An interventional study of BCG in Tuberculosis, sponsored by Liverpool School of Tropical Medicine. Not yet recruiting at 1 site in Malawi. Open to participants aged 18 Years to 50 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2023-12-21.
Sponsored by Liverpool School of Tropical Medicine · Not applicable, Interventional, and Basic science
Despite tremendous efforts, an effective tuberculosis (TB) vaccine remains elusive. TB continues to infect and kill many. In 2021, TB infected more than 10 million and killed 1.6 million people. To date, the M.bovis bacille Calmette Guerin (BCG) is the only licensed vaccine against tuberculosis (TB). Efforts to come up with new and effective vaccines have not been successful. Partially, the lack of suitable disease models and protection correlates hinders the research of new vaccines. Controlled human infection model studies (CHIM) involve administering disease-causing microbes to healthy individuals, with continued monitoring of disease response. These studies have been used to study malaria, typhoid, pneumococcal pneumonia and the recent SARS-CoV-2 vaccines. The BCG-Controlled Human Infection Model (BCG-CHIM) will allow accurate dosing with safe mycobacteria as well as minimal tissue sampling to understand immunity to mycobacteria. Considering that the M. bovis BCG is a safe living Mycobacteria, it can be used as a CHIM against which to test new vaccines.
Tuberculosis (TB) is a leading cause of death from a single infectious agent worldwide and is an acknowledged major challenge in Malawi. Globally in 2021, there were an estimated 10.6 million people unwell with TB and an estimated 1.6 million deaths caused by TB. Furthermore, the global TB incidence could be accelerated to an average of 17% per year between 2025 and 2035 owing to the disruption to TB services caused by the COVID pandemic. TB diagnosis is challenging, and drug treatment can be prolonged, harmful, costly, and complex, especially in the increasingly common context of drug resistant M. tuberculosis. For these reasons an effective vaccine to prevent disease is a global public health priority, and drugs to allow shorter courses of effective therapy are urgently needed.
At present, the only licensed vaccine is the bacille Calmette-Guérin (BCG) vaccine (BCG Bulgaria is the Malawi licensed strain). BCG has been administered globally to several billion people over the last 100 years and it has been part of the expanded program on immunisations since the early-1970s. BCG is effective in preventing disseminated TB disease, including tuberculous meningitis in childhood. However, it does not protect against pulmonary TB in many parts of the world, especially in the tropics where the incidence of TB is at its greatest. Since pulmonary TB is associated with the highest morbidity and mortality, the need to develop an effective vaccine against this disease is paramount, especially in Malawi where BCG protection is known to be minimal.
There are several novel vaccines for TB in clinical development, the most clinically advanced of which is M72/AS01E. The evaluation of candidate TB vaccines is challenging, and progress in the field is hampered by the lack of an immunological correlate of protection. Most routinely administered vaccines generate a quantifiable antibody response that correlates strongly with protection. In contrast, protection against TB is critically dependent on the cellular immune response, in particular CD4+ and also probably CD8+ T cell mediated cellular responses. The mechanisms of these responses are not fully understood .
Currently, to assess vaccine efficacy against TB there is no alternative to large randomized controlled trials. These efficacy trials for novel TB vaccines are difficult, long and very costly. For this reason, there is an urgent need for a valid, reliable, and strong evaluation technique to help distinguish between candidate TB vaccines' likely efficacy at Phase 3. Candidate vaccines which have passed successfully through phase I trials and are in Phase 2b efficacy studies could be included in human challenge protocols which could be designed to either measure prevention of infection (POI) or immunological endpoints. This would allow vaccine discovery to accelerate in a cost-effective manner. Similarly, successful development of new, safe and effective TB therapies face multiple challenges. A responsive controlled human infection model of TB infection could accelerate the development of new drugs and promote refinement of drug combination regimens.
Controlled human infection models (CHIMs) provide insight into disease pathogenesis and correlates of immune protection to support the development of novel vaccines.
