Lymph node remodelling for optimal vaccine responses

Infectious disease is a significant cause of morbidity and mortality in the elderly, and this is in part due to reduced functionality of the immune system. While vaccines are an excellent public health measure to limit infections, they are often not effective in older persons. Therefore, improved vaccine efficacy in the elderly is an important goal of vaccine research. Vaccination provides protective immunity through the generation of antibodies that prevent infections. This requires a series of interactions between immune cells, and these interactions are coordinated by lymph node stromal cells. Lymph node stromal cells form highways for immune cells, supplying migration and survival cues to immune cells and essentially governing their behaviour. Because our understanding of how stromal cells respond to vaccines is very limited, the optimal vaccine formulation remains elusive. This research aims to understand how lymph node stromal cells respond to vaccination, and find a way to use this knowledge to make vaccines more effective in older persons. I will use this fellowship to understand how stromal cell respond to vaccines, how these responses are dysfunctional with increasing age and how this could be overcome to improve vaccine efficacy. I will use state-of-the-art techniques to determine the range of different lymph node stromal cell types and determine how this differs with different vaccines. I will then determine how these different types of stromal cells control immune cell location and function - this will give important information about which types of stromal cells are critical for the best vaccine response. I will then tease apart the complexity of vaccines and use in vitro approaches to determine what specific ingredients stimulate lymph node stromal cells and drive them to acquire different functions. Finally, I will apply these methods to stromal cells isolated from aged individuals and determine which of these pathways are dysfunctional with age and how that can be overcome. The ultimate aim is to devise a route to overcome the age-associated barriers to immune responses and improve vaccine efficacy in older individuals. The outcomes of this research will not only have a direct impact on the design of vaccines with the aim to improve vaccine efficacy in older individuals, but also be relevant to other settings where vaccines have thus far been elusive, including malaria, tuberculosis and viral infections such as respiratory syncytial virus. This research, which aims to understand the fundamental biology that underpins adaptive immune responses, will also have implications for diseases where manipulation of the immune response offers therapeutic potential, such as autoimmune disease and cancer.