Interim analysis of rates of adverse events following COVID-19 mRNA vaccination

1. An interim analysis of post-vaccination surveillance data for individuals who had received either Pfizer or Moderna mRNA COVID-19 vaccinations found that rates of serious adverse events did not differ between the 1-21 day and 22-42 day post-vaccination periods, respectively.

Evidence Rating Level: 2 (Good)

Study Rundown: The development of mRNA vaccines for COVID-19 represented a welcome turn of events during the pandemic, although they remain controversial amongst much of the population owing to their relatively shortened testing and implementation periods.  Indeed, little is known about the long-term adverse events associated with this new technology. The present study reports interim surveillance data from the United States population to assess the incidence of adverse events following COVID-19 vaccination. Health surveillance data from 6.2 million Americans who had received at least one dose of either Pfizer or Moderna mRNA COVID-19 vaccinations were analyzed in this study.  The data collection period spanned from December 2020 to June 2021 and is ongoing as of September 2021. The primary outcome was the incidence of serious adverse events (23 diagnoses). Data were ascertained through weekly medical record reviews for two respective periods: days 1-21 following vaccination (“Period A”) and days 22-42 following vaccination (“Period B”). Period A was considered the risk period while Period B was considered the comparator period. Ischemic stroke was the most frequent serious adverse event of those assessed in this study (1612 per 1,000,000 person-years). Additional analysis of event incidence in unvaccinated individuals yielded no difference compared to the post-vaccination period, except for myocarditis/pericarditis which was significantly more frequent amongst vaccinated comparators. 55 confirmed cases of anaphylaxis following COVID-19 vaccination occurred. The present study by Klein et al presents a well-timed interim analysis of health risks following COVID-19 vaccination, demonstrating that risk of many feared adverse events is not significantly increased compared to unvaccinated individuals, and does not change significantly over the weeks following vaccination. The impressively large sample size adequately powers the study to detect these patterns of interest and collects information on a representative group of American patients. It also demonstrates the importance of continuing to rigorously collect data and perform surveillance: vaccine hesitancy may in part be quelled by evidence demonstrating the safety of this new technology, which is integral to moving past the current pandemic. Some limitations of this work include the reliance on relatively agranular administrative databases and the short time period over which data was collected. Additionally, the power to detect some of the less frequent adverse events evaluated in this study was low, leading to wide confidence intervals, although precision is expected to improve over time as additional data is collected.

Click to read this study in JAMA

Click to read an accompanying editorial in JAMA

Relevant Reading: Planning for a COVID-19 vaccination program

In-Depth [interim analysis, safety surveillance study]: Patient data were derived from eight health insurance plans in the United States for individuals aged 12 or over.  Variables of interest included demographic data, date & manufacturer of COVID-19 vaccination, diagnosis codes, health service utilization and COVID-19 laboratory data.  The study protocol is registered and available at the Centres for Disease Control and Prevention. Serious adverse events were diagnosed primarily through emergency room visits and inpatient hospitalizations, although the following were also ascertained through outpatient visits: immune thrombocytopenia, Bell palsy, narcolepsy, venous thromboembolism. To reduce the risk of confounding factors, patients were stratified by age group, sex, race & ethnicity, site and date of vaccination. For all outcomes except for anaphylaxis, acute respiratory distress syndrome, narcolepsy and multisystem inflammatory syndrome, a 1-sided test of the null hypothesis that vaccination did not increase risk of adverse events was conducted. Given the large sample size, a p<0.0048 was considered significantly different; none of the adverse events evaluated met this prespecified cutoff. The incidence per 1,000,000 person-years, relative risk (RR) and 95% confidence intervals (95CI) for the most commonly experienced serious adverse events in Period A versus Period B are as follows: ischemic stroke (1612 versus 1781, RR 0.97, 95CI 0.87-1.08), appendicitis (1179 versus 1345, RR 0.82, 95CI 0.73-0.93), acute myocardial infarction (935 versus 1030, RR 1.02, 95CI 0.89-1.18), venous thromboembolism (952 versus 896, RR 1.16, 95CI 1.00-1.34), and Bell palsy (822 versus 825, RR 1.00, 95CI 0.86-1.17). An additional analysis was made to compare vaccinated to unvaccinated individuals. The RR for myocarditis/pericarditis in vaccinated comparators versus unvaccinated persons was 1.39 (95CI 1.05-1.82). A total of 34 cases of myocarditis/pericarditis occurred within 21 days of vaccination, the majority of which were within the first 5 days of vaccination. The incidence of myocarditis/pericarditis during Period A was 321 per 1,000,000 person-years and 35 per 1,000,000 person-years during Period B (RR 9.83, 95CI 3.35-35.77).

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