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Antibiotics and Vaccine Immune Responses Study

PHASE4RECRUITING

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?.

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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)

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : Yes

Gender eligible for study: All

Things to know

Study dates

Study start: 2023-11-23

Primary completion: 2027-10-01

Study completion finish: 2028-10-01

Study type

BASIC_SCIENCE

Phase

PHASE4

Trial ID

NCT06148025

Intervention or treatment

BIOLOGICAL: BCG vaccine

BIOLOGICAL: Yellow Fever vaccine

DRUG: Vancomycin Oral Capsule

DRUG: Neomycin Oral Product

Conditions

• Vaccine Response Impaired

Image related to Vaccine Response Impaired

Condition: Vaccine Response Impaired
BIOLOGICAL: BCG vaccine and other drugs
Adelaide, South Australia, Australia
Sponsor: South Australian Health and Medical Research Institute

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Find a site

Closest Location:

South Australian Health and Medical Research Institute

Research sites nearby

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South Australian Health and Medical Research Institute
Adelaide, South Australia, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

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
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
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
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
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
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

Primary Outcome Measure	Primary Outcome Description	Primary Outcome 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

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome 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

Frequently Asked Questions

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References

Clinical Trials Gov: Antibiotics and Vaccine Immune Responses Study