Background rates for severe cutaneous reactions in the US: Contextual support for safety assessment of COVID-19 vaccines and novel biologics

The global COVID-19 public health crisis has resulted in extraordinary collaboration to expeditiously develop vaccines and therapeutics. The safety of these biologics is closely monitored by the US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC). Novel products may have limited safety data, and although serious medical outcomes associated with vaccination are rare, knowledge of background incidence rates of medical conditions in the US population puts reported adverse events (AEs) in perspective for further study. Although relatively minor vaccination skin reactions are common, rare instances of severe delayed hypersensitivity reactions such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome may occur. To aid in the assessment of these events, we performed a literature search in PubMed and Web of Science on the background incidence of EM, SJS, SJS/TEN, and TEN in the US population and on published reports of these conditions occurring post-vaccination. The US background annual incidence rates per million individuals of all ages ranged from 5.3 to 63.0 for SJS, from 0.4 to 5.0 for TEN, and from 0.8 to 1.6 for SJS/TEN. Since these conditions may overlap, some studies reported rates for EM/SJS/TEN combined, however we did not find studies with exclusive EM incidence rates. The published literature, including studies of reports submitted to the FDA/CDC Vaccine Adverse Event Reporting System (VAERS), describes post-vaccination EM, SJS, SJS/TEN and/or TEN as rare occurrences. The vaccines most frequently associated with these conditions were measles, mumps, and rubella; diphtheria, tetanus, and pertussis; and varicella. The majority of VAERS reports of EM, SJS, SJS/TEN, or TEN occurred in children within 30 days of vaccination. This review summarizes background rates of these disorders in the general population and published AEs among vaccine recipients, to support safety surveillance of COVID-19 vaccines and other biologics.