Antibiotics and Vaccine Immune Responses Study

Phase 4RecruitingNCT06148025

South Australian Health and Medical Research Institute348 enrolled

Overview

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?

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Enrollment

348

Conditions

Vaccine Response Impaired

Interventions

BCG vaccineBIOLOGICAL

0.1ml injected intradermally over the distal insertion of the deltoid muscle onto the humerus

Yellow Fever vaccineBIOLOGICAL

0.5ml injected subcutaneously

Vancomycin Oral CapsuleDRUG

500mg every 6 hours for 3 days

Eligibility

Sex: ALLMin age: 18 YearsMax age: 35 YearsHealthy volunteers:

Medical Language ↔ Plain English

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 vaccination * Previous YF vaccination or YFV infection (only applies to participants included in the Yellow Fever Vaccine challenge sub-study) * Evidence of TB infection (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) * Have received any vaccinations in the 28 days prior to study visits 1 and 4

Locations (1)

South Australian Health and Medical Research Institute

Adelaide, South Australia, Australia

RECRUITING

Outcomes

Primary Outcomes

Sub-study 1 BCG re-challenge

Mycobacterial load (Colony Forming Units (CFU)/mg tissue) 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)

Time frame: 2 weeks post BCG challenge

Sub-study 2 Yellow Fever vaccine

Peak Yellow Fever viremia (viral copies/ml plasma) at day 3-7 post YFV vaccination in BCG-vaccinated participants not exposed to antibiotics (BCG-No ABX) compared to BCG-vaccinated participants that were exposed to antibiotics (BCG-ABX)

Time frame: 3, 5, 7 days post YFV challenge

Secondary Outcomes

Sub-study 1 - Bacterial load

Bacterial load (16S rRNA gene copies/g stool) in ABX participants compared to No-ABX participants

Time frame: Baseline (1-2 weeks before BCG/placebo vaccination), Day of vaccination and Day of BCG challenge

Sub-study 2 - Bacterial load

Bacterial load (16S rRNA gene copies/g stool) in ABX participants compared to No-ABX participants

Time frame: Baseline (1-2 weeks before BCG/placebo vaccination), Day of vaccination and Day of YFV challenge

Sub-study 1 - Microbiota diversity

Microbiota diversity (Shannon diversity index) in ABX participants compared to No-ABX participants

Time frame: Baseline (1-2 weeks before BCG/placebo vaccination), Day of vaccination and Day of BCG challenge

Sub-study 2 - Microbiota diversity

Microbiota diversity (Shannon diversity index) in ABX participants compared to No-ABX participants

Time frame: Baseline (1-2 weeks before BCG/placebo vaccination), Day of vaccination and Day of YFV challenge

Central Contacts

David Lynn

CONTACT

+61 8 8128 4053 david.lynn@sahmri.com

Data from ClinicalTrials.gov

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