Immunogenicity and Safety of Freeze-Dried Human Rabies Vaccine (Vero Cell) With the "Essen" Immunization Schedule and a Two-Dose Booster in Chinese Healthy Subjects Aged 10-60 Years: A Randomized, Blinded, and Comparable Vaccine-Controlled Non-Inferiority Phase III Clinical Trial.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,200
- 试验地点
- 1
- 主要终点
- Geometric mean concentration (GMC) of rabies virus-specific neutralizing antibodies in pre-immunization seronegative subjects.
研究概览
简要总结
Rabies is caused by rabies virus with a 100% mortality rate in humans. Most of cases occur in Africa and Asia, mainly in underserved populations. Rabies is a vaccine-preventable disease in both humans and animals. Over the years, the Vero cell rabies vaccine has been recognized by the World Health Organization (WHO) and the European Union, and is widely used globally. Currently, one of the post-exposure prophylaxis (PEP) regimens recommended by the World Health Organization (WHO) is the five-dose "Essen" regimen (1-1-1-1-1), involving one intramuscular dose administered on days 0, 3, 7, 14, and 28 respectively. This clinical trial was to assess the immunogenicity and safety of a freeze-dried human rabies vaccine (Vero Cell) in healthy population for the large-scale developing, and explore the booster vaccination.
详细描述
Rabies is caused by rabies virus with a case fatality rate approaching 100% in humans. Studies reported that about 59000 human deaths and over 3.7 million disability-adjusted life years lost every year. Most of cases occur in Africa and Asia, mainly in underserved populations, with approximately 40% of cases in children aged <15 years. Fortunately, rabies is a vaccine-preventable disease in both humans and animals. Post-exposure prophylaxis (PEP), is the critical intervention for preventing the onset of the disease.
Conventional Vero cell rabies vaccines have been used globally for decades, demonstrating excellent safety and immunogenicity. However, their production typically requires the use of animal-derived components, such as fetal bovine serum or human serum albumin, in the cell culture medium. This practice raises potential concerns regarding the risk of contamination with adventitious agents, batch-to-batch variability, and the potential for allergic reactions. To address these limitations, a new generation of purified Vero rabies vaccine produced in serum-free medium has been developed. This vaccine uses the same Pitman-Moore virus strain as the traditional vaccines but is manufactured without any human or animal serum-derived components, significantly reducing the risk of extraneous protein contamination and representing a substantial advancement in vaccine technology and safety. The shift to a serum-free production process, while a clear advantage for safety, raises critical questions regarding the vaccine's immunogenicity and the duration of protection it confers.
This study aims to systematically evaluate the available evidence of the serum-free Vero cell rabies vaccine. First, we will critically assess its immunogenicity in PEP settings. Second, we will assess the long-term persistence of protective antibody titers following primary vaccination. Finally, we will discuss the rationale for and evidence on booster vaccination strategies.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Masking Description
入排标准
- 年龄范围
- 10 Years 至 60 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy subjects aged 10-60 years as established by medical history and clinical examination
- •The subjects are able to understand and sign the informed consent
- •Female subjects aged 18-60 years must have a negative urine pregnancy test result and commit to using contraception for 2 months following the first vaccine dose in this study.
- •Subjects who can and will comply with the requirements of the protocol
- •Subjects with temperature ≤37.0°C on axillary setting
排除标准
- •Exclusion Criteria for the first dose:
- •Subject who was administered human rabies vaccine or rabies immunoglobulin.
- •Subject that has a medical history of any of the following: allergic history, or allergic to any ingredient of vaccine, especially allergic to neomycin.
- •Has been diagnosed or suspected of having an immune deficiency, autoimmune disease, or immune system disorder.
- •History of thyroidectomy, or thyroid disease requiring treatmentin the past 12 months
- •Bleeding disorder diagnosed by a doctor or significant bruising or bleeding difficulties with injections or blood draws
- •History of epilepsy, convulsions or convulsions, or a family history of psychosis.
- •Absence of spleen, functional absence of spleen, and any circumstances leading to absence of spleen or splenectomy.
- •Have a malignant tumor in active phase, or a tumor that have been treated but not clearly cured, or may relapse during the study period.
- •In the past 6 months, there have been immunosuppressive therapy, cytotoxic therapy, inhaled corticosteroids (excluding corticosteroid spray therapy for allergic rhinitis, and surface corticosteroid therapy for acute non-complicated dermatitis).
- •Taking anti-TB or HIV treatment.
- •Any prior administration of immunoglobulin or blood products in last 3 months.
