A Feasibility Study of Controlled Human Infection With Intradermal Bacillus Calmette-Guérin Injection
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 2
- 主要终点
- To quantify BCG recovered from the intradermal BCG challenge site.
研究概览
简要总结
Tuberculosis (TB) is a disease that usually causes an infection in the lungs. The only vaccine to prevent TB is called BCG (Bacillus Calmette-Guérin). BCG contains a live germ similar to Mycobacterium tuberculosis, the germ that causes TB. BCG does not work very well, and TB remains the most common cause of death by infection worldwide. Human challenge models involve exposing healthy volunteers to an infectious disease in a safe and controlled way. This helps researchers understand more about an infectious disease and the body's response and can help develop new vaccines and treatments. The purpose of this study is to set up a human challenge model using BCG to understand how the body responds to this. If our human challenge model works well it may be used to help researchers develop new vaccines and tablets to treat TB in the future.
This study will recruit healthy volunteers, of all genders, age 18-50 years. The first part of the study (phase A) will recruit 10 participants. Participants in phase A will receive intradermal injection with BCG into the upper arm at three times the usual dose. On day 14 after BCG the following skin samples will be taken from the BCG site with the use of local anaesthetic: skin swab, microbiopsy, skin scrape and punch biopsy. Participants in this phase of the study will also have blood tests to ensure they are safe to take part and to monitor the immune response to BCG. The overall aim of this part of the study will be to ensure BCG can be isolated (grown in culture and by molecular techniques) from participants' BCG site 14 days after the injection. The investigators aim to test whether BCG can be isolated by punch biopsy and minimally invasive techniques (microbiopsy, skin scrape and skin swab). If the investigators find that they can isolate BCG successfully using the minimally invasive methods of skin sampling and the participants have not experienced any serious adverse events, they can proceed to phase B of the study.
In phase B 20 participants will be recruited. These participants will receive BCG as described for phase A. They will then have serial skin samples taken using either microbiopsy, skin scrape or skin swab on days 0, 2, 7, 14 and 28. The focus of this phase of the study is to assess immune responses to intradermal injection at the local (skin), systemic (blood) and respiratory mucosal (nose) compartments. This will involve longitudinal sampling from blood, nose and skin to measure BCG growth and the immune response over time.
详细描述
Background In 2020 an estimated 10 million people fell ill with tuberculosis (TB) and 1.5 million people died making TB the second leading infectious killer after COVID-19. Multi-drug resistant tuberculosis is a public health crisis and increasing health security threat. Despite this, the only currently available vaccine for prevention of tuberculosis is the 100-year-old Bacille Calmette-Guerin (BCG), which prevents disseminated forms of tuberculosis but has limited efficacy against pulmonary tuberculosis.
Phase 3 vaccine trials for tuberculosis are large, costly and conducted over prolonged periods. Controlled human infection models involve inoculating healthy participants with an infectious agent and can be used to accelerate vaccine development as well as improve understanding of disease pathogenesis and the host immune response and the development of new therapeutic combinations. There are current concerns in using wild type Mycobacterium tuberculosis as a human challenge agent given that infection cannot be reliably eradicated. The McShane group in Oxford have established a human challenge model using intradermal BCG and have published several peer reviewed articles. The Liverpool School of Tropical Medicine propose to replicate and further refine this model and I will be undertaking this project as part of an MD. The investigators aim to perform serial skin sampling paired with respiratory mucosal and systemic sampling to investigate and compare the immune response between these compartments. Ultimately this model may be used to select the most promising candidates for clinical trials.
Study hypothesis
- BCG SSI strain will be recovered by tissue biopsy 14 days after intradermal injection by both classical microbiological and molecular diagnostic techniques.
- Quantified BCG recovery (molecular techniques) by minimally invasive skin biopsy will be at least 90% as good as gold standard punch biopsy and will offer a more acceptable method for participants in the future.
Overall study design This is a single-centre study divided into two parts. The first part of the study (phase A) will recruit 10 participants. The participants in phase A will receive intradermal injection of BCG SSI vaccine into the upper arm on day 0 at three times the usual dose (BCG SSI 6-24 x 105 colony forming units). On day 14 after BCG injection. the following skin samples will be taken from the BCG injection site with the use of local anaesthetic: skin swab, microbiopsy, skin scrape and punch biopsy. The overall aim of this part of the study will be to ensure BCG can be isolated from participants BCG intradermal injection site 14 days after the injection. The investigators aim to test whether BCG can be isolated in comparable amounts by punch biopsy and minimally invasive techniques (microbiopsy, skin scrape and skin swab). They will proceed to phase B of the study if they are able to isolate BCG by culture or PCR using one of the minimally invasive techniques and no serious adverse events have occurred.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Resident near LSTM (<1hr drive) for the duration of the study period
- •Allows the investigators to discuss the volunteer's medical history with their GP
- •Females of childbearing potential with a negative urine pregnancy test at screening and willing to practice adequate birth control measures during the study.
