Cross protection against TB by attenuated Mycobacterium ulcerans strain 5114
Led by Dr Justice Boakye-Appiah (SGUL, UK), with Dr Rajko Reljic (SGUL, UK) and Dr Tufária Mussá (Eduardo Mondlane University, Mozambique)
Project Aims
Bacillus Calmette-Guerin (BCG) vaccine has been used since 1921 as a vaccine against tuberculosis (TB). Over these years, the extent of protection it offers has been a matter of controversy as it has been found to offer no protection at all to people of certain age groups and geographical locations, while offering up to 60% protection to others. It is commonly thought that the lack of better protection by BCG may be due to over-attenuation, that is, loss of too many virulence factors. However, we have recently shown that BCG, despite the lack of virulence, is still capable of down-regulating cellular processes which are required for optimal immune responses. We therefore propose that other mycobacteria which share significant homology with Mycobacterium tuberculosis but are less capable of manipulating the cellular immune responses involved could induce a more protective immune response against TB.
Mycobacterium ulcerans, the bacteria that cause Buruli Ulcer (BU) disease is closely related to both BCG and MTB. We have identified an avirulent strain of Mycobacterium ulcerans which by virtue of its inability to secrete the toxin mycolactone, did not cause any lesions in animal models of BU disease when we infected mice footpads. When used as a subcutaneous vaccine against BU disease, 70% of the mice were protected. When a boost vaccine (BURULIVAC) was added, protection went up to 100%.
Here, we want to determine whether or not this strain of Mycobacterium ulcerans can offer superior protection to BCG against TB, by carrying out immunizations in mice and challenging with aerosolised MTB. We will also test the responses of immune cells collected from TB patients, latently MTB-infected individuals and healthy BCG vaccinees to purified protein derivatives from this strain of Mycobacterium ulcerans, and determine the degree of immune cross-reactivity between these two pathogens.
Project Outcomes
Bacillus Calmette-Guerin (BCG) vaccine has been used since 1921 as a vaccine against tuberculosis (TB). Over these years, the extent of protection it offers has been a matter of controversy as it has been found to offer no protection at all to people of certain age groups and geographical locations, while offering up to 60% protection to others. It is commonly thought that the lack of better protection by BCG may be due to over-attenuation, that is, loss of too many virulence factors. However, we have recently shown that BCG, despite the lack of virulence, is still capable of down-regulating cellular processes which are required for optimal immune responses. We therefore propose that other mycobacteria which share significant homology with Mycobacterium tuberculosis but are less capable of manipulating the cellular immune responses involved could induce a more protective immune response against TB.
Mycobacterium ulcerans, the bacteria that cause Buruli Ulcer (BU) disease is closely related to both BCG and MTB. We have identified an avirulent strain of Mycobacterium ulcerans which by virtue of its inability to secrete the toxin mycolactone, did not cause any lesions in animal models of BU disease when we infected mice footpads. When used as a subcutaneous vaccine against BU disease, 70% of the mice were protected. When a boost vaccine (BURULIVAC) was added, protection went up to 100%.
In this project, we intended to determine whether or not this strain of Mycobacterium ulcerans can offer superior protection to BCG against TB, by carrying out immunizations in mice and challenging with aerosolised MTB. We were also to test the responses of immune cells collected from TB patients, latently MTB-infected individuals and healthy BCG vaccinees to purified protein derivatives from this strain of Mycobacterium ulcerans, and determine the degree of immune cross-reactivity between these two pathogens.
We immunised mice with mycolactone deficient Mycobacterium ulcerans boosted by its protein antigen Ag85A and some adjuvants. We also collected immune cells from TB patients, latent MTB- Infected individuals and healthy BCG vaccinees. Challenge experiments are however pending because of the prolonged COVID lockdowns and restrictions. Experiments are scheduled to continue as laboratory and animal work resume fully.
