Antibiotics and Vaccine Immune Responses Study

Vaccine Response Impaired Clinical Trial

— AVIRS  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06148025
• Other study ID #: 2023/HREC00066
• Status: Recruiting
• Phase: Phase 4
• Start date: November 23, 2023
• Est. completion date: October 2028

Study information

• Verified date: April 2024
• Source: South Australian Health and Medical Research Institute
• Contact: David Lynn
• Phone: +61 8 8128 4053
• Email: david.lynn[@]sahmri.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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?

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 348
• Est. completion date: October 2028
• Est. primary completion date: October 2027
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 35 Years

Eligibility

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)

Related Conditions & MeSH terms

• Vaccine Response Impaired

Intervention

Biological:
• BCG vaccine
0.1ml injected intradermally over the distal insertion of the deltoid muscle onto the humerus
• Yellow Fever vaccine
0.5ml injected subcutaneously

Drug:
• Vancomycin Oral Capsule
500mg every 6 hours for 3 days
• Neomycin Oral Product
1000mg every 6 hours for 3 days

Locations

Country	Name	City	State
Australia	South Australian Health and Medical Research Institute	Adelaide	South Australia

Sponsors (6)

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

Country where clinical trial is conducted

Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Sub-study 1 - Bacterial load	Day 0 bacterial load (16S copies/g stool) in all ABX participants vs No-ABX participants	5 years
Secondary	Sub-study 2 - Bacterial load	Day 0 bacterial load (16S copies/g stool) in all ABX participants vs No-ABX participants	5 years
Secondary	Sub-study 1 - Microbiota diversity	Day 0 microbiota diversity (Shannon diversity index) in all ABX participants vs No-ABX participants	5 years
Secondary	Sub-study 2 - Microbiota diversity	Day 0 microbiota diversity (Shannon diversity index) in all ABX participants vs No-ABX participants	5 years
Secondary	Sub-study 1 - Mycobacterial load	Mycobacterial load (CFU) in the skin biopsy site in BCG-vaccinated participants compared to placebo-vaccinated participants	5 years
Secondary	Sub-study 1 - Mycobacterial IFN? responses	IFN? production in pg/mL following stimulation of PBMC with mycobacteria in BCG-ABX participants versus BCG-No ABX participants	5 years
Secondary	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
Secondary	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
Secondary	Sub-study 2 - Heterologous TNFa responses following R848 stimulation	D90 PBMC TNFa responses (pg/mL) following in vitro stimulation with viral ligand R848 in BCG-ABX participants versus BCG-No ABX participants	5 years
Secondary	Sub-study 2 - Heterologous TNFa responses following LPS stimulation	D90 PBMC TNFa responses (pg/mL) following in vitro stimulation with bacterial ligand LPS in BCG-ABX participants versus BCG-No ABX participants	5 years
Secondary	Sub-study 2 - Heterologous TNFa responses following fungal stimulation	D90 PBMC TNFa 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