The Malawi Liverpool Wellcome Trust has extensive experience of delivering CHIM studies in Malawi with Streptococcus pneumoniae and established technology transfer processes with previous successful transfer of the experimental human pneumococcal carriage model from Liverpool to Blantyre, Malawi. Before the Malawi BCG study, the team will also confirm feasibility of this established BCG model in Liverpool. The Liverpool team will be able to share techniques and expertise and compare data as the Liverpool population will have a different experience of BCG and tuberculosis in the community and are likely to show different results. A TB CHIM established in both the UK and Malawi has the potential to rapidly advance development of vaccines and therapeutics fit for use in populations that need them most.
1,170 studies on the registry are indexed under Tuberculosis; 175 are open to participants now.
This study's planned enrollment of 30 is below the median of 150 across 820 interventional studies indexed under Tuberculosis.
Browse Tuberculosis studies →Liverpool School of Tropical Medicine is the lead sponsor of 57 studies on the registry; 23 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Vaccines made with a weakened form of the germ, such as measles–mumps–rubella (MMR), chickenpox and yellow fever. They can be risky when the immune system is weakened. Flu injections are not live; the nasal flu spray is.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Live vaccines
Vaccines made with a weakened form of the germ, such as measles–mumps–rubella (MMR), chickenpox and yellow fever. They can be risky when the immune system is weakened. Flu injections are not live; the nasal flu spray is.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The lowest dose of BCG (standard Malawi BCG vaccine (BCG Bulgaria 150000-600000 cfu) given as intradermal injection) will be used to determine safety and feasibility. The investigators do not expect to be able to meet study endpoints in this arm which will recruit 10 subjects.
Biological: BCG
The mid-range dose of BCG (4x standard Malawi dose (BCG Bulgaria 600000-2400000 cfu intradermal) and equal to the model tested in Oxford, UK) will be used to determine safety and feasibility. The investigators hope to to be able to meet study endpoints (measuring microbiological and immunological features of BCG skin lesion) in this arm which will recruit 10 subjects.
Biological: BCG
The highest dose of BCG (10x standard Malawi dose (BCG Bulgaria 2400000-9600000 cfu intradermal) and equal to USA dose used in Seattle) will be used to determine safety and feasibility. The investigators expect to be able to meet study endpoints in this arm which will recruit 10 subjects. In the event that study endpoints are met in the mid-range dose, the investigators will introduce a rifampicin dosing schedule to this arm.
Biological: BCG
Three dose levels of intradermal BCG
Also known as: Bacille Calmette Guerin
Culture and PCR ascertainment of BCG load
BCG will be quantified in 4mm skin punch biopsy
Time frame: 14 days
Immunological response to BCG
Innate, humoral and cellular immune functions will be quantified in 4mm skin punch biopsy, mucosal and blood samples using ELISA, flow cytometry, 10X single cell and geospatial transcriptomics.
Time frame: 14 days
Microbiology and immunology
The BCG infection quantified in Outcome 1 will be compared with the Immunology determined in Outcome 2 to provide associations which may later be tested as correlates of protection.
Time frame: Day 2, 7, 14, 21, 28
Lung cellular and humoral immune response
Bronchoalveolar lavage will be collected in a subset of volunteers willing to undergo this procedure. Bronchoalveolar lavage cells will be studied by flow cytometry for phenotype and antigen specific cytokine production. BAL fluid will be used to measure anti-BCG Ig responses by ELISA.
Time frame: Day 14 after inoculation
Plan to share: No — Anonymised data will be shared in an online database. IPD would breach data protection guidelines and will not be necessary to interpret the study.
Start is estimated for Mar 2024; primary completion for Mar 2025, 12 months later.
Of 169 non-industry interventional studies with no phase under Tuberculosis, half reached primary completion within 25 months of starting (the median), counting those still running; a quarter within 15 and three quarters within 41. This study's planned 12 months is below that.
Counting every sponsor, half of 171 studies reached it within 25 months; a quarter within 14 and three quarters within 41.
How these figures are worked out, and which studies are left out of them.
This study is not yet recruiting, as verified in Dec 2023. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: BCG Vaccine
Liverpool School of Tropical Medicine