AVIRS: Antibiotics and Vaccine Immune Responses Study

Sponsor

South Australian Health and Medical Research Institute (Other)

Overall Status

Recruiting

CT.gov ID

NCT06148025

Collaborator

Royal Adelaide Hospital (Other), Flinders University (Other), University of Sydney (Other), Telethon Kids Institute (Other), Centenary Institute of Cancer Medicine and Cell Biology (Other)

348

Enrollment

Location

Arms

Anticipated Duration (Months)

5.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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?

Condition or Disease	Intervention/Treatment	Phase
Vaccine Response Impaired	Biological: BCG vaccine Biological: Yellow Fever vaccine Drug: Vancomycin Oral Capsule Drug: Neomycin Oral Product	Phase 4

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 Design

Study Type:

Interventional

Anticipated Enrollment :

348 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention 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)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 (Participant, Investigator)

Masking Description:

Participants and Investigator are blinded to BCG vaccine or placebo.

Primary Purpose:

Basic Science

Official Title:

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

Anticipated Study Start Date :

Nov 1, 2023

Anticipated Primary Completion Date :

Oct 1, 2027

Anticipated Study Completion Date :

Oct 1, 2028

Arms and Interventions

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
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
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 Biological: Yellow Fever vaccine 0.5ml injected subcutaneously 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
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	Biological: Yellow Fever vaccine 0.5ml injected subcutaneously 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
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

Outcome Measures

Primary Outcome Measures

Sub-study 1 BCG re-challenge [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 [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)

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 35 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	South Australian Health and Medical Research Institute	Adelaide	South Australia	Australia	5000

Sponsors and Collaborators

South Australian Health and Medical Research Institute
Royal Adelaide Hospital
Flinders University
University of Sydney
Telethon Kids Institute
Centenary Institute of Cancer Medicine and Cell Biology

Investigators

Principal Investigator: Simone Barry, Royal Adelaide Hospital
Principal Investigator: David Lynn, South Australian Health and Medical Research Institute