Daan Pieren

12 Chapter 1 these naive T cells, which are crucial processes for the anti-viral response [33- 36]. As a result, the few antigen-specific naive T cells expand into a specialized memory T-cell subset. Once the primary infection is cleared, memory T cells that recognize parts of the virus remain present, as well as antibodies that were produced by B cells [23]. Upon secondary encounter, preexisting antibodies may limit infection and memory T cells will respond quickly to prevent spread of the virus by eliminating infected cells and to protect against disease, as has been shown for influenza-virus infection [37]. The goal of vaccination is to mimic the primary response to a pathogen without causing disease, enticing the host to build up protection against subsequent encounters with the infectious pathogen. On a critical note, the main goal of the majority of vaccines against infectious diseases that have been developed or are under development is to elicit protective antibody levels [38]. Indeed, presence of functional antibodies can protect against viral infection. However, antibodies that are generated in response to infection are known to wane over time, especially in the elderly, leaving the individual susceptible to a recurrent infection. For recovery from infection, cellular responses are required [39]. T cells target internal proteins of viruses that generally are more conserved and these T-cell responses may therefore be better preserved. The role of T cells is somewhat neglected in development of vaccines, whereas it has been shown that CD4 + follicular helper T cells boost generation of antibodies [40], and that CD8 + T-cell responses are better correlates of vaccine protection compared to antibody levels, particularly in the elderly [41]. Moreover, waning of protective antibody levels opens a window for infection, which then needs to be resolved by generated memory T cells from previous exposure and/or vaccination. As an example, antibodies elicited after SARS-CoV-2 infection rapidly decline within two to three months after recuperation [42,43], highlighting the importance of T cells as a protective immune barrier against subsequent SARS-CoV-2 infections. Thus, a proper T-cell response induced by vaccination is important in the elderly, in the face of declining antibody levels. THE ACCUMULATION OF REGULATORY T CELLS DURING AGING The composition of the T-cell population changes during aging in both the CD4 + and CD8 + T-cell fractions and these changes are thought to lead to susceptibility to disease and impaired vaccine-responses in the elderly. For example, one of such changes in T-cell population composition is the decline in proportion of naive T cells with age, whereas the proportion of memory T cells increases [44].