2010 Sep 11;376(9744):895-902. doi: 10.1016/S0140-6736(10)61030-6. Epub 2010 Aug 20.
citation: Wu T, Huang SJ, Zhu FC, Zhang XF, Ai X, Yan Q, Wang ZZ, Yang CL, Jiang HM, Liu XH, Guo M, Du HL, Ng MH, Zhang J, Xia NS. Immunogenicity and safety of hepatitis E vaccine in healthy hepatitis B surface antigen positive adults. Hum Vaccin Immunother. 2013 Nov;9(11):2474-9. doi: 10.4161/hv.25814. Epub 2013 Jul 25.
citation: Wu T, Zhu FC, Huang SJ, Zhang XF, Wang ZZ, Zhang J, Xia NS. Safety of the hepatitis E vaccine for pregnant women: a preliminary analysis. Hepatology. 2012 Jun;55(6):2038. doi: 10.1002/hep.25522. No abstract available.
citation: Zhu FC, Huang SJ, Wu T, Zhang XF, Wang ZZ, Ai X, Yan Q, Yang CL, Cai JP, Jiang HM, Wang YJ, Ng MH, Zhang J, Xia NS. Epidemiology of zoonotic hepatitis E: a community-based surveillance study in a rural population in China. PLoS One. 2014 Jan 31;9(1):e87154. doi: 10.1371/journal.pone.0087154. eCollection 2014.
citation: Zhang J, Zhang XF, Zhou C, Wang ZZ, Huang SJ, Yao X, Liang ZL, Wu T, Li JX, Yan Q, Yang CL, Jiang HM, Huang HJ, Xian YL, Shih JW, Ng MH, Li YM, Wang JZ, Zhu FC, Xia NS. Protection against hepatitis E virus infection by naturally acquired and vaccine-induced immunity. Clin Microbiol Infect. 2014 Jun;20(6):O397-405. doi: 10.1111/1469-0691.12419. Epub 2013 Nov 18.
citation: Kmush BL, Yu H, Huang S, Zhang X, Wu T, Nelson KE, Labrique AB. Long-term Antibody Persistence After Hepatitis E Virus Infection and Vaccination in Dongtai, China. Open Forum Infect Dis. 2019 Mar 28;6(4):ofz144. doi: 10.1093/ofid/ofz144. eCollection 2019 Apr.
citation: Chen S, Zhou Z, Wei FX, Huang SJ, Tan Z, Fang Y, Zhu FC, Wu T, Zhang J, Xia NS. Modeling the long-term antibody response of a hepatitis E vaccine. Vaccine. 2015 Aug 7;33(33):4124-9. doi: 10.1016/j.vaccine.2015.06.050. Epub 2015 Jun 28.
citation: Zhang J, Zhang XF, Huang SJ, Wu T, Hu YM, Wang ZZ, Wang H, Jiang HM, Wang YJ, Yan Q, Guo M, Liu XH, Li JX, Yang CL, Tang Q, Jiang RJ, Pan HR, Li YM, Shih JW, Ng MH, Zhu FC, Xia NS. Long-term efficacy of a hepatitis E vaccine. N Engl J Med. 2015 Mar 5;372(10):914-22. doi: 10.1056/NEJMoa1406011.