Towards a better TB vaccine: understanding improved local immune control by mucosal BCG vaccination
Led by Dr Paula Niewold (LUMC, The Netherlands), with Dr Frank Verreck (BPRC, The Netherlands)
Project Aims
Tuberculosis is an infectious disease of the lung caused by Mycobacterium tuberculosis. It can spread between people via coughing and yearly 10 million people become infected, with 1.5 million people dying as a result of infection. Treatment consists of multiple months of antibiotics, but infection is becoming more difficult to treat as antibiotic resistance is increasing. Furthermore, the only approved vaccine, BCG, has limited efficacy. Ongoing attempts to develop improved vaccines are hampered by a lack of knowledge on the characteristics of the optimally effective immune response against Mycobacterium tuberculosis.
Non-human primates are an important representative model for human infection with Mycobacterium tuberculosis as they have an immune system and disease presentation very similar to humans. Recent studies in this animal model have shown that BCG vaccination in the lung, e.g. the site of Mycobacterium infection, results in a more effective protection than standard BCG vaccination in the skin. Here, we want to find out why and how lung vvaccination improves protection against infection. To achieve this, we will compare lung material from animals that were BCG vaccinated in the skin or lung and subsequently infected with Mycobacterium tuberculosis. We will study the organisation of immune cells within the lung as well as the type of cells present at the site of infection to explain why lung vaccination gives a more protective response against Mycobacterium tuberculosis than skin vaccination.
This knowledge will help us understand which immune responses are required to control Mycobacterium tuberculosis infection and disease. This will inform improved vaccine design to achieve better protection against Mycobacterium tuberculosis infection and ultimately reduce the burden of tuberculosis.
Project Outcomes
We found that BGC vaccination induced cells that are relevant to the immune response to Mycobacterium tuberculosis in the lung via both routes of infection. However, in the lungs of vaccinated animals, the number of these cells were higher and they grouped together, which suggests improved collaboration likely leading to a more successful anti-mycobacterial response. In addition, lung vaccination yielded more activated cells and specific phenotypes associated with improved protection against Mycobacterium tuberculosis. This indicates that lung vaccination results in more immune cells in the lung, the cells are of a type that is effective in fighting the bacterium, they are located close together enabling them to interact and these cells are more activated. Overall, this shows that the improved protection seen after lung vaccination is a result of an improvement in all four aspects of the immune response over the original skin vaccination. These findings are very relevant to TB vaccine development, as many of the factors that are important for a protective response against Mycobacterium tuberculosis are still unclear. By identifying these factors underlying improved protection by lung vaccination, we gain a clearer picture of what type of immune responses we should be targeting with vaccines against tuberculosis. In addition, it gives an insight of how lung vaccination impacts the immune response in general, which may be of interest for other diseases or existing vaccines with limited efficacy when administered via the skin.
