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This study analyzes immune responses to SARS-CoV-2 vaccination and infection, including asymptomatic cases, focusing on infection risks during the Omicron wave, particularly among high-risk healthcare workers. In the KoCo-Impf study, we monitored 6088 vaccinated participants in Munich aged 18 and above. From 13 May to 31 July 2022, 2351 participants were follow-uped. Logistic regression models evaluated primary, secondary, and breakthrough infections (BTIs). Roche Elecsys ® Anti-SARS-CoV-2 assays detected prior infections (via anti-Nucleocapsid antibodies) and assessed vaccination/infection impact (via anti-Spike antibodies) using dried blood spots. Our findings revealed an anti-Nucleocapsid seroprevalence of 44.1%. BTIs occurred in 38.8% of participants, with reinfections in 48.0%. Follow-up participation was inversely associated with current smoking and non-vaccination, while significantly increasing with age and receipt of three vaccine doses. Larger household sizes and younger age increased infection risks, whereas multiple vaccinations and older age reduced them. Household size and specific institutional subgroups were risk factors for BTIs. The anti-Nucleocapsid value prior to the second infection was significantly associated with reinfection risk. Institutional subgroups influenced all models, underscoring the importance of tailored outbreak responses. The KoCo-Impf study underscores the importance of vaccination, demographic factors, and institutional settings in understanding SARS-CoV-2 infection risks during the Omicron wave.