Tuberculosis
Conditions
Keywords
Tuberculosis, BCG, Human challenge, Aerosol BCG challenge
Brief summary
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
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.
Interventions
BIOLOGICALBCG Danish
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.
Sponsors
University of Oxford
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Quantify BCG Recoverable From Bronchial Sample | Day 14 | Quantification of BCG culture by mycobacterial growth indicator tube (PCR quantification and DNA strip assay speciation as required) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | Up to day 168 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Identify Laboratory Markers of Immune Response That Correlate With the Levels of BCG Recovered From Bronchial and Other Samples. | Up to day 168 | Laboratory markers of innate and adaptive immunity, determined by ex-vivo ELISpot |
| Identify Laboratory Markers of Immune Response That Correlate With the Levels of BCG Recovered From Bronchial Samples. | Up to day 168 | Laboratory markers of innate and adaptive immunity, determined by ELISA |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1: 1 x 10^4 Cfu Aerosol Inhaled BCG 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.
BCG Danish: 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. | 3 |
| Group 2: 1 x 10^5 Cfu Aerosol Inhaled BCG 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.
BCG Danish: 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. | 3 |
| Group 3: 1 x 10^6 Cfu Aerosol Inhaled BCG 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.
BCG Danish: 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. | 3 |
| Group 4: 1 x 10^7 Cfu Aerosol Inhaled BCG 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.
BCG Danish: 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. | 3 |
| Total | 12 |
Baseline characteristics
| Characteristic | Group 1: 1 x 10^4 Cfu Aerosol Inhaled BCG | Group 2: 1 x 10^5 Cfu Aerosol Inhaled BCG | Group 3: 1 x 10^6 Cfu Aerosol Inhaled BCG | Group 4: 1 x 10^7 Cfu Aerosol Inhaled BCG | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 12 Participants |
| Race and Ethnicity Not Collected | — | — | — | — | 0 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 8 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 3 / 3 | 1 / 3 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 |
Outcome results
Primary
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)
Time frame: Day 14
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: 1 x 10^4 Cfu Aerosol Inhaled BCG | To Quantify BCG Recoverable From Bronchial Sample | 0 Volunteers with detectable BCG |
| Group 2: 1 x 10^5 Cfu Aerosol Inhaled BCG | To Quantify BCG Recoverable From Bronchial Sample | 0 Volunteers with detectable BCG |
| Group 3: 1 x 10^6 Cfu Aerosol Inhaled BCG | To Quantify BCG Recoverable From Bronchial Sample | 0 Volunteers with detectable BCG |
| Group 4: 1 x 10^7 Cfu Aerosol Inhaled BCG | To Quantify BCG Recoverable From Bronchial Sample | 0 Volunteers with detectable BCG |
Secondary
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.
Time frame: Up to day 168
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: 1 x 10^4 Cfu Aerosol Inhaled BCG | Adverse Events | 3 Number of participants reporting events |
| Group 2: 1 x 10^5 Cfu Aerosol Inhaled BCG | Adverse Events | 1 Number of participants reporting events |
| Group 3: 1 x 10^6 Cfu Aerosol Inhaled BCG | Adverse Events | 3 Number of participants reporting events |
| Group 4: 1 x 10^7 Cfu Aerosol Inhaled BCG | Adverse Events | 3 Number of participants reporting events |
Other Pre-specified
Identify Laboratory Markers of Immune Response That Correlate With the Levels of BCG Recovered From Bronchial and Other Samples.
Laboratory markers of innate and adaptive immunity, determined by ex-vivo ELISpot
Time frame: Up to day 168
Other Pre-specified
Identify Laboratory Markers of Immune Response That Correlate With the Levels of BCG Recovered From Bronchial Samples.
Laboratory markers of innate and adaptive immunity, determined by ELISA
Time frame: Up to day 168
Other Pre-specified
Identify Laboratory Markers of Immune Response That Correlate With the Levels of BCG Recovered From Bronchial Samples.
Laboratory markers of innate and adaptive immunity, determined by RNA sequence analysis
Time frame: Up to day 168
Other Pre-specified
Identify Laboratory Markers of Immune Response That Correlate With the Levels of BCG Recovered From Bronchial Samples.
Laboratory markers of innate and adaptive immunity, determined by intracellular cytokine staining of blood and bronchial samples
Time frame: Up to day 168
Other Pre-specified
Identify Laboratory Markers of Immune Response That Correlate With the Levels of BCG Recovered From Bronchial Samples.
Laboratory markers of innate and adaptive immunity, determined by BCG cfu counts and or molecular diagnostics on induced sputum
Time frame: Up to day 168
Other Pre-specified
Identify Laboratory Markers of Immune Response That Correlate With the Levels of BCG Recovered From Bronchial Samples.
Laboratory markers of innate and adaptive immunity, determined by matrix from adapted mask collection
Time frame: Up to day 168