Aerosol BCG Challenge Study in Historically BCG-vaccinated Volunteers

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the human clinical response to BCG challenge in historically BCG-vaccinated healthy adult volunteers. It will involve 12 participants in a controlled dose escalation. Bronchoscopies will be performed 14 days post-challenge to measure BCG recovered from bronchial samples. Blood tests will be taken to look at potential immunological markers of immunity.

Detailed Description
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Tuberculosis (TB) remains one of the deadliest infectious disease killers worldwide. Key research priorities include the development of an effective vaccine. Currently, the only licensed vaccine against TB is the BCG (Bacille Calmette-Guérin). This works well against TB in childhood but is often ineffective in adults. Developing a new TB vaccine is difficult, as it is hard to determine which will be effective. In other diseases, e.g. influenza or malaria, it is possible to experimentally-infect volunteers with the disease to see if the proposed vaccine is effective. This is called a controlled human challenge or infection model and is possible in easily treatable or self-limiting diseases. This is not possible with TB, where treatments may be harmful and complex. Using a related but less infectious bacterium is a feasible alternative. The BCG is a live attenuated (weakened) strain of the bacteria that causes TB in cattle. The BCG bacteria do not cause disease in healthy individuals. As the BCG and TB bacteria are similar, a challenge model using the BCG as an infectious agent to mimic TB infection is being developed. Mycobacterium tuberculosis, the bacterium that causes TB, infects people by inhalation into the lungs. Therefore, inhaled BCG more closely imitates TB infection than an injection. A previous (TB041) and current study (TB043) in this group use aerosol inhaled BCG in volunteers who have not received the standard BCG vaccination before. The purpose of this study is to evaluate the human clinical response to BCG challenge in historically BCG-vaccinated healthy adult volunteers. It will involve 12 participants in a controlled dose escalation. Bronchoscopies will be performed 14 days post-challenge to measure BCG recovered from bronchial samples. Blood tests will be taken to look at potential immunological markers of immunity.

Official Title
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A Clinical Challenge Study to Evaluate Controlled Human Infection With BCG Administered by the Aerosol Inhaled Route in Historically BCG-vaccinated Healthy Adult Volunteers

Conditions
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Tuberculosis

Intervention / Treatment
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* Biological: BCG Danish


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adults aged 18-50 years Previously vaccinated with the BCG (at least 6 months prior to enrolment, as evidenced by a visible scar or documentation in medical or occupational health records) Resident in or near Oxford for the duration of the study period Provide written informed consent Willing to allow the investigators to discuss the volunteer's medical history with their General Practitioner (or review summary care record, if available) Allow the investigator to register volunteer details with a confidential database (The Over-volunteering Protection Service) to prevent concurrent entry into clinical studies/trials Agreement to refrain from blood donation during the course of the study For women of child-bearing potential only, willingness to practice continuous effective contraception (see below) during the study and a negative pregnancy test on the day(s) of screening, challenge and bronchoscopy Able and willing (in the investigator's opinion) to comply with all study requirements No clinically relevant findings in medical history or on physical examination Screening IGRA negative Willing to be tested for evidence of SARS-CoV-2 infection and to allow public health notification of the results Exclusion Criteria: Any clinically significant respiratory disease, including asthma Current smoker (defined as any smoking including e-cigarettes in the last 3 months) History of anaphylaxis to vaccination or any allergy likely to be exacerbated by any component of the study agent, any essential study procedure, sedative drugs, or any local or general anaesthetic agents Clinically significant history of skin disorder, allergy, atopy, cancer (except BCC of the skin or CIS of the cervix), cardiovascular disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder, neurological illness, psychiatric disorder, drug or alcohol abuse Any autoimmune conditions or immunodeficiency (including HIV) Previous diagnosis or treatment for TB disease or latent TB infections Clinical, radiological, or laboratory evidence of current active TB disease or latent TB infection Previous receipt of any investigational TB vaccine Positive HBsAg, HCV or HIV antibodies Concurrent use of oral, inhaled or systemic steroid medication or use for more than 14 days within the last 6 months (steroids used as a cream or ointment are permissible), or the use of other immunosuppressive agents concurrently or for more than 14 days within the last 6 months Administration of immunoglobulins and/or any blood products within the three months preceding the planned study challenge date Current use of any medication or other drug taken through the nasal or inhaled route including cocaine or other recreational drugs Any nasal, pharyngeal, or laryngeal finding which precludes bronchoscopy Pregnancy, lactation or intention to become pregnant during study period Previously resident for more than 12 months concurrently in a tropical climate where significant non-tuberculous mycobacterial exposure is likely Shares a household with someone with clinically significant immunodeficiency (either from infection or medication) who is deemed to be at risk of developing disseminated BCG infection if exposed to BCG Participation in another research study involving receipt of an investigational product in the 30 days preceding enrolment, or planned use during the study period Clinically significant abnormality on screening chest radiograph Clinically significant abnormality of lung function testing Any clinically significant abnormality of screening blood or urine tests Laboratory confirmed (PCR or antibody) SARS-Cov-2 infection, evidence of viral pneumonitis on chest radiograph or a high clinical suspicion of COVID-19 disease in the 3 months preceding enrolment. A body mass index (BMI) of <18.5 or >45 Any other significant disease, disorder, or finding, which, in the opinion of the investigator, may either put the volunteer at risk, affect the volunteer's ability to participate in the study or impair interpretation of the study data

