Antibiotics and Vaccine Immune Responses Study (AVIRS)

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

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?

Study Overview

• Status: Recruiting
• Conditions: Vaccine Response Impaired
• Intervention / Treatment: Biological: BCG vaccine; Drug: Vancomycin Oral Capsule; Drug: Neomycin Oral Product; Biological: Yellow Fever vaccine; Drug: Metoclopramide (Maxolon); Drug: Loperamide HCl

Detailed Description

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
• Enrollment (Estimated): 348
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: David Lynn; Phone Number: +61 8 8128 4053; Email: david.lynn@sahmri.com

Study Locations

• Australia
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Recruiting
      • South Australian Health and Medical Research Institute
      • Contact: David Lynn; Phone Number: +61 8 8128 4053; Email: david.lynn@sahmri.com
      • Principal Investigator: David Lynn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Biological: BCG vaccine; 0.1ml injected intradermally over the distal insertion of the deltoid muscle onto the humerus; Drug: Vancomycin Oral Capsule; 500mg every 6 hours for 3 days; Other Names: Firvanq; Vancocin HCl Pulvules; Drug: Neomycin Oral Product; 1000mg every 6 hours for 3 days; Other Names: Neo-Fradin; Drug: Metoclopramide (Maxolon); 10mg every 8 hours; Drug: Loperamide HCl; 2mg tablets/capsules: 2 tablets/capsules initially, followed by 1 tablet after each loose motion, to a maximum of 8 tablets/capsules per day
Experimental: 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	Biological: BCG vaccine; 0.1ml injected intradermally over the distal insertion of the deltoid muscle onto the humerus
Experimental: 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	Biological: BCG vaccine; 0.1ml injected intradermally over the distal insertion of the deltoid muscle onto the humerus; Drug: Vancomycin Oral Capsule; 500mg every 6 hours for 3 days; Other Names: Firvanq; Vancocin HCl Pulvules; Drug: Neomycin Oral Product; 1000mg every 6 hours for 3 days; Other Names: Neo-Fradin; Drug: Metoclopramide (Maxolon); 10mg every 8 hours; Drug: Loperamide HCl; 2mg tablets/capsules: 2 tablets/capsules initially, followed by 1 tablet after each loose motion, to a maximum of 8 tablets/capsules per day
Experimental: 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	Biological: BCG vaccine; 0.1ml injected intradermally over the distal insertion of the deltoid muscle onto the humerus
Experimental: 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	Biological: BCG vaccine; 0.1ml injected intradermally over the distal insertion of the deltoid muscle onto the humerus; Drug: Vancomycin Oral Capsule; 500mg every 6 hours for 3 days; Other Names: Firvanq; Vancocin HCl Pulvules; Drug: Neomycin Oral Product; 1000mg every 6 hours for 3 days; Other Names: Neo-Fradin; Biological: Yellow Fever vaccine; 0.5ml injected subcutaneously; Drug: Metoclopramide (Maxolon); 10mg every 8 hours; Drug: Loperamide HCl; 2mg tablets/capsules: 2 tablets/capsules initially, followed by 1 tablet after each loose motion, to a maximum of 8 tablets/capsules per day
Experimental: 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	Biological: BCG vaccine; 0.1ml injected intradermally over the distal insertion of the deltoid muscle onto the humerus; Biological: Yellow Fever vaccine; 0.5ml injected subcutaneously
Experimental: 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	Drug: Vancomycin Oral Capsule; 500mg every 6 hours for 3 days; Other Names: Firvanq; Vancocin HCl Pulvules; Drug: Neomycin Oral Product; 1000mg every 6 hours for 3 days; Other Names: Neo-Fradin; Biological: Yellow Fever vaccine; 0.5ml injected subcutaneously; Drug: Metoclopramide (Maxolon); 10mg every 8 hours; Drug: Loperamide HCl; 2mg tablets/capsules: 2 tablets/capsules initially, followed by 1 tablet after each loose motion, to a maximum of 8 tablets/capsules per day
Experimental: 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	Biological: Yellow Fever vaccine; 0.5ml injected subcutaneously

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: South Australian Health and Medical Research Institute
• Collaborators: University of Sydney; Telethon Kids Institute; Flinders University; Royal Adelaide Hospital; Centenary Institute
• Investigators: Principal Investigator: Simone Barry, Royal Adelaide Hospital; Principal Investigator: David Lynn, South Australian Health and Medical Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2023
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2028

Study Registration Dates

• First Submitted: September 29, 2023
• First Submitted That Met QC Criteria: November 17, 2023
• First Posted (Actual): November 28, 2023

Study Record Updates

• Last Update Posted (Actual): December 10, 2025
• Last Update Submitted That Met QC Criteria: December 3, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Antibiotics; BCG vaccine; Yellow Fever vaccine; Healthy participants; 18-35 years old
• Additional Relevant MeSH Terms: Peptides; Amino Acids, Peptides, and Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Carboxylic Acids; Hydroxy Acids; Hydrocarbons, Aromatic; Glycosides; Amides; Piperidines; Phenols; Benzene Derivatives; Aminoglycosides; Glycoconjugates; Biological Products; Complex Mixtures; Acids, Carbocyclic; Glycopeptides; para-Aminobenzoates; Aminobenzoates; Benzoates; Hydroxybenzoates; Bacterial Vaccines; Vaccines; Phenyl Ethers; Benzamides; Chlorobenzoates; Tuberculosis Vaccines; Viral Vaccines; Hydroxybenzoate Ethers; Vancomycin; BCG Vaccine; Neomycin; Metoclopramide; Loperamide; Yellow Fever Vaccine
• Other Study ID Numbers: 2023/HREC00066

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Non-identifiable individual participant data from the study may be made available long-term for use by future researchers from a recognised research institution whose proposed use of the data has been ethically reviewed and approved by an independent committee and who accept SAHMRI's conditions, under a collaborator agreement, for accessing:

• Individual participant data that underlie the results reported in our articles after deidentification (text, tables, figures and appendices)
• Study protocol, Statistical Analysis Plan, PICF

Molecular data generated from this study (i.e. transcriptomic, epigenomic and metagenomic) will be labelled with a unique identification code and stored on an appropriate data repository (e.g. Gene Expression Omnibus, Sequence Read Archive) with demographic information (age and sex). No identifying participant information will be shared.

• IPD Sharing Time Frame: At time of publication. Data will be available indefinitely.
• IPD Sharing Access Criteria: Researchers from a recognised research institution can approach SAHMRI for access of data. The researcher will need to provide evidence that the proposed use of the data has been ethically reviewed and approved by an Institutional Review Board (IRB)/ Human Research Ethics Committee(HREC), and accept SAHMRI's conditions, under a collaborator agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No