Recent approval of two novel mRNA SARS-CoV-2/COVID-19 vaccines by various regulatory agencies has provided hope that we may finally be able to end the pandemic that has claimed hundreds of thousands of lives. The vaccines come not a moment too soon as the numbers of COVID-19-related hospitalizations and deaths reach record, horrifying numbers. Administration of the first vaccine approved to prevent COVID-19 (Pfizer-BioNTech) began in the United Kingdom in December 2020. Within days, there were reports of two or possibly three anaphylactic reactions that occurred following vaccination [1]. The same vaccine was subsequently given emergency use authorization (EUA) by the United States Food and Drug Administration (FDA)[2] and again within days, there were reports of at least two anaphylactic reactions [3]. A second, similar vaccine (Moderna) has also now been approved [4]. In general, anaphylactic reactions to vaccinations are very rare, occurring at a rate of about 1 per million [5]. These reports indicate that the rate may be higher with these vaccines. The vaccine manufacturers and regulatory agencies are investigating these cases in an attempt to confirm that they were in fact anaphylactic events and to determine the cause. These investigations will likely include performing immediate-type allergy skin tests on the patients who suffered these apparent reactions as well as control subjects. If such tests are positive on the patients and negative on controls, it would imply an IgE-mediated mechanism but would not identify the culprit allergen. In vitro assays would also be performed to search for serum specific IgE directed against specific vaccine components.

Anaphylaxis is a multisystem, potentially life-threatening event that occurs due to widespread release of histamine and other mediators from mast cell granules [6]. It is typically triggered by an IgE-mediated mechanism whereby prior exposure to an allergen in a genetically predisposed person can lead to the production of allergen-specific IgE antibodies. These allergic antibodies then coat the surface of mast cells by means of high-affinity IgE Fc receptors. With subsequent exposure, the allergen cross-links adjacent IgE antibody molecules on the surface of the mast cells, leading to ‘‘degranulation” and the release of these mediators into the local tissues and circulation. Other substances such as opioids and radiocontrast media can lead to non-IgE-mediated, so-called ‘‘di-