On Monday 10 May, Helena Clemmensen will defend her PhD thesis "Differential characteristics of antigens during Mycobacterium tuberculosis infection -Implications for next-generation tuberculosis vaccines".
Time: 13:00
Place: Zoom: https://dtudk.zoom.us/meeting/register/u5MocOCuqzwoE9ShUkeSGYZGl79CTlrL1QtB
Please note registration is required via the link to participate.
Supervisor: Professor Sine Reker Hadrup
Co-Supervisor: Gregers Jungersen, Statens Serum Institut
Co-Supervisor: Rasmus Mortensen, Statens Serum Institut
Assessment committee:
Professor Peter Heegard, DTU Health Tech
Professor Anders Woetmann, University of Copenhagen
Professor Pere-Joan Cardona, Autonomous University of Barcelona
Chairperson: Associate Professor Katharina Lahl
Abstract:
Tuberculosis (TB) is an infectious disease caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb). Mtb has coevolved with humans throughout history and still haunts us to this day with 1.4 million deaths every year. Despite access to antibiotic treatment and mass vaccination with the only licensed TB vaccine, BCG, the global TB epidemic is still raging. According to the World Health Organization, vaccination is the most cost-effective and sustainable intervention, which stresses the need for a more effective vaccines against TB.
CD4 T cells are essential for controlling Mtb infection and priming of an optimal vaccine-induced CD4 T cell response is therefore ultimate goal for future TB vaccines. Chronic antigen exposure to Mtb antigens, however, pushes CD4 T cells towards a gradual loss of immune function to a non-protective state known as “terminal T cell differentiation”. The aims of this thesis were to study the conditions for antigen-specific T cell differentiation during murine Mtb infection and design vaccination strategies to mitigate T cell differentiation for optimal immunity. This includes identification of the optimal vaccination regimen for combining BCG with subunit vaccines.
The research presented in this thesis address knowledge gaps in protective T cell immunity and optimal antigen selection for TB vaccine development. Collectively, these results urge future TB antigen discovery programs to identify Mtb antigens with the highest in vivo expression and accompanied T cell differentiation degree as targeted vaccination against these antigen “hot-spots” can prevent excessive T cell differentiation and improve vaccine efficacy. Moreover, future studies should evaluate protective efficacy of TB vaccine candidates in long-term studies to minimize the chances of making a poor antigen choice, as the most pronounced differences in antigen-specific T cell differentiation and protection is found during chronic infection. Based on this research and the most recent insight in TB immunology, this thesis also introduces a novel and highly protective TB vaccine, H107, which is designed to bypass BCG-mediated T cell differentiation and is suitable for co-administration with BCG due to lack of cross-reactivity immune responses. H107 represents a next-generation TB vaccine candidate ready for clinical testing, which has potential for enhanced efficacy in both infants and adolescents/adults.