A Human Experimental Medicine Study to Assess Whether the Gut Microbiota Regulates Specific and Non-specific Immune Responses to Vaccination
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 348
- 试验地点
- 1
- 主要终点
- Sub-study 1 BCG re-challenge
研究概览
简要总结
The goal of this clinical trial is to examine immune responses to the BCG vaccine in healthy adults who have, or who have not, taken antibiotics to deplete their gut bacteria prior to vaccination.
The main question it aims to answer is: does depletion of the gut microbiota lead to impaired BCG-induced protection against specific and non-specific to challenges to the immune system?
详细描述
The study is divided into two sub-studies. The first sub-study (BCG re-challenge) is an experimental medicine study in 168 healthy participants to determine if depletion of the gut microbiota leads to impaired BCG-induced protection against a subsequent Mycobacterium bovis BCG intradermal challenge.
The second sub-study (Yellow Fever vaccine) has a very similar experimental design to the first but will determine if depletion of the gut microbiota leads to impaired BCG-induced protection against other infections. To assess this, participants in this sub-study (n=180) will be re-challenged after 3 months with a live attenuated viral vaccine, the Yellow Fever vaccine, which induces a mild viremia.
In both sub-studies, participants will initially be randomised to receive a 3 day course of antibiotics or none (comparator group). The two groups in each sub-study will be randomised again to receive either BCG vaccine or 0.9% NaCl placebo injection in the left arm.
BCG re-challenge sub-study (Sub-study 1): Six months following randomisation, all participants will receive a BCG vaccine challenge in the right arm. A punch skin biopsy will be taken of this challenge site 2 weeks after the challenge to assess M. bovis BCG bacterial load in the skin.
Yellow Fever vaccine sub-study (Sub-study 2): Three months following randomisation, all participants will receive a Yellow Fever vaccine challenge in the right arm. Blood samples will be collected from Yellow Fever vaccinated participants at day 3, 5 and 7 following Yellow Fever vaccine challenge to quantify Yellow Fever viral load in blood.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
盲法说明
Participants and Investigator are blinded to BCG vaccine or placebo.
入排标准
- 年龄范围
- 18 Years 至 35 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •18-35 years old
- •Provided a signed and dated informed consent form
- •BCG naïve (Arm 1) and BCG and YF vaccine naïve (Arm 2)
- •Willing to take short antibiotic course
- •Willing to undergo a punch biopsy (Arm 1)
- •Willing to have up to 7 blood samples and 3 stool samples collected over 5-7 months
- •Not pregnant or intending to get pregnant for the duration of the study (a pregnancy test will be offered to females)
排除标准
- •Previous BCG or YF vaccination
- •Previous YF infection
- •Evidence of latent TB infection (LTBI) (assessed through a questionnaire) (IGRA to confirm if needed)
- •People with contraindications for BCG vaccination:
- •malignancies involving bone marrow or lymphoid systems, primary or secondary immunodeficiencies, HIV infection
- •moderate/severe skin disease including eczema, dermatitis or psoriasis
- •requiring immunosuppressive drugs or other immune modifying drugs e.g. corticosteroids, non-biological immunosuppressants, biological agents (such as monoclonal antibodies against tumour necrosis factor (TNF)-alpha)
- •People with contraindications to YF vaccination:
- •History of thymus disease, including myasthenia gravis, thymoma, thymectomy, DiGeorge syndrome, thymic damage from chemoradiotherapy or graft-versus-host disease
- •YF vaccination is contraindicated in immunocompromised individuals, including individuals who have HIV infection, primary immunodeficiencies (including inherited IFNAR1 deficiency), or are taking corticosteroids or other immunosuppressive agents and haematopoietic stem cell transplant recipients
- •People who have had a haematopoietic stem cell transplant
- •Individuals with history of severe allergic reactions to egg or chicken proteins
- •Pregnant or breastfeeding or planning to become pregnant
- •History of renal disease/insufficiency
- •Tattoo obscuring BCG vaccination site(s)
- •Any history of severe allergic reaction or anaphylaxis to vaccination or antibiotics
- •People with chronic serious underlying illness
- •Have received any prescribed oral or intravenous antibiotic in the 28 days prior to study visits 1 and 4 (including isoniazid, rifampicin, streptomycin and ethambutol as these particular antibiotics have activity against M. bovis)
研究组 & 干预措施
Substudy 1 - BCG vaccine, antibiotics and placebo vaccine
Randomised to receive antibiotics, a placebo vaccine at visit 1 and a BCG vaccine 6 months later
干预措施: Metoclopramide (Maxolon) (Drug)
Substudy 1 - BCG vaccine, antibiotics and 2nd BCG vaccine
Randomised to receive antibiotics and a BCG vaccine at visit 1 and a second BCG vaccine 6 months later
干预措施: BCG vaccine (Biological)
Substudy 1 - BCG vaccine, antibiotics and 2nd BCG vaccine
Randomised to receive antibiotics and a BCG vaccine at visit 1 and a second BCG vaccine 6 months later
干预措施: Vancomycin Oral Capsule (Drug)
Substudy 1 - BCG vaccine, antibiotics and 2nd BCG vaccine
Randomised to receive antibiotics and a BCG vaccine at visit 1 and a second BCG vaccine 6 months later
干预措施: Neomycin Oral Product (Drug)
Substudy 1 - BCG vaccine, antibiotics and 2nd BCG vaccine
Randomised to receive antibiotics and a BCG vaccine at visit 1 and a second BCG vaccine 6 months later
干预措施: Metoclopramide (Maxolon) (Drug)
Substudy 1 - BCG vaccine, antibiotics and 2nd BCG vaccine
Randomised to receive antibiotics and a BCG vaccine at visit 1 and a second BCG vaccine 6 months later
干预措施: Loperamide HCl (Drug)
Substudy 1 - BCG vaccine, no antibiotics and 2nd BCG vaccine
Randomised to receive no antibiotics and a BCG vaccine at visit 1 and a second BCG vaccine 6 months later
干预措施: BCG vaccine (Biological)
Substudy 1 - BCG vaccine, antibiotics and placebo vaccine
Randomised to receive antibiotics, a placebo vaccine at visit 1 and a BCG vaccine 6 months later
干预措施: BCG vaccine (Biological)
Substudy 1 - BCG vaccine, antibiotics and placebo vaccine
Randomised to receive antibiotics, a placebo vaccine at visit 1 and a BCG vaccine 6 months later
干预措施: Vancomycin Oral Capsule (Drug)
Substudy 1 - BCG vaccine, antibiotics and placebo vaccine
Randomised to receive antibiotics, a placebo vaccine at visit 1 and a BCG vaccine 6 months later
干预措施: Neomycin Oral Product (Drug)
Substudy 1 - BCG vaccine, antibiotics and placebo vaccine
Randomised to receive antibiotics, a placebo vaccine at visit 1 and a BCG vaccine 6 months later
干预措施: Loperamide HCl (Drug)
Substudy 1 - BCG vaccine, no antibiotics and placebo vaccine
Randomised to receive no antibiotics, a placebo vaccine at visit 1 and a BCG vaccine 6 months later
干预措施: BCG vaccine (Biological)
Substudy 2 - Yellow Fever vaccine, antibiotics and BCG vaccine
Randomised to receive antibiotics, a BCG vaccine at visit 1 and a Yellow Fever vaccine 3 months later
干预措施: BCG vaccine (Biological)
Substudy 2 - Yellow Fever vaccine, antibiotics and BCG vaccine
Randomised to receive antibiotics, a BCG vaccine at visit 1 and a Yellow Fever vaccine 3 months later
干预措施: Yellow Fever vaccine (Biological)
Substudy 2 - Yellow Fever vaccine, antibiotics and BCG vaccine
