Study design, setting, and population

This is a retrospective study of individuals who underwent polymerase chain reaction (PCR) testing for suspected SARS-CoV-2 infection at the Mayo Clinic and hospitals affiliated with the Mayo Clinic Health System.

The cohorts of vaccinated and unvaccinated individuals considered for this study are identical to the cohorts considered in a previous analysis: “FDA-authorized COVID-19 vaccines are effective per real-world evidence synthesized across a multi-state health system.”²¹ In total, there were 572,291 individuals in the Mayo electronic health record (EHR) database who received a PCR test between February 15, 2020 and February 8, 2021. To obtain the study population, we defined the following inclusion criteria: (1) at least 18 years old; (2) no positive SARS-CoV-2 PCR test before December 1, 2020; (3) resides in a locale (based on zip code) with at least 25 individuals who have received BNT162b2 or mRNA-1273; (4) has no record of receiving the Johnson & Johnson (J&J) COVID-19 vaccine (Ad26.COV2.S). This population included 324,992 individuals, of whom 86,184 have received BNT162b2 or mRNA-1273 and 238,808 have no record of COVID-19 vaccination. Vaccinated individuals who had tested positive for SARS-CoV-2 by PCR between December 1, 2020 and the date of their first vaccine dose were excluded, as were individuals with zero follow-up days after vaccination (i.e., those who received the first vaccine dose on the last date of data collection). Individuals who had received their second vaccine dose four or more days earlier than recommended (17 or fewer days after the first dose for BNT162b2; 24 or fewer days after the first dose for mRNA-1273) were also excluded, leaving 85,676 eligible individuals for the final vaccinated cohort.

A propensity matched unvaccinated cohort was selected from the previously derived set of 238,808 unvaccinated individuals. The purpose of this cohort was to establish the baseline frequency of EHR documentation for each adverse effect of interest in a cohort which is clinically similar to our vaccinated cohort. These baseline, or expected, frequencies can then be compared to the observed frequencies to determine whether or not these adverse effects are reported at unexpectedly high rates among patients receiving a COVID-19 vaccine. A detailed description of the matching procedure is given in the related vaccine effectiveness manuscript.²¹ Briefly, for each vaccinated individual, we attempted to identify an unvaccinated individual who (i) resides in the same location (per zip code), (ii) is of the same sex, (iii) has the same current status regarding long term care facility residence, and (iv) has a similar propensity score accounting for age, race, ethnicity, and history of testing for SARS-CoV-2 and influenza during the past year. Propensity scores were calculated for all eligible individuals (both vaccinated and unvaccinated) by training a logistic regression model to predict vaccination status using the statsmodels v0.10.0 package in Python.³¹

We were able to identify valid matches for 68,266 of the 85,676 eligible vaccinated individuals. Thus, our final overall vaccinated and unvaccinated cohorts each contained 68,266 individuals (n = 51,795 each for BNT162b2, and n = 16,471 each for mRNA-1273). Demographic and clinical characteristics of these cohorts are provided in Tables S1 and S2, and the age distributions of the cohorts before and after matching are shown in Figure S1; note that these tables and this figure are identical to those in the related manuscript that utilizes the same cohorts.²¹ Of the 51,795 individuals who received at least one dose of BNT162b2, 39,058 received two doses; of the 16,471 individuals who received at least one dose of mRNA-1273, 11,851 received two doses. The distribution of time between doses for BNT162b2 and mRNA-1273 is shown in Figure S2, which is also duplicated from the previous manuscript.²¹ The selection algorithm and its associated counts are summarized in Figure 1, and additional cohort characterization details can be found in the related manuscript.²¹