- •Coagulopathy (such as coagulation factor deficiency, coagulative disorders, platelet abnormalities) or obvious bruising or coagulation impairment
- •Any prior administration of other research drugs in last 30 days
- •Any prior administration of attenuated live vaccine in last 4 weeks
- •Any prior administration of subunit or inactivated vaccines in last 2 weeks
- •Have acute diseases, severe chronic diseases, acute exacerbation of chronic diseases, or those with fever
- •Suspected or have a history of injury caused by warm-blooded mammals in last 3 months.
- •Women who are breastfeeding, pregnant, or planning to become pregnant in 2 months past the first dose.
- •Use of antipyretic, analgesic, or antiallergic drugs within 3 days
- •Having used other investigational or unregistered products (drugs or vaccines) within 6 months prior to the vaccination of the study vaccine, or having plans to participate in other clinical studies after enrollment in this clinical study (except for emergency-use novel coronavirus vaccines, but the vaccination details must be recorded in the concomitant medication section)
- •Planning to move out of the local area or be away from the local area for a long time before the end of the study;
- •Any condition that in the opinion of the investigator, may interfere with the evaluation of study objectives
- •Exclusion Criteria for other doses:
- •Any incidences in the first dose exclusion criteria occur after inclusion
- •Grade 3 or higher systemic adverse reactions related to this study, or intolerable injection site adverse reactions, that occurred between the previous vaccination and the current vaccination.
- •Any serious adverse events caused by vaccination.
- •Other reactions that in the opinion of the investigator ( include: severely serious symptom of pain, swelling, Limitation of motion, continuous high fever, headache and other Systemic or local reactions )
研究组 & 干预措施
the tested group
receive the lyophilized human rabies vaccine (Vero Cells) produced by Shanghai Rongsheng Biotech Co., Ltd.
干预措施: the tested vaccine (Biological)
the control group
receive the lyophilized human rabies vaccine (Vero Cells) produced by Liaoning Chengda Biotechnology Co., Ltd.
干预措施: the control vaccine (Biological)
Sub tested A
Subjects from the tested group with freeze-dried human rabies vaccine (Vero Cell) (Shanghai Rongsheng Biotech Co., Ltd.) vaccinated according to booster schedule on day 0,3 at month 3 following the full-course immunization.
干预措施: the tested vaccine (Biological)
Sub tested B
Subjects from the experimental 1 with freeze-dried human rabies vaccine (Vero Cell) (Shanghai Rongsheng Biotech Co., Ltd.) vaccinated according to booster schedule on day 0,3 at month 12 following the full-course immunization.
干预措施: the tested vaccine (Biological)
结局指标
主要结局
Geometric mean concentration (GMC) of rabies virus-specific neutralizing antibodies in pre-immunization seronegative subjects.
时间窗: 14 days following the 5 doses full-course immunization
GMC, concentration of participants with rabies virus neutralizing antibody concentration, the experimental group is non-inferior to the control group, non-inferiority margin for GMC ratio:0.67.
Seroconversion rate of rabies virus-specific neutralizing antibodies (RFFIT) in pre-immunization seronegative subjects.
时间窗: 14 days following the first dose
Seroconversion rate, percentage of participants with rabies virus neutralizing antibody concentration ≥0.5 IU/ml, the experimental group is non-inferior to the control group, non-inferiority margin for seroconversion rate:-5%.
Geometric mean concentration (GMC) of rabies virus-specific neutralizing antibodies in pre-immunization seronegative subjects.
时间窗: 14 days following the first dose
GMC, concentration of participants with rabies virus neutralizing antibody concentration, the experimental group is non-inferior to the control group, non-inferiority margin for GMC ratio:0.67.
Seroconversion rate of rabies virus-specific neutralizing antibodies (RFFIT) in pre-immunization seronegative subjects.
时间窗: 14 days following the 5 doses full-course immunization
Percentage of participants with rabies virus neutralizing antibody concentration ≥0.5 IU/ml, the experimental group is non-inferior to the control group, non-inferiority margin for seroconversion rate:-5%.
次要结局
- Percentage of participants with rabies virus neutralizing antibody concentration ≥0.5 IU/ml or increase by 4 folds after vaccination(7、14 days post the first dose and 14 days post the 5 doses full-course immunization)
- Geometric mean concentration (GMC) of rabies virus-specific neutralizing antibodies(7、14 days post the first dose and 14 days post the 5 doses full-course immunization)
- Percentage of participants with rabies virus neutralizing antibody concentration ≥0.5 IU/ml after vaccination.(Month 3、6、12 following the 5 doses full-course immunization)
- GMC of rabies virus neutralizing antibody(Month 3、6、12 following the 5 doses full-course immunization)
- Proportion of subjects reporting adverse events(Day 30 post-each dose)
- Proportion of subjects with Serious Adverse Events occurring throughout the trial(Day 0 up to month 12 following the full-course immunization)
研究者
Fengcai Zhu
Principal Investigator
Jiangsu Province Centers for Disease Control and Prevention