Background: Serological diagnosis of COVID-19 is complex due to the emergence of different SARS-CoV-2 variants. Methods: 164 serum samples from (I) patients who recovered from COVID-19 (n = 62) as well as (II) vaccinated individuals (n = 52) and (III) vaccinated individuals who were infected with different SARS-CoV-2 variants after vaccination (n = 50) were included. All samples were tested using EIA (binding antibodies) and a virus neutralization test (VNT) using the Wuhan strain (NT antibodies). Group III was further tested with a VNT using the Alpha/Delta/Omicron strains. Results: The highest antibody index (AI) was observed in vaccinated individuals infected with COVID-19 (median AI = 50, IQR = 27-71) and the lowest in vaccinated individuals (median AI = 19, IQR = 8-48). Similarly, NT antibody titer was highest in vaccinated individuals infected with COVID-19 (median 128; IQR = 32-256) compared to vaccinated individuals (median 32, IQR = 4-128) and patients with COVID-19 (median 32, IQR = 8-64). The correlation between AI and NT titer was strongly positive in vaccinated individuals and moderately positive in patients with COVID-19. No significant correlation was observed in vaccinated individuals infected with COVID-19. In patients infected with Alpha and Delta, the lowest VNT positivity rate was for the Omicron variant (85.0%/83.3%). Patients infected with the Alpha variant showed the lowest NT titer for the Omicron variant (median titer 32) compared to the Wuhan/Delta variants (64/128). Patients infected with the Delta variant had the lowest NT titer to the Omicron variant (median 32), compared to the Wuhan/Alpha variants (64/128). Patients infected with the Omicron variant showed similar titers to the Delta/Wuhan variants (128) and higher to the Alpha variant (256). Conclusions: The cross-immunity to SARS-CoV-2 is lowest for the Omicron variant compared to the Alpha/Delta variants.