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This is a phase I dose-escalation clinical challenge study in historically BCG-vaccinated healthy adult volunteers in which BCG will be administered via the aerosol inhaled route. There will be four study groups with three volunteers in each group. Volunteers will be sequentially enrolled into each group in turn based on their availability. The first volunteer in each group will be challenged at least 1 hour apart from any subsequent volunteers. There will be a review of safety data at least 7 days after challenge of all volunteers within each dose group. This safety review will be performed by the Safety Monitoring Committee (SMC). Dose escalation into the next group will only occur if there are no safety concerns. Safety review will include assessment of symptom diary card, safety bloods and lung function results.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: 1 x 10^4 cfu aerosol inhaled BCG<br>3 historically BCG-vaccinated volunteers will receive 1 x 10^4 cfu aerosol inhaled BCG. All Group 1 volunteers will have a bronchoscopy 14 days post challenge. | Biological: BCG Danish<br>* BCG Danish 1331 is on the WHO list of pre-qualified vaccines and has a well-defined side effect profile. BCG is licensed for delivery via the intradermal route. It is not licensed for delivery via the aerosol route.<br>|
| Experimental: Group 2: 1 x 10^5 cfu aerosol inhaled BCG<br>3 historically BCG-vaccinated volunteers will receive 1 x 10^5 cfu aerosol inhaled BCG. All Group 2 volunteers will have a bronchoscopy 14 days post challenge. | Biological: BCG Danish<br>* BCG Danish 1331 is on the WHO list of pre-qualified vaccines and has a well-defined side effect profile. BCG is licensed for delivery via the intradermal route. It is not licensed for delivery via the aerosol route.<br>|
| Experimental: Group 3: 1 x 10^6 cfu aerosol inhaled BCG<br>3 historically BCG-vaccinated volunteers will receive 1 x 10^6 cfu aerosol inhaled BCG. All Group 3 volunteers will have a bronchoscopy 14 days post challenge. | Biological: BCG Danish<br>* BCG Danish 1331 is on the WHO list of pre-qualified vaccines and has a well-defined side effect profile. BCG is licensed for delivery via the intradermal route. It is not licensed for delivery via the aerosol route.<br>|
| Experimental: Group 4: 1 x 10^7 cfu aerosol inhaled BCG<br>3 historically BCG-vaccinated volunteers will receive 1 x 10^7 cfu aerosol inhaled BCG. All Group 3 volunteers will have a bronchoscopy 14 days post challenge. | Biological: BCG Danish<br>* BCG Danish 1331 is on the WHO list of pre-qualified vaccines and has a well-defined side effect profile. BCG is licensed for delivery via the intradermal route. It is not licensed for delivery via the aerosol route.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To quantify BCG recoverable from bronchial sample | Quantification of BCG culture by mycobacterial growth indicator tube (PCR quantification and DNA strip assay speciation as required) | Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Evaluation of the human clinical response to BCG challenge via collection of data on adverse events at each visit, via diary cards and lung function test results. | Up to day 168 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberculosis, BCG, Human challenge, Aerosol BCG challenge