Assessing COVID-19 Infection and Severe Disease Risk in Cancer Patients and Survivors: The Role of Vaccination Status, Circulating Variants, and Comorbidities—A Population-Based Study in Northern Italy

<b>Background</b>: Cancer patients are particularly vulnerable to severe outcomes from COVID-19 due to immune suppression, treatment effects, and comorbidities. This population-based study aimed to assess how vaccination, circulating variants, and comorbidities influenced infections and severe disease risks in cancer patients compared with the general population. <b>Methods</b>: The study included 538,516 residents of Reggio Emilia Province, Italy, alive on 20 February 2020, followed until 30 September 2022. Cancer diagnoses (1996-2021) were obtained from the Reggio Emilia Cancer Registry and linked with COVID-19 surveillance, vaccination, hospitalization, and mortality data. Vaccination and prior infection were modelled as time-dependent variables. Hazard ratios for infection (HRs) and odds ratios for severe disease in those infected (ORs) were estimated using Cox and logistic regression models adjusting for sex, age, and comorbidities. <b>Results</b>: Among the 33,307 residents who had cancer, 9135 SARS-CoV-2 infections were recorded. Infection risk was similar to the general population before Omicron (HR 1.00; 95%CI 0.96-1.05) and slightly higher during Omicron (HR 1.08; 95%CI 1.05-1.11). Cancer patients showed higher probability of severe disease once infected (OR 1.33 pre-Omicron; 1.67 Omicron), with the greatest excess in recent diagnoses. Vaccination substantially reduced infections and severe outcomes in both groups in the pre-Omicron period; while only hybrid immunity reached high protection from Omicron infection. <b>Conclusions</b>: Vaccinations were effective in the populations with and without cancer; hybrid immunity conferred the strongest protection. However, because cancer patients, especially those recently diagnosed, retain a higher baseline risk of severe disease, vaccination yields even greater individual and public health benefits.