Vaccine Response Impaired
Conditions
Keywords
Healthy participants, 18-35 years old, BCG vaccine, Yellow Fever vaccine, Antibiotics
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.
Interventions
BIOLOGICALBCG vaccine
0.1ml injected intradermally over the distal insertion of the deltoid muscle onto the humerus
BIOLOGICALYellow Fever vaccine
0.5ml injected subcutaneously
500mg every 6 hours for 3 days
DRUGNeomycin Oral Product
1000mg every 6 hours for 3 days
10mg every 8 hours
DRUGLoperamide HCl
2mg tablets/capsules: 2 tablets/capsules initially, followed by 1 tablet after each loose motion, to a maximum of 8 tablets/capsules per day
Sponsors
South Australian Health and Medical Research Institute
Royal Adelaide Hospital
Flinders University
University of Sydney
Telethon Kids Institute
Centenary Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Masking description
Participants and Investigator are blinded to BCG vaccine or placebo.
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)
Eligibility
Sex/Gender
ALL
Age
18 Years to 35 Years
Healthy volunteers
Yes
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 vaccination * Previous YF vaccination or YFV infection (only applies to participants included in the Yellow Fever Vaccine challenge sub-study) * Evidence of TB infection (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 or antibiotics * 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) * Have received any vaccinations in the 28 days prior to study visits 1 and 4
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sub-study 1 BCG re-challenge | 2 weeks post BCG challenge | Mycobacterial load (Colony Forming Units (CFU)/mg tissue) 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) |
| Sub-study 2 Yellow Fever vaccine | 3, 5, 7 days post YFV challenge | Peak Yellow Fever viremia (viral copies/ml plasma) at day 3-7 post YFV vaccination in BCG-vaccinated participants not exposed to antibiotics (BCG-No ABX) compared to BCG-vaccinated participants that were exposed to antibiotics (BCG-ABX) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sub-study 1 - Bacterial load | Baseline (1-2 weeks before BCG/placebo vaccination), Day of vaccination and Day of BCG challenge | Bacterial load (16S rRNA gene copies/g stool) in ABX participants compared to No-ABX participants |
| Sub-study 2 - Bacterial load | Baseline (1-2 weeks before BCG/placebo vaccination), Day of vaccination and Day of YFV challenge | Bacterial load (16S rRNA gene copies/g stool) in ABX participants compared to No-ABX participants |
| Sub-study 1 - Microbiota diversity | Baseline (1-2 weeks before BCG/placebo vaccination), Day of vaccination and Day of BCG challenge | Microbiota diversity (Shannon diversity index) in ABX participants compared to No-ABX participants |
| Sub-study 2 - Microbiota diversity | Baseline (1-2 weeks before BCG/placebo vaccination), Day of vaccination and Day of YFV challenge | Microbiota diversity (Shannon diversity index) in ABX participants compared to No-ABX participants |
| Sub-study 1 - Mycobacterial load | 2 weeks post BCG challenge | Mycobacterial load (CFU/mg tissue) in the skin biopsy site of BCG-vaccinated participants compared to placebo-vaccinated participants |
| Sub-study 1 - Mycobacterial-specific IFNγ responses | Baseline (1-2 weeks before BCG/placebo vaccination), 2 weeks post vaccination, Day of BCG challenge and 2 weeks post BCG challenge | Mycobacterial-specific IFNγ responses (number of spot-forming units) in BCG-ABX participants compared to BCG-No ABX participants |
| Sub-study 1 - Mycobacterial-specific CD4+ T cell activation marker responses | Baseline (1-2 weeks before BCG/placebo vaccination), 2 weeks post vaccination, Day of BCG challenge and 2 weeks post BCG challenge | Mycobacterial-specific T cell activation-induced marker expression (frequency of OX40+CD137+ CD4+ T cells) in BCG-ABX participants compared to BCG-No ABX participants |
| Sub-study 1 - Mycobacterial-specific CD8+ T cell activation marker responses | Baseline (1-2 weeks before BCG/placebo vaccination), 2 weeks post vaccination, Day of BCG challenge and 2 weeks post BCG challenge | Mycobacterial-specific T cell activation-induced marker expression (frequency of CD69+CD137+ cells of CD8+ T cells) in BCG-ABX participants compared to BCG-No ABX participants |
| Sub-study 2 - Peak viraemia | 3, 5 and 7 days post YFV challenge | Peak viraemia (viral copies/ml plasma) at day 3-7 post YFV challenge in BCG-vaccinated participants compared to placebo-vaccinated participants |
| Sub-study 2 - Heterologous TNFα responses following R848 stimulation | Baseline (1-2 weeks before BCG/placebo vaccination) and Day of YFV challenge | TNFα cytokine production (pg/mL) following stimulation of PBMC with resiquimod (R848) in BCG-ABX participants compared to BCG-No ABX participants |
| Sub-study 2 - Heterologous TNFα responses following LPS stimulation | Baseline (1-2 weeks before BCG/placebo vaccination) and Day of YFV challenge | TNFα cytokine production (pg/mL) following stimulation of PBMC with lipopolysaccharide (LPS) in BCG-ABX participants compared to BCG-No ABX participants |
| Sub-study 2 - Heterologous TNFα responses following HKCA stimulation | Baseline (1-2 weeks before BCG/placebo vaccination) and Day of YFV challenge | TNFα cytokine production (pg/mL) following stimulation of PBMC with heat-killed Candida albicans (HKCA) in BCG-ABX participants compared to BCG-No ABX participants |
Countries
Australia
Contacts
CONTACTDavid Lynn
PRINCIPAL_INVESTIGATORDavid Lynn
South Australian Health and Medical Research Institute
PRINCIPAL_INVESTIGATORSimone Barry
Royal Adelaide Hospital
Outcome results
None listed