Randomised to receive antibiotics, a BCG vaccine at visit 1 and a Yellow Fever vaccine 3 months later
干预措施: Vancomycin Oral Capsule (Drug)
Substudy 2 - Yellow Fever vaccine, antibiotics and BCG vaccine
Randomised to receive antibiotics, a BCG vaccine at visit 1 and a Yellow Fever vaccine 3 months later
干预措施: Neomycin Oral Product (Drug)
Substudy 2 - Yellow Fever vaccine, antibiotics and BCG vaccine
Randomised to receive antibiotics, a BCG vaccine at visit 1 and a Yellow Fever vaccine 3 months later
干预措施: Metoclopramide (Maxolon) (Drug)
Substudy 2 - Yellow Fever vaccine, antibiotics and BCG vaccine
Randomised to receive antibiotics, a BCG vaccine at visit 1 and a Yellow Fever vaccine 3 months later
干预措施: Loperamide HCl (Drug)
Substudy 2 - Yellow Fever vaccine, no antibiotics and BCG vaccine
Randomised to receive no antibiotics, a BCG vaccine at visit 1 and a Yellow Fever vaccine 3 months later
干预措施: BCG vaccine (Biological)
Substudy 2 - Yellow Fever vaccine, no antibiotics and BCG vaccine
Randomised to receive no antibiotics, a BCG vaccine at visit 1 and a Yellow Fever vaccine 3 months later
干预措施: Yellow Fever vaccine (Biological)
Substudy 2 - Yellow Fever vaccine, antibiotics and placebo vaccine
Randomised to receive antibiotics, a placebo vaccine at visit 1 and a Yellow Fever vaccine 3 months later
干预措施: Yellow Fever vaccine (Biological)
Substudy 2 - Yellow Fever vaccine, antibiotics and placebo vaccine
Randomised to receive antibiotics, a placebo vaccine at visit 1 and a Yellow Fever vaccine 3 months later
干预措施: Vancomycin Oral Capsule (Drug)
Substudy 2 - Yellow Fever vaccine, antibiotics and placebo vaccine
Randomised to receive antibiotics, a placebo vaccine at visit 1 and a Yellow Fever vaccine 3 months later
干预措施: Neomycin Oral Product (Drug)
Substudy 2 - Yellow Fever vaccine, antibiotics and placebo vaccine
Randomised to receive antibiotics, a placebo vaccine at visit 1 and a Yellow Fever vaccine 3 months later
干预措施: Metoclopramide (Maxolon) (Drug)
Substudy 2 - Yellow Fever vaccine, antibiotics and placebo vaccine
Randomised to receive antibiotics, a placebo vaccine at visit 1 and a Yellow Fever vaccine 3 months later
干预措施: Loperamide HCl (Drug)
Substudy 2 - Yellow Fever vaccine, no antibiotics and placebo vaccine
Randomised to receive no antibiotics, a placebo vaccine at visit 1 and a Yellow Fever vaccine 3 months later
干预措施: Yellow Fever vaccine (Biological)
结局指标
主要结局
Sub-study 1 BCG re-challenge
时间窗: 5 years
Mycobacterial load (Colony Forming Units (CFU)) in the skin biopsy site in BCG-vaccinated participants not exposed to antibiotics (BCG-No ABX) compared to BCG-vaccinated participants that were exposed to antibiotics (BCG-ABX)
Sub-study 2 Yellow Fever vaccine
时间窗: 5 years
Yellow Fever viremia (viral copies/ml blood) at D3-7 post YF vaccination in BCG-vaccinated participants not exposed to antibiotics (BCG-No ABX) compared to BCG-vaccinated participants that were exposed to antibiotics (BCG-ABX)
次要结局
- Sub-study 2 - Heterologous TNFα responses following LPS stimulation(5 years)
- Sub-study 2 - Heterologous TNFα responses following fungal stimulation(5 years)
- Sub-study 1 - Bacterial load(5 years)
- Sub-study 1 - Mycobacterial T cell activation marker responses(5 years)
- Sub-study 2 - Heterologous TNFα responses following R848 stimulation(5 years)
- Sub-study 2 - Bacterial load(5 years)
- Sub-study 1 - Microbiota diversity(5 years)
- Sub-study 2 - Peak viraemia(5 years)
- Sub-study 2 - Microbiota diversity(5 years)
- Sub-study 1 - Mycobacterial load(5 years)
- Sub-study 1 - Mycobacterial IFNγ responses(5 years)
研究者
David Lynn
Director, Computational & Systems Biology Program
South Australian Health and Medical Research Institute