Antibiotics and Vaccine Immune Responses Study (AVIRS)

South Australian Health and Medical Research Institute

Status and phase: Enrolling; Phase 4

Conditions: Vaccine Response Impaired

Treatments: Biological: Yellow Fever vaccine; Drug: Vancomycin Oral Capsule; Drug: Neomycin Oral Product; Biological: BCG vaccine

Study type: Interventional

Funder types: Other

Identifiers

NCT06148025

2023/HREC00066

Details and patient eligibility

About

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?

Full 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.

Enrollment: 348 estimated patients

Sex: All

Ages: 18 to 35 years old

Volunteers: Accepts Healthy Volunteers

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)

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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348 participants in 8 patient groups

Substudy 1 - BCG vaccine, antibiotics and 2nd BCG vaccine

Experimental group

Description:

Randomised to receive antibiotics and a BCG vaccine at visit 1 and a second BCG vaccine 6 months later

Treatment:

Drug: Neomycin Oral Product

Drug: Vancomycin Oral Capsule

Biological: BCG vaccine

Substudy 1 - BCG vaccine, no antibiotics and 2nd BCG vaccine

Experimental group

Description:

Randomised to receive no antibiotics and a BCG vaccine at visit 1 and a second BCG vaccine 6 months later

Treatment:

Biological: BCG vaccine

Substudy 1 - BCG vaccine, antibiotics and placebo vaccine

Experimental group

Description:

Randomised to receive antibiotics, a placebo vaccine at visit 1 and a BCG vaccine 6 months later

Treatment:

Drug: Neomycin Oral Product

Drug: Vancomycin Oral Capsule

Biological: BCG vaccine

Substudy 1 - BCG vaccine, no antibiotics and placebo vaccine

Experimental group

Description:

Randomised to receive no antibiotics, a placebo vaccine at visit 1 and a BCG vaccine 6 months later

Treatment:

Biological: BCG vaccine

Substudy 2 - Yellow Fever vaccine, antibiotics and BCG vaccine

Experimental group

Description:

Randomised to receive antibiotics, a BCG vaccine at visit 1 and a Yellow Fever vaccine 3 months later

Treatment:

Biological: Yellow Fever vaccine

Drug: Neomycin Oral Product

Drug: Vancomycin Oral Capsule

Biological: BCG vaccine

Substudy 2 - Yellow Fever vaccine, no antibiotics and BCG vaccine

Experimental group

Description:

Randomised to receive no antibiotics, a BCG vaccine at visit 1 and a Yellow Fever vaccine 3 months later

Treatment:

Biological: Yellow Fever vaccine

Biological: BCG vaccine

Substudy 2 - Yellow Fever vaccine, antibiotics and placebo vaccine

Experimental group

Description:

Randomised to receive antibiotics, a placebo vaccine at visit 1 and a Yellow Fever vaccine 3 months later

Treatment:

Biological: Yellow Fever vaccine

Drug: Neomycin Oral Product

Drug: Vancomycin Oral Capsule

Substudy 2 - Yellow Fever vaccine, no antibiotics and placebo vaccine

Experimental group

Description:

Randomised to receive no antibiotics, a placebo vaccine at visit 1 and a Yellow Fever vaccine 3 months later

Treatment:

Biological: Yellow Fever vaccine