Antibiotics and Vaccine Immune Responses Study

Study Overview
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Brief Summary
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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?

Detailed Description
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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. All participants in both sub-studies will have blood samples collected at randomisation, before each vaccination, 2 weeks after each BCG vaccination and in the Yellow Fever vaccine sub-study at day 3, 5 and 7 following Yellow Fever vaccination. Stool samples will be collected prior to randomisation, and prior to each vaccination.

Official Title
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A Human Experimental Medicine Study to Assess Whether the Gut Microbiota Regulates Specific and Non-specific Immune Responses to Vaccination

Conditions
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Vaccine Response Impaired

Intervention / Treatment
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* Biological: BCG vaccine
* Biological: Yellow Fever vaccine
* Drug: Vancomycin Oral Capsule
* Drug: Neomycin Oral Product


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) Exclusion Criteria: 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 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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants are allocated to Substudy 1 (BCG re-challenge) or Substudy 2 (Yellow Fever vaccine) Participants are randomised to receive antibiotics or comparator (unblinded) and BCG vaccine or placebo (blinded) BCG vaccine or Yellow Fever vaccine (unblinded)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Substudy 1 - BCG vaccine, antibiotics and 2nd BCG vaccine<br>Randomised to receive antibiotics and a BCG vaccine at visit 1 and a second BCG vaccine 6 months later | Biological: BCG vaccine<br>* 0.1ml injected intradermally over the distal insertion of the deltoid muscle onto the humerus<br>Drug: Vancomycin Oral Capsule<br>* 500mg every 6 hours for 3 days<br>* Other names: Vancocin HCl Pulvules;Drug: Neomycin Oral Product<br>* 1000mg every 6 hours for 3 days<br>* Other names: Neo-Fradin;|
| Experimental: Substudy 1 - BCG vaccine, no antibiotics and 2nd BCG vaccine<br>Randomised to receive no antibiotics and a BCG vaccine at visit 1 and a second BCG vaccine 6 months later | Biological: BCG vaccine<br>* 0.1ml injected intradermally over the distal insertion of the deltoid muscle onto the humerus<br>|
| Experimental: Substudy 1 - BCG vaccine, antibiotics and placebo vaccine<br>Randomised to receive antibiotics, a placebo vaccine at visit 1 and a BCG vaccine 6 months later | Biological: BCG vaccine<br>* 0.1ml injected intradermally over the distal insertion of the deltoid muscle onto the humerus<br>Drug: Vancomycin Oral Capsule<br>* 500mg every 6 hours for 3 days<br>* Other names: Vancocin HCl Pulvules;Drug: Neomycin Oral Product<br>* 1000mg every 6 hours for 3 days<br>* Other names: Neo-Fradin;|
| Experimental: Substudy 1 - BCG vaccine, no antibiotics and placebo vaccine<br>Randomised to receive no antibiotics, a placebo vaccine at visit 1 and a BCG vaccine 6 months later | Biological: BCG vaccine<br>* 0.1ml injected intradermally over the distal insertion of the deltoid muscle onto the humerus<br>|
| Experimental: Substudy 2 - Yellow Fever vaccine, antibiotics and BCG vaccine<br>Randomised to receive antibiotics, a BCG vaccine at visit 1 and a Yellow Fever vaccine 3 months later | Biological: BCG vaccine<br>* 0.1ml injected intradermally over the distal insertion of the deltoid muscle onto the humerus<br>Biological: Yellow Fever vaccine<br>* 0.5ml injected subcutaneously<br>Drug: Vancomycin Oral Capsule<br>* 500mg every 6 hours for 3 days<br>* Other names: Vancocin HCl Pulvules;Drug: Neomycin Oral Product<br>* 1000mg every 6 hours for 3 days<br>* Other names: Neo-Fradin;|
| Experimental: Substudy 2 - Yellow Fever vaccine, no antibiotics and BCG vaccine<br>Randomised to receive no antibiotics, a BCG vaccine at visit 1 and a Yellow Fever vaccine 3 months later | Biological: BCG vaccine<br>* 0.1ml injected intradermally over the distal insertion of the deltoid muscle onto the humerus<br>Biological: Yellow Fever vaccine<br>* 0.5ml injected subcutaneously<br>|
| Experimental: Substudy 2 - Yellow Fever vaccine, antibiotics and placebo vaccine<br>Randomised to receive antibiotics, a placebo vaccine at visit 1 and a Yellow Fever vaccine 3 months later | Biological: Yellow Fever vaccine<br>* 0.5ml injected subcutaneously<br>Drug: Vancomycin Oral Capsule<br>* 500mg every 6 hours for 3 days<br>* Other names: Vancocin HCl Pulvules;Drug: Neomycin Oral Product<br>* 1000mg every 6 hours for 3 days<br>* Other names: Neo-Fradin;|
| Experimental: Substudy 2 - Yellow Fever vaccine, no antibiotics and placebo vaccine<br>Randomised to receive no antibiotics, a placebo vaccine at visit 1 and a Yellow Fever vaccine 3 months later | Biological: Yellow Fever vaccine<br>* 0.5ml injected subcutaneously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sub-study 1 BCG re-challenge | 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) | 5 years | 
| Sub-study 2 Yellow Fever vaccine | 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) | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sub-study 1 - Bacterial load | Day 0 bacterial load (16S copies/g stool) in all ABX participants vs No-ABX participants | 5 years | 
| Sub-study 2 - Bacterial load | Day 0 bacterial load (16S copies/g stool) in all ABX participants vs No-ABX participants | 5 years | 
| Sub-study 1 - Microbiota diversity | Day 0 microbiota diversity (Shannon diversity index) in all ABX participants vs No-ABX participants | 5 years | 
| Sub-study 2 - Microbiota diversity | Day 0 microbiota diversity (Shannon diversity index) in all ABX participants vs No-ABX participants | 5 years | 
| Sub-study 1 - Mycobacterial load | Mycobacterial load (CFU) in the skin biopsy site in BCG-vaccinated participants compared to placebo-vaccinated participants | 5 years | 
| Sub-study 1 - Mycobacterial IFNγ responses | IFNγ production in pg/mL following stimulation of PBMC with mycobacteria in BCG-ABX participants versus BCG-No ABX participants | 5 years | 
| Sub-study 1 - Mycobacterial T cell activation marker responses | % of CD69+CD137+ CD4 T cells following stimulation of PBMC with mycobacteria in BCG-ABX participants versus BCG-No ABX participants | 5 years | 
| Sub-study 2 - Peak viraemia | Peak viraemia (viral copies/ml blood) at D3-7 post YF vaccination in BCG-vaccinated participants compared to placebo-vaccinated participants | 5 years | 
| Sub-study 2 - Heterologous TNFα responses following R848 stimulation | D90 PBMC TNFα responses (pg/mL) following in vitro stimulation with viral ligand R848 in BCG-ABX participants versus BCG-No ABX participants | 5 years | 
| Sub-study 2 - Heterologous TNFα responses following LPS stimulation | D90 PBMC TNFα responses (pg/mL) following in vitro stimulation with bacterial ligand LPS in BCG-ABX participants versus BCG-No ABX participants | 5 years | 
| Sub-study 2 - Heterologous TNFα responses following fungal stimulation | D90 PBMC TNFα responses (pg/mL) following in vitro stimulation with fungal ligand heat-killed C. albicans in BCG-ABX participants versus BCG-No ABX participant | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy participants, 18-35 years old, BCG vaccine, Yellow Fever vaccine, Antibiotics