A Randomized, Safety, Immunogenicity & Efficacy Study of Autoclaved Leishmania Major Plus BCG vs. BCG (Double Blind) or Placebo (Open), in Healthy High Risk Iranian Volunteers With no Response to Leishmanin
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 150
- 试验地点
- 1
- 主要终点
- Occurrence of local and/or systemic adverse events (AEs) within 30 days after vaccination assessed by interview, physical examination.
研究概览
简要总结
Development of a safe and effective vaccine against leishmaniasis started more than 10 years ago under WHO/TDR supervision. An autoclaved L. major vaccine (ALM) mixed with BCG has been tested in human in Iran, Pakistan and Sudan. Long term follow up of the vaccinees showed no untoward reactions except the skin reaction at the site of injection. The efficacy results of ALM was not satisfactory. In order to enhance immunogenicity of the vaccine, ALM was adsorbed to alum (Aluminum hydroxide). Alum-ALM plus adjuvant showed to induce protection in Rhesus monkeys against cutaneous leishmaniasis and in Languor monkeys against visceral leishmaniasis. Two trials of a single injection of different doses of Alum-ALM mixed with 1/10th of normal dose of BCG was carried out in healthy volunteers from a non endemic area of Sudan. The safety/immunogenicity parameters of the volunteers were closely monitored and the results showed that side effects were minimal and confined to the site of injection in the form of mild local pain, induration and ulceration, all associated with BCG vaccination. The immunogenicity results showed the strongest immune response seen in any Leishmania vaccine trials so far. It seems that this new formulation is an appropriate candidate for further development. Inoculation with live virulent Leishmania to produce a lesion for the purpose of preventing natural infection is known as leishmanization. The induced lesion heals and the person is usually protected against further infections. This method of prevention was practiced for centuries in the region. In this study volunteers with no response to leishmanin will be injected twice (30 days apart) with Alum-ALM 200 ug + 1/10 of BCG (n = 50) or BCG (n = 50) or BCG diluent alone (n = 50) as control. All volunteers will be leishmanized on day 60 post vaccination. In this trial, volunteers are protected either by vaccine or by leishmanization. The leishmanized volunteers will be visited by weekly and the development and healing process of the lesion will be monitored until complete healing of every volunteer. The immune responses of the volunteers will be evaluated. Vaccine efficacy is defined by the percent reduction in the number of volunteers developing a lesion following leishmanization as compared to controls on days 240.
详细描述
Background Information Leishmaniases encompass diverse clinical manifestations produced by different species of the protozoan parasite, Leishmania, transmitted by the bites of infected female sand flies. Due to the diversity of epidemiological characteristics, vector and reservoir control are impractical, costly and usually require political environment and infrastructures beyond the means of the countries suffering most from this disease. It was the aim of WHO/TDR to develop a safe and effective vaccine, which can be locally produced and thereby affordable for the populations of the poorest developing countries.
Beginning in the 1930's and 40's, Latin American scientists used killed whole parasite as a vaccine against leishmaniasis (1). Different forms of the vaccine, with or without adjuvant for prophylaxis or therapy have been studied in several countries in the past few decades (2), none has been efficacious for prophylaxis, but efficacy has been observed for immuno-chemotherapy (3). Over the past decade, we have produced and tested different preparations of killed L. major plus BCG. The autoclaved L. major (ALM) mixed with BCG (1/10th of the dose normally used as a vaccine against tuberculosis) was studied extensively in several clinical trials. The ALM + BCG formulation was shown to be safe and immunogenic (4-8). However, results from several phase III trials with a single or double-dose of this candidate vaccine against CL or VL did not show significant overall protection compared to immunization with BCG alone (6-8). Even three injections were not sufficiently protective against cutaneous leishmaniasis (CL).
In order to enhance immunogenicity of ALM + BCG, ALM was adsorbed to alum (Aluminum hydroxide), and the resulting alum-ALM was mixed with BCG to produce a new formulation for this vaccine. Indeed, the addition of alum to ALM leads to enhanced immunogenicity. It was demonstrated that a single injection of ALM in alum plus IL-12 induced protection in Rhesus monkeys against CL (10). Likewise, Alum-ALM + BCG protected Langur monkeys against visceral leishmaniasis (11).
The results of 2 dose escalating trials of a single intra-dermal injection of Alum-ALM (10 - 400 ug of Leishmania proteins) mixed with 1/10th normal dose of BCG showed the highest skin test conversion seen in any Leishmania vaccine trials so far (12). The safety parameters of the volunteers were closely monitored for 90 days after vaccination for local and systemic side effects. Side effects were minimal and confined to the site of injection. No systemic side effect was recorded. In the second TDR-sponsored trial in Sudan 10, 100 and 320 ug of the protein plus BCG were tested with results confirming the immunogenicity of the alum-ALM+BCG vaccine. Thus, Alum precipitated ALM mixed with 1/10th of BCG appears to constitute a safe vaccine and an appropriate candidate for further development.
Leishmanization (LZ):
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
- Double
入排标准
- 年龄范围
- 16 Years 至 60 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Men or women age between 16 to 60 years.
- •Generally in good health.
- •No known immunological deficiency, including HIV infection (by medical history).
- •No fever at the time of vaccination i.e. oral body temperature <37.5°C.
- •No history/suspicion/presence of kala-azar or cutaneous leishmaniasis (CL).
- •No history of leishmanization.
- •No history of vaccination against leishmaniasis.
- •No involvement in other drug or vaccine trial(s) during the study period.
- •No other known or planned vaccination within 1 month prior to the study and during the study period.
- •No current or foreseeable use of immunosuppressors (i.e. corticosteroids) within one month prior to the vaccination and during the period of the study.
- •No known allergy to a vaccine component (e.g. BCG, alum hydroxide, etc.).
- •Written informed consent provided. If the volunteer is under 18 years old, the legal guardian's signature is required on the informed consent.
排除标准
- •Pregnancy.
- •Women should not be pregnant and/or lactating and/or planning pregnancy throughout the study period until complete healing of the lesion induced by vaccination and/or leishmanization. A urinary pregnancy test will be performed for all women of child bearing potential at entry and adequate contraception throughout the study should be used if applicable.
- •Evidence of prior CL or leishmaniasis (e.g. sign of scar resembling leishmaniasis, confirmed by physical examination).
- •Evidence of serious diseases, allergy or allergic conditions leading to medical consultation and treatment especially with steroids or levamisole, recent surgery or hospitalisation, according to the physical examination and medical history interview.
- •Presence of any chronic illness/disease including diabetes mellitus, tuberculosis, leprosy, epilepsy and hypertension.
- •Abnormal haematology and clinical chemistry (See Sections 8.1.2.1 and 8.1.2.2 for normal ranges of laboratory values).
- •Presence of fever at the time of vaccination, i.e. body temperature (by mouth) > 37.5 °C.
结局指标
主要结局
Occurrence of local and/or systemic adverse events (AEs) within 30 days after vaccination assessed by interview, physical examination.
Percentage of volunteers protected against CL (absence of a lesion) compared to controls at day 180 + 15 after LZ.
次要结局
- Percentage of volunteers partially protected against CL compared to controls at day 180 + 15 post LZ.
- To assess the safety, non expected adverse events after leishmanization, assessed by interview and physical examination (local reactions at the injection site and systemic side effects) until the lesions are completely healed.
- In vivo test: Leishmanin skin tests (LST) prior to vaccination (baseline), at Day 23-28 after first injection and at day 52-58 and (before leishmanization) to assess the