Abstract With the ongoing emergence of SARS-CoV-2 variants, there is a need for standard approaches to characterize the risk of vaccine breakthrough. We aimed to estimate the association between variant and vaccination status in case-only surveillance data. Included cases were symptomatic adult laboratory-confirmed COVID-19 cases, with onset between January 2021 and April 2022, reported by five European countries (Estonia, Ireland, Luxembourg, Poland, and Slovakia) to The European Surveillance System. Associations between variant and vaccination status were estimated using conditional logistic regression, within strata of country and calendar date, and adjusting for age and sex. We included 80,143 cases including 20,244 Alpha (B.1.1.7), 152 Beta (B.1.351), 39,900 Delta (B.1.617.2), 361 Gamma (P.1), 10,014 Omicron BA.1, and 9,472 Omicron BA.2. Partially vaccinated cases were more likely than unvaccinated cases to be Beta than Alpha (adjusted odds ratio [aOR] 2.48, 95% CI 1.29–4.74), and Delta than Alpha (aOR 1.75, 1.31–2.34). Fully vaccinated cases were relative to unvaccinated cases more frequently Beta than Alpha (aOR 4.61, 1.89–11.21), Delta than Alpha (aOR 2.30, 1.55–3.39), and Omicron BA.1 than Delta (aOR 1.91, 1.60–2.28). We found signals of increased breakthrough infections for Delta and Beta relative to Alpha, and Omicron BA.1 relative to Delta.