This nationwide register-based cohort study comprised all nursing home residents in Denmark from January 1, 2015, to the last date of data availability on October 6, 2021. In this study, nursing home residents are defined as individuals who have been living at a valid nursing home address and were between the ages of 50 and 102 within the study period. The upper age limit of 102 year was chosen as only 14 persons was above this age and these were necessary to exclude as it was not possible to identify complete matches. The information on nursing homes was obtained from the Danish Health Data Authority, which administrates a full address list of all Danish nursing homes since 2014 [9]. Through both the Danish Health Data Authority and Statistics Denmark, it was possible to obtain civil personal registration number of each nursing home resident living at a nursing home address.

In Denmark, each resident is assigned a unique civil personal registration number at birth or upon immigration. This identification is used in national administrative registries for economic, social, and healthcare purposes and enables linkage between all Danish administrative registries. From the Danish Nursing Home register, the following information was obtained: nursing home address, validity dates, moving-in and -out dates of nursing home residents [9]. Information on date of birth, sex, and date of death was obtained from the Danish Civil Registration System [10]. Information on SARS-CoV-2 test results and date of tests was obtained from the Danish Microbiology Database, which automatically receives test results from the country's microbiology departments [11, 12]. Information on all hospitalizations, related diagnoses, and dates was obtained from the Danish National Patient Register [13]. Information on redeemed medication prescriptions was obtained from the Danish National Prescription Register [14]. Information on dates of first and second vaccines was obtained from the Danish Vaccination Register [15]. Lastly, information on date of death was also obtained from the Danish Cause of Death Register when available [16].

Chronic conditions were based on all-time primary- and secondary-diagnoses registered in the Danish National Patient Register and coded according to the International Classification of Disease, Eighth and Tenth Revision (ICD-8 and ICD-10) [17]. The chronic conditions included were cardiac diseases, other circulatory diseases, all types of cancer except non-melanoma skin cancer, chronic airways diseases (chronic obstructive pulmonary diseases, asthma, and interstitial lung diseases), diabetes, chronic kidney disease, Alzheimer’s, and dementia; for further details see supplementary Table S1 in supplemental appendix. Cardiovascular disease was assessed as a combination of cardiac diseases and other circulatory diseases. Nursing home residents were also classified as having diabetes if they ever had a redeemed prescription for an antidiabetic drug (ATC-code; A10). Likewise, residents were classified as having hypertension if they had a minimum of two redeemed prescriptions for antihypertensive drugs within 180 days prior to January 1 each year. All chronic conditions above except cancer were considered permanent, and only cancer diagnoses within 10 years or less prior to January 1 each year were considered permanent, in accordance with previously published study [18]. Nursing home residents’ age and sex were retrieved from the Danish Civil Registration System. In the calculation, weeks was classified as starting on January 1 of each year from 2015 through to 2021. The SARS-CoV-2-infection status of nursing home residents was retrieved from the Danish Microbiology Database [11, 12] and classified into two categories, negative and positive polymerase chain reaction tests for SARS-CoV-2, as well as according to the date when the tests were taken. The vaccine status of the nursing home residents was assessed through dates of first and second vaccine [15]. Nursing homes residents were defined as fully vaccinated on the date the resident has received both vaccine doses of the same type of vaccine.

The primary outcome was all-cause mortality. Secondary outcomes were lifetime lost due to the SARS-CoV-2-infection in 2020, compared to the pre-pandemic years of 2015 to 2019, and lifetime lost due to SARS-CoV-2-infection among vaccinated nursing home residents in 2021.

To calculate the weekly mortality rates, the number of deaths in the nursing homes was divided by the number of person days in nursing homes in that week. We used the age distribution (1-year intervals) and sex distribution of all nursing home residents on January 1, 2020, as reference in the calculations. The standardized weekly mortality rates, as number of events per 100,000 person-weeks, were reported for each year from 2015 to October 6, 2021. We performed a sensitivity analysis starting time in week 40 to investigate seasonal infectious disease variation. The standardized yearly mortality rates with 95% confidence intervals (95% CI) were likewise reported for each year as number of events per 100,000 person-years using the same reference distribution, using the Gamma method [19]. For all SARS-CoV-2-infected residents in 2020, the index date was set at the date of positive SARS-CoV-2 test. Each infected resident (i.e., case) was matched with 5 nursing home residents (i.e., controls) from 2018 who had the same sex and age. The index date for the controls was set 2 years before the case’s index date. In the supplementary appendix analysis, the same matching approach was used, but instead controls were selected from the other pre-pandemic years (i.e., 2015, 2016, 2017, and 2019). Similarly, we considered all first breakthrough SARS-CoV-2 cases in 2021, i.e., SARS-CoV-2-infection that occurred after the 2nd vaccination date and set the index date at the date of infection. For each case, 5 controls were matched from the vaccinated nursing home population in 2021 who did not yet have SARS-CoV-2 at the case index date. Separately for case/control groups and according to sex, we estimated the survival probability curve after the index date using the Kaplan–Meier method. The restricted mean lifetime was calculated as the area under the survival curve up to 180 days after the index date. The lifetime lost was calculated as the difference between 180 days and the restricted mean lifetime [20]. We report the difference between the lifetime lost in days among cases versus matched controls with 95% CI using the plug-in estimator [21]. We performed sensitivity analyses extending the area under the survival curve up to 365 days after the index date to test if this altered the results. Data management and analyses were performed using R statistical software version 4.0.3 [22].

In Denmark, register-based studies that are performed for the sole purpose of statistics and scientific research do not require ethical committee approval or patient consent, in accordance with The Danish Data Protection Act [23]. Approval to use the data sources for research purposes was granted by the data responsible institute in the Capital Region of Denmark (approval number P-2019-191), in accordance with the General Data Protection Regulation (GDPR). Data are accessed on secure servers under Statistics Denmark and cannot be shared according to Danish legislation.