DOI: 10.37349/ei.2026.1003268 ISSN: 2768-6655

COVID-19, immunity, and vaccination: unravelling the interplay of sex, gender, age, and the exposome

Anna Calabrò, Giulia Accardi, Emanuele Montomoli, Graham Pawelec, Claudia Maria Trombetta, Calogero Caruso
Show PDF Cite
Sex- and gender-related differences profoundly influence immune responses to SARS-CoV-2 infection and vaccination but remain insufficiently considered in research and public health strategies. This review explores how sex, gender, age, and the exposome interact to shape susceptibility to coronavirus-19 disease (COVID-19), disease severity, Long COVID, and vaccine-induced immunity. Males experience higher rates of severe disease, hospitalisation, and mortality, whereas females generally mount stronger innate and adaptive immune responses, contributing to greater resilience. These differences arise from a complex interplay between biological factors and gender-related determinants, including occupational exposures, healthcare access, health-related behaviours, socioeconomic conditions, and the microbiota, which contribute to the individual exposome. This review also highlights the impact of ageing on SARS-CoV-2 immunity, highlighting the preserved immune regulation observed in centenarians, which may contribute to protection against severe COVID-19 despite advanced age. Current evidence on Long COVID is discussed, including its higher prevalence among females and the sex-specific immunological pathways that may underlie persistent symptoms. We examine age-, sex-, and gender-related differences in vaccine response, distinguishing efficacy from effectiveness. Although females generally mount stronger antibody responses, this advantage does not necessarily translate into greater clinical protection. The relative benefit of vaccination appears greater in males because of their higher baseline risk of severe disease. Finally, we discuss how exposomic factors, including lifestyle, microbiota composition, and environmental and social determinants, influence vaccine responsiveness and hesitancy. Integrating sex, gender, age, and the exposome perspectives is essential for developing more equitable and personalised strategies to prevent and manage COVID-19 and future emerging diseases.

More from our Archive