ABSTRACT Background To inform future response planning we aimed to assess SARS‐CoV‐2 trends in infection‐ and/or vaccine‐induced immunity, including breakthrough infections, among (sub)groups, professions and regions in the Dutch population during the Variant of Concern (VOC)‐era. Methods In this prospective population‐based cohort, randomly selected participants ( n = 9985) aged 1–92 years (recruited early‐2020) donated home‐collected fingerstick‐blood samples at six timepoints in 2021/2022, covering waves dominated by Alpha, Delta, and multiple Omicron (sub‐)variants. IgG antibody assessment against Spike‐S1 and Nucleoprotein was combined with vaccination‐ and testing data to estimate infection‐induced (inf) and total (infection‐ and vaccination‐induced) seroprevalence. Results Nationwide inf‐seroprevalence rose modestly from 12% (95% CI 11–13) since Alpha to 26% (95% CI 24–28) amidst Delta, while total seroprevalence increased rapidly to 87% (95% CI 85–88), particularly in elderly and those with comorbidities (i.e., vulnerable groups). Interestingly, highest infection rates were noticeable among low/middle educated elderly, non‐Western, those in contact professions, adolescents and young adults, and in low‐vaccination coverage regions. Following Omicron emergence, inf‐seroprevalence elevated sharply to 62% (95% CI 59–65) and further to 86% (95% CI 83–90) in late‐2022, with frequent breakthrough infections and decreasing seroprevalence dissimilarities between most groups. Whereas > 90% of < 60‐year‐olds had been infected at least once, 30% of vaccinated vulnerable individuals had still not acquired hybrid immunity. Conclusions Groups identified to have been infected disproportionally during the acute phase of the pandemic require specific attention in evaluation of control measures and future response planning worldwide. Furthermore, ongoing tailored vaccination efforts and (sero‐)monitoring of vulnerable groups may remain important.