TB044: Aerosol BCG challenge study in BCG-vaccinated volunteers
Research type
Research Study
Full title
A clinical challenge study to evaluate controlled human infection with BCG administered by the aerosol inhaled route in historically BCG-vaccinated healthy adult volunteers
IRAS ID
276608
Contact name
Helen McShane
Contact email
Sponsor organisation
University of Oxford / Research Governance, Ethics & Assurance
Clinicaltrials.gov Identifier
206331/Z/17/Z , Wellcome Trust grant Reference Number
Duration of Study in the UK
1 years, 6 months, 0 days
Research summary
Research Summary
Tuberculosis (TB) is responsible for more deaths worldwide than any infectious disease. 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, we are developing a challenge model using the BCG as an infectious agent to mimic TB infection.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 our 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 people who have previously been vaccinated with BCG. It will involve 12 subjects in a controlled dose escalation. We will perform bronchoscopies 14 days post-challenge to measure BCG recovered from the bronchial samples. We will take blood tests to look at potential immunological markers of immunity.
Summary of Results
Tuberculosis (TB) remains the leading cause of death from a single infectious agent. Although a vaccine against TB exists called BCG, it is not particularly effective at protecting people, particularly in countries where the risk of TB infections is greatest.
Despite significant research we have not yet discovered an effective vaccine against TB in adults. One of the major difficulties has been in the cost, size and complexity of testing if a vaccine works to protect people against TB in a phase 3 clinical trial. This is one reason why TB vaccine development is slow and expensive. One way to demonstrate if a vaccine works or not is to give a vaccinated person that infection on purpose, this is called a “Controlled Human Infection Model” or “CHIM”. In this study we were trying to develop a CHIM to test TB vaccines, by asking volunteers to breathe in a weakened version of the bacteria which causes TB, this bacteria called BCG, has been used as a injectable vaccine for over 100 years. The BCG bacteria cannot cause TB, and does not cause infections in people with a normal immune system. In this study we wanted to show that it was safe for healthy adults to breathe in BCG, if they had previously been given BCG as vaccine under their skin.
We recruited 12 healthy UK adults aged 18-50 years into our study. The study was split into 4 groups, depending which group the volunteer was enrolled into they were given either very low, low, medium or a high dose of BCG. We took a cautious approach to increasing the dose, and only did so after reviewing the symptoms and side effects of each volunteer in the low dose group.
The BCG was given as a fine mist (aerosol) which they breathed in over a few minutes. We recorded the symptoms which the volunteers had, measured the function of their lungs and took measurements of their heart rate, and oxygen levels. We took blood tests to measure how the volunteer’s immune systems was responding the controlled infection, and we attempted to measure the amount of live BCG in the lungs 14 days after infection by taking washings using a fibreoptic camera in a procedure called a bronchoscopy. Being able to measure the amount of BCG in these washings will allow us to measure how effective a new vaccine might be. We also investigated how much BCG was being breathed out at various time points during the study using specially adapted face masks and samples of phlegm (sputum).
This study found that it was safe to give aerosol BCG even at the highest dose that we planned. There were no serious side effects in any of the volunteers during the study. All volunteers did report some side effects after breathing in BCG, however, these were mostly short lived, lasting on average less than 4 days. None of the symptoms experienced were classed as severe during the first 14 days after BCG infection. We did find that that volunteers in the high BCG dose reported symptoms on more days than in the other three lower dose groups, and the number and intensity of symptoms varied from person to person. The lung function tests of people in the study did not significantly change after breathing in BCG. We did not find that any of the volunteers in the study had live BCG detectable in the washings of the lungs 14 days after the infection. This was different to another study where we performed a controlled BCG infection in UK adults who had never previously been vaccinated with BCG. In that study we could grow BCG after 14 days in volunteers given various doses of BCG by inhalation. In the current study, we could detect some evidence of genetic material from BCG in the breath of volunteers even up to 14 days after infection. This suggested to us that BCG may still be present, but it was either already killed by the immune system or present in very low amounts. When investigating the immune system response to BCG infection, we found that immune cells responding to BCG were highly active in the first two weeks after infection, but antibody levels which were specific to BCG did not increase, this is similar to what we have seen in previous studies.
Overall, this study shows that a controlled infection with BCG as a mist (aerosol) can be given safely to healthy UK adults at all the doses we investigated. We showed that the immune systems of volunteers were activated after being given BCG, and it is therefore likely that the reason that we were unable to grow BCG from lung washing was because the volunteer’s immune system was able to fight off the bacteria quickly, within the first 14 days. As some people in this study had more symptoms than others, we think it is important to do further research on other healthy adults to understand the full range of side effects to the infection. However, the results suggest that it is safe to take this controlled human infection model of aerosol forward using the highest dose of BCG we tested. We think that this tool could be next be used to test an experimental TB vaccine to provide an indication of whether the vaccine is likely to work or not in a phase 3 trial and in real life.
REC name
South Central - Oxford A Research Ethics Committee
REC reference
20/SC/0059
Date of REC Opinion
13 May 2020
REC opinion
Favourable Opinion