key: cord-1019709-2t1lv3pp
authors: Bardenheier, Barbara H.; Gravenstein, Stefan; Blackman, Carolyn; Gutman, Roee; Sarkar, Indra Neil; Feifer, Richard A.; White, Elizabeth M.; McConeghy, Kevin; Nanda, Aman; Bosco, Elliott; Mor, Vincent
title: Adverse Events Following One Dose of mRNA COVID-19 Vaccination among U.S. Nursing Home Residents with and without a Previous SARS-CoV-2 Infection
date: 2021-08-28
journal: J Am Med Dir Assoc
DOI: 10.1016/j.jamda.2021.08.024
sha: 272871fa220073faf86dec449795bf4abe05c557
doc_id: 1019709
cord_uid: 2t1lv3pp

Objectives To compare rates of adverse events following COVID-19 vaccination among nursing home residents with and without previous SARS-CoV-2 infection. Design Prospective cohort. Setting and Participants 20,918 nursing home residents who received the first dose of mRNA COVID-19 vaccine from December 18, 2020 through February 14, 2021 in 284 facilities within Genesis Healthcare, a large nursing home (NH) provider spanning 24 U.S. states. Methods We screened the electronic health record for adverse events, classified by the Brighton Collaboration, occurring within 15 days of residents’ first COVID-19 vaccine dose. All events were confirmed by physician chart review. To obtain risk ratios, multilevel logistic regression model that accounted for clustering (variability) across nursing homes was implemented. To balance the probability of prior SARS-CoV-2 infection (previous positive test or ICD-10-CM diagnosis) more than 20 days prior to vaccination, we used inverse probability weighting. To adjust for multiplicity of adverse events tested, we used a false discovery rate procedure. Results Statistically significant differences existed between those without (n=13,163) and with previous SARS-CoV-2 infection (symptomatic (n=5,617) and asymptomatic (n=2,138)) for all baseline characteristics assessed. Only one adverse event was reported among those with previous SARS-CoV-2 infection (asymptomatic), venous thromboembolism (46.8 per 100,000 residents 95%CI 8.3, 264.5) which was not significantly different from the rate reported for those without previous infection (30.4 per 100,000 95%CI: 11.8, 78.1). Several other adverse events were observed for those with no previous infection, but were not statistically significantly higher than those reported with previous infection after adjustments for multiple comparisons. Conclusions and Implications Although reactogenicity increases with pre-existing immunity, we did not find that vaccination among those with previous SARS-CoV-2 infection resulted in higher rates of adverse events than those without previous infection. This study stresses the importance of monitoring novel vaccines for adverse events of in this vulnerable population.

Little is known about vaccine-related adverse events following COVID-19 vaccination among 29 adults with prior SARS-CoV-2 infection. One study found that adults with pre-existing natural 30 immunity at time of vaccination more frequently reported side effects such as injection site pain, 31 swelling and erythema as well as systemic symptoms such as fatigue and headaches, after the 32 first dose of either of the mRNA vaccines, compared to those without a previous infection. 1 

Given that reactogenicity increases with pre-existing immunity, such side effects are biologically 34 plausible. However, age-related declines in immune system function might suggest that we 35

would not observe the same reactogenicity in the nursing home population. Regardless, no 36 studies have assessed significant adverse events, such as acute myocardial infarction or stroke, 37 following COVID-19 vaccination among older adults with previous SARS-CoV-2 infection. 38

We observed in a prior study that, compared to unvaccinated nursing home residents, 39 vaccinated residents experienced similar adverse events rates following the first or second 40 COVID-19 mRNA vaccine dose. 2 In that study, residents were classified as vaccinated or 41 unvaccinated, regardless of previous SARS-CoV-2 infection, except those who had tested 42 positive for SARS-CoV-2 within 20 days prior to vaccination were excluded to be consistent 43 with CDC guidelines. 3 Here we compare rates of adverse events following vaccination for 44 nursing home residents with: (1) The study residents received their first dose of mRNA vaccine between December 18, 61 2020 and February 14, 2021. Consistent with CDC guidelines, 3 we excluded residents with a 62 positive SARS-CoV-2 diagnostic test within 20 days prior to vaccination, as well as those treated 63 with SARS-CoV-2 monoclonal antibodies for 90 days prior to vaccination. 64

The three groups compared included those who, at time of vaccination, had (1) no 66 previous diagnosis of SARS-CoV-2, (2) previous infection with symptoms (more than 20 days 67 before vaccination), and (3) previous infection without symptoms symptoms (more than 20 days 68 before vaccination). For residents with prior SARS-CoV-2 infection, we obtained symptom data 69 from change in condition notes which nurses complete when residents present with any new 70 symptoms. We classified residents as having asymptomatic or symptomatic infection based on 71 J o u r n a l P r e -p r o o f whether they had any SARS-CoV-2-related symptoms from five days before up to 14 days after 72 a positive test or diagnosis. 73

Outcomes 74

Serious outcomes such as mortality were monitored for seven days post-vaccination. If a 75 resident died in the hospital shortly after transfer, or when they were expected to return to a 76 Genesis facility, Genesis was notified of the death, and thus the death was captured in this 77 analysis. Other adverse events that could manifest somewhat longer post-vaccination were 78 monitored for 15 days using ICD-10-CM codes included in residents' EHR problem lists. Those 79 events, listed in Table 1 , were classified by the Brighton Collaboration 4 using ICD-10-CM codes 80 for diagnoses and exclusions available from the CDC's Vaccine Safety Datalink. 5 For most 81 events, prevalent cases were excluded to ensure capturing only incident cases. 82

