Daan Pieren

10 Chapter 1 AGING AND INFECTIOUS DISEASES The proportion of people aged 60 years or older among the total world population has risen during the past years and is projected to further increase significantly during the upcoming years [1]. As stated by the World Health Organization: “the first time in history when there will be more older people than younger people is rapidly approaching” [2]. Aging highly increases the risk of acquiring infectious diseases and the course of disease is prolonged and more severe at old age. Especially respiratory infectious pathogens such as influenza virus, respiratory syncytial virus (RSV), and Streptococcus pneumoniae highly contribute to disease in older adults and often are the pathogens leading to hospitalization and death among aged individuals [3-9]. In addition to these well-known pathogens, West Nile Virus [10] and the currently ongoing pandemic of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID- 19) [11,12], are examples of pathogens that emphasize the susceptibility of older adults. It has been shown that especially older adults are at higher risk of severe disease, hospitalization, and death following SARS-CoV-2 infection compared to younger individuals [11,13]. In addition, the rate of hospitalization as a consequence of community-acquired pneumonia after infection with a respiratory pathogen is especially high amongst the elderly [9]. Furthermore, hospitalization of older adults accelerates the occurrence of chronic conditions that are often the cause for disability in daily living activities [14]. Developing strategies to prevent or ameliorate infectious-disease related hospitalization is therefore important. Vaccination against pathogens that cause disease in the elderly is used as a strategy to prevent or, more realistically, reduce the severity of clinical disease. Indeed, it has been shown that vaccination against influenza reduces the hospitalization rate amongst elderly [14,15]. However, vaccine-induced protection becomes impaired with progressing age. Studies investigating the efficacy of vaccination in elderly generally report diminished protective responses after vaccination against influenza [16-18], Japanese Encephalitis [19], Hepatitis B virus [20], and S. pneumoniae [21]. The immune system is one of the most important lines of defense against pathogens and can be regarded a highly specialized and balanced system: its task is to clear infections effectively enough to eradicate the pathogen, but at the same time to limit its own response to minimize collateral damage. To achieve this delicate balance, all immune processes are tightly regulated. However, during aging, the immune system undergoes changes that bring