Clinical trial NCT06148025: Antibiotics and Vaccine Immune Responses Study
Official title: A Human Experimental Medicine Study to Assess Whether the Gut Microbiota Regulates Specific and Non-specific Immune Responses to Vaccination
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Vaccine Response Impaired
Keywords: Healthy participants
18-35 years old
BCG vaccine
Yellow Fever vaccine
Antibiotics
Lead sponsor: South Australian Health and Medical Research Institute
Sponsor class: OTHER
Collaborators: name: Royal Adelaide Hospital
name: Flinders University
name: University of Sydney
name: Telethon Kids Institute
name: Centenary Institute of Cancer Medicine and Cell Biology
First posted: 2023-11-28
Enrollment: 348
Sex: ALL
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
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)
Primary purpose: BASIC_SCIENCE

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?

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Sub-study 1 BCG re-challenge
timeFrame: 5 years
measure: Sub-study 2 Yellow Fever vaccine
timeFrame: 5 years
Secondary outcomes:
measure: Sub-study 1 - Bacterial load
timeFrame: 5 years
measure: Sub-study 2 - Bacterial load
timeFrame: 5 years
measure: Sub-study 1 - Microbiota diversity
timeFrame: 5 years
measure: Sub-study 2 - Microbiota diversity
timeFrame: 5 years
measure: Sub-study 1 - Mycobacterial load
timeFrame: 5 years
measure: Sub-study 1 - Mycobacterial IFNγ responses
timeFrame: 5 years
measure: Sub-study 1 - Mycobacterial T cell activation marker responses
timeFrame: 5 years
measure: Sub-study 2 - Peak viraemia
timeFrame: 5 years
measure: Sub-study 2 - Heterologous TNFα responses following R848 stimulation
timeFrame: 5 years
measure: Sub-study 2 - Heterologous TNFα responses following LPS stimulation
timeFrame: 5 years
measure: Sub-study 2 - Heterologous TNFα responses following fungal stimulation
timeFrame: 5 years
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: South Australian Health and Medical Research Institute
state: South Australia
Study officials:
affiliation: Royal Adelaide Hospital
name: Simone Barry
role: PRINCIPAL_INVESTIGATOR
affiliation: South Australian Health and Medical Research Institute
name: David Lynn
role: PRINCIPAL_INVESTIGATOR
References: