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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

    Study type

    BASIC_SCIENCE

    phase

    Phase

      PHASE4

    trial

    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

    Find a site

    Closest Location:

    South Australian Health and Medical Research Institute

    Research sites nearby

    Select from list below to view details:

    • South Australian Health and Medical Research Institute

      Adelaide, South Australia, Australia

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    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/ArmIntervention/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 MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    Sub-study 1 BCG re-challengeMycobacterial 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 vaccineYellow 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 MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    Sub-study 1 - Bacterial loadDay 0 bacterial load (16S copies/g stool) in all ABX participants vs No-ABX participants5 years
    Sub-study 2 - Bacterial loadDay 0 bacterial load (16S copies/g stool) in all ABX participants vs No-ABX participants5 years
    Sub-study 1 - Microbiota diversityDay 0 microbiota diversity (Shannon diversity index) in all ABX participants vs No-ABX participants5 years
    Sub-study 2 - Microbiota diversityDay 0 microbiota diversity (Shannon diversity index) in all ABX participants vs No-ABX participants5 years
    Sub-study 1 - Mycobacterial loadMycobacterial load (CFU) in the skin biopsy site in BCG-vaccinated participants compared to placebo-vaccinated participants5 years
    Sub-study 1 - Mycobacterial IFNγ responsesIFNγ production in pg/mL following stimulation of PBMC with mycobacteria in BCG-ABX participants versus BCG-No ABX participants5 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 participants5 years
    Sub-study 2 - Peak viraemiaPeak viraemia (viral copies/ml blood) at D3-7 post YF vaccination in BCG-vaccinated participants compared to placebo-vaccinated participants5 years
    Sub-study 2 - Heterologous TNFα responses following R848 stimulationD90 PBMC TNFα responses (pg/mL) following in vitro stimulation with viral ligand R848 in BCG-ABX participants versus BCG-No ABX participants5 years
    Sub-study 2 - Heterologous TNFα responses following LPS stimulationD90 PBMC TNFα responses (pg/mL) following in vitro stimulation with bacterial ligand LPS in BCG-ABX participants versus BCG-No ABX participants5 years
    Sub-study 2 - Heterologous TNFα responses following fungal stimulationD90 PBMC TNFα responses (pg/mL) following in vitro stimulation with fungal ligand heat-killed C. albicans in BCG-ABX participants versus BCG-No ABX participant5 years

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    References

    Clinical Trials Gov: Antibiotics and Vaccine Immune Responses Study

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