To the editor,

Anaphylactic reactions to mRNA COVID-19 vaccines have been reported, with the polyethylene glycol (PEG) they contain being considered a possible culprit allergen.¹ Sellaturay et al describe a patient who had a past anaphylactic reaction to a PEG-containing oral medication and urticarial reactions to topical application of PEG-containing personal care products, who subsequently had an anaphylactic reaction to the Pfizer/BioNTech mRNA COVID-19 vaccine.² It is likely that this patient's anaphylactic reaction to the vaccine was the result of IgE-mediated allergy to PEG as the authors conclude. The result of her prick skin test to a 1% (10 mg/ml) solution of PEG 4000 was positive and also induced an anaphylactic reaction. This implies that she is exquisitely sensitive to PEG, since prick skin testing introduces only a tiny amount of the tested substance into the skin. However, the result of a prick skin test with the Pfizer/BioNTech mRNA COVID-19 vaccine itself, which contains 0.05 mg 2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide per 0.3 ml dose (0.17 mg/ml) in the nanoparticles that deliver the mRNA,³ was negative. The likely explanation for this is that, even in this highly PEG-allergic patient, not enough PEG was introduced into the skin by the prick test with the vaccine to produce a positive result. An intradermal skin test with the vaccine was not performed, presumably due to the risk of a systemic reaction in this patient.

As the authors note, there were some potentially inconsistent features of her case. First, her serum mast cell tryptase level was not elevated with her anaphylactic reaction to the vaccine nor with her anaphylactic reaction to the PEG prick skin test, although this does not exclude the diagnosis. Second, her prick skin test results were positive only to PEG 4000 and not to higher molecular weight PEGs, although as they suggest, this may have been due to a delay in reaction time and suppression by treatment. Anaphylaxis is a clinical diagnosis, and the patient's constellation of symptoms is certainly consistent with this,⁴ yet there is a differential diagnosis to include immunization stress-related response.^{5, 6}

The positive PEG skin test result demonstrates mast cell degranulation, but not the mechanism of this degranulation, which is likely IgE-mediated, but could also include other mechanisms such as direct engagement of other mast cell receptors such as Mas-Related G Protein-Coupled Receptor-X2 (MRGPRX2) or complement activation-related pseudoallergy (CARPA). Another recent publication, using skin testing as well as basophil activation testing (BAT), suggests that PEGylated nanoparticles may be better able than PEG alone to cross-link cell-bound IgE or stimulate CARPA reactions.⁷ However, serum-specific IgE assays to PEGylated nanoparticles were not performed and the BAT assay was not performed on patients who had actually had apparent allergic reactions to vaccine administration.⁸

Given the importance of determining definitively that IgE-mediated allergy to the PEG contained in mRNA COVID-19 vaccines can be a cause for anaphylactic reactions to these vaccines, it would seem appropriate to pursue additional evaluation of the patient reported by Sellaturay et al. These tests could include using the patient's serum for specific IgE antibody testing (“RAST”), an inhibition immunoassay (”RAST inhibition”) and a gel electrophoresis / immunoblotting assay (analogous to Western blot, but looking for IgE to PEG and other non-protein vaccine constituents), all using PEGs of various molecular weights and the vaccines themselves.

中文翻译：

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IgE 介导的对聚乙二醇 (PEG) 的过敏是对 mRNA COVID-19 疫苗过敏的原因

给编辑，

已经报道了对 mRNA COVID-19 疫苗的过敏反应，其中含有的聚乙二醇 (PEG) 被认为是可能的罪魁祸首过敏原。¹ Sellaturay 等人描述了一名患者，该患者既往对含 PEG 的口服药物有过敏反应，对局部应用含 PEG 的个人护理产品有荨麻疹反应，随后对辉瑞/BioNTech mRNA COVID-19 疫苗产生过敏反应. ²正如作者得出的结论，该患者对疫苗的过敏反应很可能是 IgE 介导的对 PEG 过敏的结果。她对 1% (10 mg/ml) PEG 4000 溶液的皮肤点刺试验结果为阳性，并且还诱发了过敏反应。这意味着她对 PEG 非常敏感，因为皮肤点刺测试仅将极少量的测试物质引入皮肤。然而，辉瑞/BioNTech mRNA COVID-19 疫苗本身的皮肤点刺试验结果，每 0.3 毫升剂量 (0.17 毫克/毫升) 含有 0.05 毫克 2[(聚乙二醇)-2000]-N,N-二十四烷基乙酰胺在传递 mRNA 的纳米颗粒中，³为阴性。对此的可能解释是，即使在这个高度 PEG 过敏的患者中，通过疫苗的点刺试验也没有将足够的 PEG 引入皮肤以产生阳性结果。未进行疫苗皮内皮试，可能是由于该患者存在全身反应的风险。

正如作者所指出的，她的案例存在一些可能不一致的特征。首先，她的血清肥大细胞类胰蛋白酶水平未因她对疫苗的过敏反应而升高，也未因她对 PEG 点刺皮肤试验的过敏反应而升高，尽管这不能排除诊断。其次，她的点刺皮肤试验结果仅对 PEG 4000 呈阳性，而对更高分子量的 PEG 不呈阳性，尽管正如他们所暗示的，这可能是由于反应时间延迟和治疗抑制所致。过敏反应是一种临床诊断，患者的一系列症状肯定与此一致，⁴但存在包括免疫应激相关反应在内的鉴别诊断。^5、6

PEG 皮肤试验阳性结果表明肥大细胞脱粒，但不是这种脱粒的机制，这可能是 IgE 介导的，但也可能包括其他机制，例如直接参与其他肥大细胞受体，如 Mas 相关 G 蛋白偶联受体-X2 (MRGPRX2) 或补体激活相关假性过敏 (CARPA)。最近的另一份出版物使用皮肤测试和嗜碱性粒细胞活化测试 (BAT)，表明 PEG 化的纳米颗粒可能比单独的 PEG 更能交联细胞结合的 IgE 或刺激 CARPA 反应。⁷然而，未对聚乙二醇化纳米颗粒进行血清特异性 IgE 测定，也未对实际上对疫苗施用有明显过敏反应的患者进行 BAT 测定。⁸

鉴于明确确定 IgE 介导的对 mRNA COVID-19 疫苗中所含 PEG 的过敏可能是对这些疫苗产生过敏反应的原因的重要性，对 Sellaturay 等人报道的患者进行额外评估似乎是合适的。这些测试可能包括使用患者的血清进行特异性 IgE 抗体测试（“RAST”）、抑制免疫测定（“RAST 抑制”）和凝胶电泳/免疫印迹测定（类似于蛋白质印迹，但寻找 IgE 到 PEG 和其他非-蛋白质疫苗成分），均使用各种分子量的 PEG 和疫苗本身。