The new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic resulted in an unprecedented fast development of vaccines for coronavirus disease 2019 (COVID-19). Many SARS-COV-2 vaccines make use of novel vaccine platforms and were firstly to be used in such large numbers. The mRNA vaccines developed by Pfizer-BioNTech (BNT162b2) [1] and Moderna (mRNA-1273) [2] contain mRNA encoding the spike protein trimer receptor-binding domain (RBD) subunit of the SARS-CoV-2 virus [3]. The vaccine developed by the University of Oxford and AstraZeneca (AZD1222) [4] makes use of a recombinant adenovirus with DNA encoding the spike protein. Furthermore, several protein subunit or inactivated vaccines are available, including the Medigen/Novavax (MVC-COV1901) [5] and Sinovac (CoronaVac) [6], respectively. A number of studies have confirmed the ability of SARS-CoV-2 vaccines to provide robust protection against SARS-CoV-2 by generating neutralizing antibodies or memory B cells [[7], [8], [9]].

Allergic and hypersensitivity reactions to SARS-COV-2 vaccines have been reported [[10], [11], [12], [13], [14], [15], [16], [17], [18]], with several excipients in the vaccine formulations being the potential cause of these allergic or hypersensitivity reactions. Severe allergic responses to vaccines are generally rare, with approximately <2% of individuals after receiving SARS-COV-2 mRNA vaccine [[14], [15], [16], [17],19,20]. However, the incidence of severe immediate allergic reactions to SARS-COV-2 vaccines was higher than that of other vaccines [15,17,19,20]. In addition to local reactions (COVID-19 arm), urticaria and/or angioedema is one of the most common cutaneous reactions induced by SARS-COV-2 vaccines [10,11]. Both mRNA vaccines (such as BNT162b2 and mRNA-1273) contain polyethylene glycol (PEG) 2000. The use of PEG in vaccines is used to protect the nanoparticles from degradation. Furthermore, the mRNA-1273 vaccine contains tromethamine, and the AZD1222 vaccine contains polysorbate 80, which all may be regarded as the causing components of allergic and hypersensitivity reactions [12,16,18]. Furthermore, mild allergic and cutaneous reactions to these vaccines are not considered a contraindication to revaccination [14,[21], [22], [23]], and risk factors for immediate anaphylactic shock to SARS-COV-2 vaccines include previous immediate allergic reactions to insect bites, food, drug [17], vaccine or one of the vaccine excipients in other formulations that are either injected or taken orally [18].

A growing number of patients are reported to develop immediate allergic and urticarial reactions after SARS-COV-2 vaccination with variable prolonged and chronic courses. However, the pathomechanism behind the development of the symptoms remain largely unclear. Mast cells are considered the critical immune cells responsible for immediate allergic and urticarial reactions, as they release histamine and inflammatory cytokines to induce various immune responses [24]. For the immune mechanism of autoimmune chronic urticaria (CU), it has been reported that mast cell degranulation can be triggered by IgE, IgG anti-IgE, or IgG anti-FcεRI (an IgE receptor) [25,26]. Most of autoimmune CU patients is correlated with IgE antibodies against autoantigens (such as thyroid peroxidase [TPO], IL-24, etc.) while <10% of autoimmune CU patients is mediated by IgG, IgM, or IgA autoantibodies that induce mast cells degranulation [25,26]. Furthermore, the low sensitivity of ex vivo testing (such as skin prick test [SPT], intradermal skin test or basophil activation test [BAT]) for patients with SARS-COV-2 vaccines-induced immediate allergic reactions have been reported previously [[27], [28], [29], [30], [31], [32], [33], [34]], suggesting that the immune mechanisms underlying the allergic and urticarial reactions induced by SARS-COV-2 vaccines are complicated. To date, no early diagnosis markers and useful methods have been identified for patients developed prolonged urticaria after SARS-COV-2 vaccination.

In this study, we investigated the risk factors and immune mechanisms for patients with SARS-COV-2 vaccines-induced immediate allergic and urticarial reactions. We further provide effective therapeutic strategy for patients with recalcitrant CU induced by SARS-COV-2 vaccines, and assessed the recurrent rate for patients experienced immediate allergic reactions and prolonged urticaria induced by SARS-COV-2 vaccines for sequential vaccination.