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One of the most appreciated consequences of immunosenescence is an impaired response to vaccines with advanced age. While most studies report impaired antibody responses in older adults as a correlate of vaccine efficacy, it is now widely appreciated that this may fail to identify important changes occurring in the immune system with age that may affect vaccine efficacy. The impact of immunosenescence on vaccination goes beyond the defects on antibody responses as T cell-mediated responses are reshaped during aging and certainly affect vaccination. Likewise, age-related changes in the innate immune system may have important consequences on antigen presentation and priming of adaptive immune responses. Importantly, a low-level chronic inflammatory status known as inflammaging has been shown to inhibit immune responses to vaccination and pharmacological strategies aiming at blocking baseline inflammation can be potentially used to boost vaccine responses. Yet current strategies aiming at improving immunogenicity in the elderly have mainly focused on the use of adjuvants to promote local inflammation. More research is needed to understand the role of inflammation in vaccine responses and to reconcile these seemingly paradoxical observations. Alternative approaches to improve vaccine responses in the elderly include the use of higher vaccine doses or alternative routes of vaccination showing only limited benefits. This review will explore novel targets and potential new strategies for enhancing vaccine responses in older adults, including the use of anti-inflammatory drugs and immunomodulators.