Despite the different variants of SARS-CoV-2 that have been emerging since the beginning of the pandemic, or those that may appear in the near future, mass vaccination of the population is of vital importance to control both the harmful effects and the spread of the virus. However, fear of the occurrence of adverse events, especially hypersensitivity reactions, has triggered mistrust in the population. Although such reactions are rare, it is necessary to establish an effective protocol to detect patients at risk of developing them.
Concurrently to our study, similar studies have also been conducted in other regions of Spain and in other regions of the world with similar results (4, 19, 21, 28–35). After 282,064 doses administered during the period studied in our Health Department Area, we identified 16 (0.005%) patients with suspected hypersensitivity reaction to the vaccines (0.009% with Vaxzevria®, 0.004% with Spikevax®, and 0.007% with Comirnaty®), similar to that described by other authors with the first dose of Comirnaty® (28, 36, 37). It is important to highlight that most adverse events occurred in women, with a mean age of 52 years, and a history of previous allergic reactions.
Of the hypersensitivity reactions identified in our study, 8 were immediate reactions (6 mild and 3 severe) and 8 were delayed reactions (6 mild and 1 severe), especially cutaneous (urticaria and/or angioedema) and with the first dose of Comirnaty®. These findings were similar to those previously described. However, the form of presentation varied from one study to another. Loli-Ausejo et al. reported no anaphylaxis and attributed the symptoms to non-IgE-mediated mechanisms (28); the CDC reported 83 cases of mild cutaneous or respiratory reactions (0.0044%) and 21 cases of anaphylaxis with Comirnaty® (38); and Blumenthal et al. described 1.95% of acute allergic reactions and a rate of 2.47 cases of anaphylaxis per 100,000 doses administered (35). In contrast, Shavit et al. observed that 98% of the 429 subjects who received a dose of Comirnaty® had no immediate allergic events, 1.4% had only minor allergic reactions, and 0.7% had anaphylactic reactions (39). There are other studies where only delayed reactions were described, due to a delayed type IV hypersensitivity mediated by T-cells (29, 32, 33).
We have observed that SPT with vaccine and SPT and IDT (immediate and delayed reading) with excipients have not been effective in the diagnosis of immediate or delayed hypersensitivity reactions, so that, as other authors believe, skin tests with excipients have very low sensitivity and specificity (1, 11). Some authors use Refrech Tears® (containing PS80) as a reagent, which has an irritant effect and is therefore not recommended (1, 11), but others believe that SPT with vaccine and excipients can be useful for diagnosis, despite the fact that in some of them the test was negative (28, 36, 37). Even so, there are isolated published cases of positive SPT with PEG6000 and positive IDT with Comirnaty® 1/100 dilution (21), and positive SPT with PS80 and Comirnaty®, without performing IDT (19), even positive SPT with PEG4000 at 1% with associated systemic reaction in which IDT is not recommended (15). Nevertheless, these studies attempted to complete the vaccination protocol, and the majority of patients tolerated the second doses, either fractionated or with premedication (20, 21). As in other studies, we have observed that skin patch tests with vaccine and excipients did not contribute to the diagnosis of delayed reactions, so it was recommended to complete the vaccination program, especially in cases of mild exanthema and large local reactions (29, 35).
In our study, attention was drawn to the 11 patients with positive IDT (6 with immediate reactions, 3 with delayed reactions, and 2 with both) at 24-48 hours with the vaccine diluted at 1/100, specially with the vaccine diluted at 1/10 or undiluted, without presenting associated systemic reaction. Some authors do not perform IDT when the SPT is positive with the vaccine or its excipients and others do not recommend it (15, 19, 28). According to some studies, IDT with Comirnaty® should not exceed 1/100 dilution to avoid irritant reactions or false positives, or even severe anaphylactic reactions (15, 21). However, others claim that SPT and IDT with Comirnaty® can be useful at 1/10 dilution and undiluted as they have been shown to be non-irritant in predicting immediate reactions (13, 14). Bianchi et al. also used IDT with Comirnaty® at 1/1000 and 1/100 dilution with positive results in 6 patients with mucous-cutaneous adverse reactions and in 12 vaccinated volunteers and negative in 6 unvaccinated volunteers, concluding that this may be a sign of cellular immune protection rather than an allergy to the SARS-CoV-2 spike protein or vaccine components (34). Turner et al. reported that the vaccine is capable of eliciting a delayed intradermal response in vaccinated subjects without PEG allergy (4). However, further studies are needed to investigate the usefulness of SPT and IDT with vaccines and to clarify the pathological mechanism of IDT reactions.
Interestingly, in contrast to LTT results, intradermal injection of the vaccine in the two patients selected for immunohistochemical study did produce a reaction involving T-lymphocytes; CD4 predominance in one case and a mixture of CD4 and CD8 in the other. This in vivo response could be due to the production of SARS-CoV-2 spike protein encoded by the vaccine-containing RNA, by antigen presenting cells of the skin, and by memory T-cells to peptides derived from this protein. Recent reports have described that in previously exposed patients, intradermal injection of recombinant spike protein induces a delayed-type hypersensitivity response involving T-lymphocytes (30, 31). The negativity of the in vitro cellular response could be due to the inefficiency of the liposomal vaccine construct to induce spike protein expression from the vaccine RNA under the culture conditions used, so that the vaccine components do not appear to be directly responsible for a cellular hypersensitivity reaction. BAT was negative in both cases to all dilutions of the vaccine, suggesting the absence of specific IgE to the vaccine components in the basophils of the two patients. Surprisingly, Warren et al. described 17 patients with anaphylaxis with positive BAT to vaccine and PEG and negative skin tests to vaccine components (10). The histological and immunohistochemical findings are similar to other published studies with large local reactions after administration of Spikevax®, using a single skin biopsy, but which have been considered as T-cell-mediated type IV delayed hypersensitivity reactions (32, 33). We wonder if in these cases, we are also facing a sign of protective cell-mediated immunity rather than a delayed type IV hypersensitivity reaction, considering that most of them tolerated the second doses (33).
According to the result of the 11 positive IDT and the immunohistochemical study in the 2 selected patients, in which we observed intense lymphocyte activity in the IDT with the undiluted vaccine, in addition to the negative result in LTT and BAT, and based on the bibliographic references consulted on the protective role of cellular immunity (4, 30, 31, 34), we decided to inoculate the second doses or an alternative vaccine in these patients, in order to ensure that the majority of them completed the vaccination protocol.
The main strength of the study is the clinical idea that justifies it, since the objective is to assess the impact of an interventional screening program in high-risk patients. However, due to the small number of patients, who belong to a very specific region, caution should be taken when extrapolating these results to the general population. Therefore, further studies with a larger population and a greater representation of all possible regions are needed.