Impaired selection of germinal centre B cells in ageing diminishes the quality of antibody mediated immunity upon vaccination

One of the major achievements of the modern era is the extension of the human lifespan. The consequent shift towards older populations creates a challenge for science, to understand the ageing process in order to facilitate healthy ageing. As we age, we are more likely to have poor health outcomes after infection. This, sadly, has been demonstrated by the COVID-19 pandemic with older people more likely to be hospitalised and/or die after infection. Vaccination is currently the most effective way to prevent infectious disease, but changes in the immune system over our lifetimes mean that older people are often less well protected by vaccines than younger people.

Most vaccines work by stimulating B cells, a type of white blood cell, to produce antibodies that can effectively neutralise pathogens and stop an infection in its tracks. To generate potent antibody responses upon vaccination, B cells need to interact with other immune cells in hubs called germinal centres. Within germinal centres, B cell receive instructions from both T cells, another type of white blood cell, and other neighbouring cells that provide structure and survival signals. These instructions help improve the quality of the antibody response to the vaccine, creating a long-lived, high quality antibody response after vaccination. In older individuals, the germinal centres that form upon vaccination are smaller and the quality of the antibody response that comes from these hubs is poorer than in younger individuals. This project will investigate whether ageing impairs the delivery of appropriate instructions from T cells and structural cells to B cells, or whether older B cells are unable to be properly educated in the germinal centre. From this research, we will understand why older individuals are more likely to have a poor-quality antibody response to vaccination. It is our aim to use this knowledge to inform future vaccination strategies that are more effective in older bodies in order to promote health across the lifespan.

Infections are a major cause of morbidity and mortality in older people. Whilst vaccination is an excellent preventative for infectious disease, older individuals often do not generate protective immunity after vaccination, resulting in an increased prevalence of preventable disease in older people.

Most vaccines provide protection by generating antibodies that block the ability of a pathogen to infect the host. Long-lived antibody-secreting cells are formed within germinal centres, microanatomical structures that form in secondary lymphoid tissues. Germinal centres are unique in that they are the only site in which antibody responses can be improved during the immune response to vaccination, by increasing the affinity with which resulting antibodies bind to vaccine (and pathogen) antigens. With advancing age, affinity-based selection within the germinal centre is impaired, which reduces the production of antibody-secreting cells able to secrete antibodies that bind pathogens with high affinity, thereby reducing the potency of the antibody response. This project aims to determine the mechanism that underpins poor affinity maturation of the antibody response in ageing.

Within the germinal centre, selection of high affinity variants is an iterative process in which mutation is targeted to the genes encoding the B cell receptor, followed by a two-step cell selection process. First B cells test the capacity of their mutated B cell receptor to bind antigen held on the surface of follicular dendritic cells; then, if they pass this test successfully, they internalise antigen and present it to T follicular helper cells, from which they receive survival signals. This project will determine whether age-related defects in follicular dendritic cells and T follicular helper cells cause impaired affinity maturation in ageing, or whether B cell intrinsic changes with age are responsible.