Ageing is often associated with a reduction in antibody-secreting cell formation and vaccine-induced antibody titres, resulting in poor vaccine responses among the older population. Understanding the mechanisms underlying this age-related defect is imperative for guiding strategies to improve vaccine responses in older people.

Here, I tested the hypothesis that B-cell intrinsic changes with age contribute to the impaired antibody response to vaccination during ageing. I show that B cells from older people do not have defects in their proliferation and differentiation into antibody-secreting cells in vitro compared to those from younger donors. Adoptive transfer of B cells from aged SW_HEL mice into young adult recipient mice showed that differentiation into extrafollicular plasma cells was favoured at the expense of B cells entering the germinal centre (GC) during the early stages of GC formation, compared to those from young donors. Nevertheless, by the peak of the GC response, GC B cells derived from B cells of aged mice had expanded to the same extent as those from the younger donors. This indicates that age-related intrinsic B cell changes might delay the GC response but are not responsible for the impaired antibody-secreting response or smaller peak GC response in ageing.

Using the B1-8i adoptive transfer system, I replicated the data showing that B cells from aged B1-8i mice were equally able to differentiate into extrafollicular plasma cells and mount a peak GC response, compared to their younger counterparts. Furthermore, GC B cells from aged donor mice had no defects in receiving positive selection signals and undergoing affinity maturation to produce high-affinity clones. Conversely, the transfer of B cells from young adult mice into aged recipient mice resulted in smaller numbers of antigen-specific GC B cells and impaired affinity maturation, compared to transfers into young recipient mice. Together, this work shows that B cells from older bodies are not intrinsically defective in responding to stimulation and becoming high-affinity clones. Rather, B cell-extrinsic factors contribute to the age-associated impairment in humoral immunity.

To have an unbiased approach in identifying mechanisms that drive defects in antibody response among older people, I employed a systems immunology approach to investigate the molecular pathways and cellular populations associated with antibody responses to seasonal flu vaccination in individuals aged above 64 years old. Although bulk RNA sequencing analysis of pre-vaccination and day 1 post-vaccination blood samples did not yield differentially expressed genes between vaccine responders and nonresponders, responders exhibited a trend of enhanced upregulation of type I interferon (IFN-I) response genes at day 1 post-vaccination. Furthermore, flow cytometric analysis of peripheral blood mononuclear cells (PBMCs) collected 6-10 days post-vaccination revealed that long-lasting antibody responses to H1N1 antigen positively correlated with higher proportions of HA-binding plasmablasts and circulating T follicular helper (cTfh) cells. These findings suggest that an effective response to seasonal flu vaccine among older individuals relies on a robust antiviral response via IFN-I signalling, coupled with the generation of plasmablasts and cTfh cells.

Together, the results from this thesis contribute to the understanding of mechanisms underlying age-related defects in humoral response to vaccines, which can be used to guide the design of more effective vaccine strategies to protect vulnerable members of our population.