Cutaneous Adverse Reactions to COVID-19 Vaccines: Insights from an Immuno-Dermatological Perspective

Abstract

(1) Background: Numerous vaccines are under preclinical and clinical development for prevention of severe course and lethal outcome of coronavirus disease 2019 (COVID-19). In light of high efficacy rates and satisfactory safety profiles, some agents have already reached approval and are now distributed worldwide, with varying availability. Real-world data on cutaneous adverse drug reactions (ADRs) remain limited. (2) Methods: We performed a literature research concerning cutaneous ADRs to different COVID-19 vaccines, and incorporated our own experiences. (3) Results: Injection site reactions are the most frequent side effects arising from all vaccine types. Moreover, delayed cutaneous ADRs may occur after several days, either as a primary manifestation or as a flare of a pre-existing inflammatory dermatosis. Cutaneous ADRs may be divided according to their cytokine profile, based on the preponderance of specific T-cell subsets (i.e., Th1, Th2, Th17/22, Tregs). Specific cutaneous ADRs mimic immunogenic reactions to the natural infection with SARS-CoV-2, which is associated with an abundance of type I interferons. (4) Conclusions: Further studies are required in order to determine the best suitable vaccine type for individual groups of patients, including patients suffering from chronic inflammatory dermatoses.

Keywords: COVID-19; adverse event; exanthema; vaccines.

Figure 1

Most commonly used vaccine platforms and selected COVID-19 vaccines. From left to right: mRNA-based vaccines contain genetic information of the spike protein of SARS-CoV-2 in a lipid-nanoparticle-enveloped structure; viral vector vaccines contain DNA of the SARS-CoV-2 spike glycoprotein in a virus other than a coronavirus, most commonly an adenovirus; inactivated coronavirus vaccines contain a multitude of SARS-CoV-2 antigens, and are not limited to the spike glycoprotein; recombinant protein vaccines are specifically engineered molecules to evoke antiviral immunogenicity. Abbreviations: PEG—polyethylene glycol; mRNA—messenger ribonucleic acid; DNA—deoxyribonucleic acid; SARS-CoV-2—severe acute respiratory syndrome coronavirus 2.

Figure 2

Supposed mechanisms of IgE-dependent (type I allergic) and non-IgE-dependent (pseudoallergic) immediate reactions to COVID-19 vaccines adapted from [27,30,32]. Type I allergic reactions occur due to dimerization of high-affinity IgE receptors (FcεRI) in sensitized individuals after contact with an allergen (e.g., PEGs). Non-IgE-dependent immediate reactions may occur via direct interaction of pseudoallergens with G-protein-coupled receptors (e.g., MRG-PX2), or as a result of complement activation (C3a, C5a) in individuals with specific IgG against components of the vaccine (e.g., anti-PEG IgG). Synchronized mast cell degranulation is the result of all three pathways, and causes an abrupt increase in blood levels of histamine, leukotrienes, prostaglandins, and other cytokines. Clinical symptoms such as angioedema, bronchial obstruction, and decreased blood pressure (shock) occur according to the extent of the anaphylactic/anaphylactoid reaction, and may be life-threatening.

Figure 3

The mode of action varies among the different vaccine types, but it ultimately leads to increased expression of IFN-γ, which is a prerequisite for sufficient antiviral immunogenicity. Notably, mRNA and viral vector vaccines activate different TLRs; therefore, immunological differences appear plausible [36,37]. Moreover, vaccines comprise various molecules that potentially act as haptens to elicit type IV allergic reactions [38]. At this point, it is not clear whether specific vaccine types impose a larger risk for severe cutaneous ADRs to specific groups of patients, e.g., psoriatic patients. A dysregulation of regulatory T cells may shift macrophages to initiate granulomatous reactions, and longstanding inflammatory activity might induce fibrogenic alterations of the dermis to result in circumscribed scleroderma (morphea). Abbreviations: TLR—Toll-like receptor; RLR—RIG-I-like receptors; T_RM—Tissue-resident memory T cell; PEG—polyethylene glycol. This immunological scheme is adapted from [35].