Physician chart review was conducted on all flagged cases of adverse events to confirm 84 the diagnoses. To do this, the de-identified EHR record was shared back with Genesis for secure 85 linkage to the original medical record number, so that the physician could review the resident's 86 chart directly in the nursing home's EHR. The purposes of the chart reviews were to identify 87 whether events were incident (new onset), recent prevalent conditions (within the past 30 days), 88 or incorrectly coded diagnoses. 89

We used SAS version 9.4 software for data management and to compute frequencies and 91 chi-squared tests to assess statistical differences in baseline characteristics of residents. Adverse 92 events identified, and their rates and 95% Wilson's confidence intervals (CI) were calculated per 93 100,000 residents. 6 We used STATA version 16 software for the adjusted analysis, using 94 balance the probability of prior SARS-CoV-2 infection more than 20 days prior to vaccination, 96 we used inverse probability weighting. This was incorporated into the logistic regression model 97 to adjust for the baseline probability of prior SARS-CoV-2 infection. A sandwich estimator was 98 used to account for correlation within facilities. 7,8 Variables in the propensity score model 99 included age, sex, race/ethnicity, diabetes, COPD, chronic kidney disease, congestive heart 100 failure, coronary artery disease, dementia, hypertension, activities of daily living score, mortality 101 risk and cognitive function scale score. To adjust for multiplicity, we used a false discovery rate 102 procedure. 9 103

Although the focus of this study was to determine whether adverse event rates after 105 vaccination differed between those with and without previous SARS-CoV-2 infection, we also 106 compared the incidence of adverse events among the vaccinated and unvaccinated groups. 107

Because our population was mostly vaccinated by mid-February 2021, the best unvaccinated 108 comparator group was the 'yet-to-be vaccinated', unvaccinated population from our previous 109 study. 2 Although reactogenicity increases with pre-existing immunity, 10 we did not observe 148 higher rates of adverse events among nursing home residents with versus without prior natural 149 infection. In fact, our study suggests that SARS-CoV-2 infection, regardless of whether it was 150 symptomatic or asymptomatic, did not increase the risk of adverse events following COVID-19 151 vaccination. Although we identified some adverse events following vaccination among those 152 with no previous SARS-CoV-2 infection that did not occur among the unvaccinated, no 153 differences in rates were statistically significant after adjustment for multiplicity using a false 154 discovery rate procedure. 9 155

One reason for the lower mortality among those with previous SARS-CoV-2 infection, 156 symptomatic or asymptomatic, compared to those with no previous infection could be selective 157 survival, or immortal time bias. 11 In other words, those who survived SARS-CoV-2 infection and 158

were healthy enough to get vaccinated months later may have been less likely to die than those 159 coming into the nursing home with no previous infection, even after adjustments for 160 comorbidities. Because of the disparity in long-stay (i.e., those with previous infection were 161 more likely to be long-stay than those with no previous infection), we ran the mortality analyses 162 there are still indications that there may be other unobserved factors that may influence the lack 174 of significant evidence for differences in adverse events rates among these populations. Second, 175 to conduct timely analyses, adverse events were only included if they were diagnosed by the 176 medical provider with a supporting ICD-10-CM code. Third, the relatively small sample size to 177 assess rare adverse events resulted in an inability to generate precise estimates. However, the 178 extremely low number of suspected adverse events was reassuring and an important finding of 179 the study. 180

This study contributes new evidence that older, frail nursing home residents with 181 previous SARS-CoV-2 infection do not seem to be at higher risk of adverse events following the 182 first dose of mRNA vaccine than their vaccinated counterparts with no previous infection, nor do 183 they seem to be at a higher risk of adverse events compared to their unvaccinated counterparts. 184

In addition, it is important to stress the finding in our previous study that mortality rates after 185 vaccination were not higher than mortality rates among the unvaccinated. 2 This research supports 186 previous reports from the original randomized trials of these vaccines, 12,13 although nursing 187 home residents were not included in those trials. Moreover, the mRNA-based vaccines have 188 demonstrated safety, and offer the prospect of being life-saving for nursing home residents who 189 have borne a disproportionate share of morbidity and mortality from COVID-19. 14 190

Our study suggests that frail, nursing home residents with a previous SARS- J o u r n a l P r e -p r o o f 

Acute Myocardial Infarction (AMI) 

Death 93

Robust spike antibody responses and increased 199 reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA 200 vaccine

Accessed 03/11/2021. 211 5. Vaccine Safety Datalink. Rapid Cycle Analysis (RCA) to monitor the safety of COVID-212 19 vaccines in near real-time within the Vaccine Safety Datalink. Centers for Disease 213 Control and Prevention

Model Robust Confidence-Intervals Using Maximum-Likelihood Estimators. 218 International Statistical Review

Comparison of 224 medium-term adverse reactions induced by the first and second dose of mRNA 225 BNT162b2 (Comirnaty, Pfizer-BioNTech) vaccine: a post-marketing Italian study 226 conducted between 1

The New England journal of medicine

Safety of SARS-CoV-2 vaccines: a systematic review 233 and meta-analysis of randomized controlled trials

Nursing Home Care in Crisis in the Wake of COVID-19

Note: Residents with a positive SARS-CoV-2 test within 20 days of vaccination (since they should not have been vaccinated), or who were on monoclonal antibodies within 90 days of vaccination were excluded. Previous SARS-CoV-2 diagnosis or positive test were 21 or more days prior to vaccination