- •Fluent spoken English - to ensure a comprehensive understanding of the research project and their proposed involvement
- •Capacity to provide written informed consent
- •Able and willing (in the investigators opinion) to comply with all the study requirements
排除标准
- •Laboratory evidence at screening of latent M. tb infection as indicated by a positive ELISPOT response to ESAT6 or CFP10 antigens
- •Clinical, radiological, or laboratory evidence of current active TB disease
- •Previous vaccination with BCG, or any candidate TB vaccine
- •Within the last year had close household contact with an individual with smear positive pulmonary tuberculosis
- •Clinically significant history of skin disorder, allergy, immunodeficiency (including HIV), cancer, cardiovascular disease, respiratory disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder, neurological illness or psychiatric disorder.
- •Current medical issues
- •Acute respiratory tract infection in the four weeks preceding recruitment
- •Any uncontrolled medical or surgical condition at the discretion of the study doctor
- •Female participants who are pregnant
- •Female participants who are lactating
- •Female participants who intend to become pregnant during the study
- •Female participants who are unable to take contraception measures during the study
- •Current (defined as ≥5/week) or ex-smoker (cigarettes / cigars / e-cigarette / vaping / smoking of recreational drugs) in the last 6 months.
- •Previous significant smoking history (more than 20 cigarettes per day for 20 years or the equivalent [>20 pack years]).
- •Current alcohol and recreational drug use
- •Regularly drinks ≥3units/day (male) or ≥2units/day (female)
- •Uses recreational drugs
- •Participants may be excluded at the discretion of the research clinician
- •Concurrent oral or systemic steroid medication or the concurrent use of other immunosuppressive agents
- •History of anaphylaxis to vaccination or any allergy likely to be exacerbated by any component of the challenge agent
- •Has received any vaccination within one month of screening visit.
- •Has not completed at least two COVID-19 vaccination doses
- •Any abnormality of screening blood or urine tests that is deemed to be clinically significant or that may compromise the safety of the volunteer in the study b
- •Positive HBsAg, HCV or HIV antibodies
- •Current involvement in another trial that involves regular blood tests or an investigational medicinal product
- •Use of an investigational medicinal product or non-registered drug, live vaccine, or investigational medical device for four weeks prior to dosing with the study challenge agent
- •Administration of immunoglobulins and/or any blood products within the three months preceding the planned challenge date
- •Participants who meet STOP criteria at the time of screening (see table 2)
- •Any other issue which, in the opinion of the study staff, may
- •Put the participant or their contacts at risk because of participation in the study,
- •Adversely affect the interpretation of the study results, or
- •Impair the participant's ability to participate in the study.
结局指标
主要结局
To quantify BCG recovered from the intradermal BCG challenge site.
时间窗: Day 14 (post BCG injection), phase A.
Culture and PCR quantification of BCG at intradermal challenge site by punch biopsy at day 14, Phase A.
次要结局
- To monitor for adverse events and any serious adverse events in participants(Daily symptom diary for 14 days, clinic review on day 2, 7, 14, 21 and 28 post BCG injection)
- Confirm agreement between BCG recovery between punch biopsy and minimally invasive skin biopsy.(Day 14, phase A.)
- Assess antibody response to BCG injection in systemic circulation(Day 2, 7, 14, 21, 28, Phase B.)
- Confirm agreement between BCG recovery between punch biopsy and minimally invasive skin scrape.(Day 14, phase A.)
- Evaluate the immune response to BCG at intradermal injection site from skin biopsy(Day 2, 7, 14, 21, 28, Phase B.)
- Assess cellular immune response to BCG in systemic circulation.(Day 2, 7, 14, 21, 28, Phase B.)
- Measure antibody response to BCG injection in respiratory mucosa.(Day 2, 7, 14, 21, 28, Phase B.)
- Measure cellular immune response to BCG injection in respiratory mucosa.(Day 2, 7, 14, 21, 28, Phase B.)
- Longitudinal quantification of BCG recovery from the intradermal BCG challenge site.(Day 2, 7, 14, 21, 28, Phase B)