This is a spontaneous report received from contactable reporter(s) (Physician and Other HCP) from medical information team for the following literature source(s): "Allergenic components of the mRNA-1273 vaccine for COVID-19: Possible involvement of polyethylene glycol and IgG-mediated complement activation", Allergy, 2021; Vol:76(11), pgs:3307-3313, DOI:10.1111/all.14794. A 23-year-old female patient received bnt162b2 (BNT162B2), administration date 23Mar2021 (Lot number: EN6208, Expiration Date: 30Jun2021) as dose 1, single for Covid-19 immunisation. The patient's relevant medical history and concomitant medications were not reported. The following information was reported: ANGIOEDEMA (hospitalization, medically significant) with onset 23Mar2021, outcome "not recovered", described as "full body angioedema/her angioedema is getting worse"; TYPE 1 DIABETES MELLITUS (medically significant), outcome "not recovered", described as "insulin dependent diabetes"; SWOLLEN TONGUE (medically significant), PHARYNGEAL SWELLING (medically significant) all with onset Feb2022, outcome "not recovered" and all described as "tongue and throat swelling". The events "full body angioedema/her angioedema is getting worse", "tongue and throat swelling" and "tongue and throat swelling" were evaluated at the emergency room visit. Therapeutic measures were taken as a result of angioedema, type 1 diabetes mellitus, pharyngeal swelling. Clinical Course: Reporter Stated, I have a patient who was hospitalized after the first dose of COVID vaccine and has continued full body angioedema since. Pfizer lot: EN6208 Exp:30Jun2021 23Mar2021 was the date of the vaccine. There is an article in Allergy. Nov2021, 76(11):3307 discussing polyethylene glycol 2000, complement activation-related pseudoallergy (CARPA) that has been described in similar liposomes. It also describes tromethamine (trometamol) as a possible substance causing anaphylaxis. She improved somewhat on liquid prednisone, but she has developed insulin dependent diabetes. She has been to the emergency room again Feb2022, with tongue and throat swelling, and required Ruconest two doses and Epinephrine to improve. She lives in (city withheld), but is going to do telemedicine with at "PRIVATE". Her adverse event report was filed, but I don't think there has been follow up and her angioedema is getting worse, and not controlled with two preventive HAE and two acute HAE medications, epinephrine about 2 times per month and fresh frozen plasma twice per week (helps for about 24 hours). literature report received from a contactable physician from Allergenic components of the mRNA-1273 vaccine for COVID-19: Possible involvement of polyethylene glycol and IgG-mediated complement activation. This report included that: Abstract: Following the emergency use authorization of the mRNA-1273 vaccine on the 18Dec2020, two mRNA vaccines are in current use for the prevention of coronavirus disease 2019 (COVID-19). For both mRNA vaccines, the phase III pivotal trials excluded individuals with a history of allergy to vaccine components. Immediately after the initiation of vaccination in the "PRIVATE", "PRIVATE", and "PRIVATE", anaphylactic reactions were reported. While the culprit trigger requires investigation, initial reports suggested the excipient polyethylene glycol 2000 (PEG-2000) contained in both vaccines as the PEG-micellar carrier system as the potential culprit. Surface PEG chains form a hydrate shell to increase stability and prevent opsonization. Allergic reactions to such PEGylated lipids can be IgE-mediated, but may also result from complement activation-related pseudoallergy (CARPA) that has been described in similar liposomes. In addition, mRNA-1273 also contains tromethamine (trometamol), which has been reported to cause anaphylaxis to substances such as gadolinium-based contrast media. Skin prick, intradermal and epicutaneous tests, in vitro sIgE assessment, evaluation of sIgG/IgM, and basophil activation tests are being used to demonstrate allergic reactions to various components of the vaccines. INTRODUCTION: On the 18Dec2020, an emergency use authorization (EUA) provided by the "PRIVATE" permitted the immediate use of the mRNA-1273 vaccine developed by Moderna Therapeutics for the prevention of coronavirus disease 2019 (COVID-19). The EUA allowed the immediate distribution and use of the mRNA-1273 COVID-19 vaccine in "PRIVATE" in subjects 18 years of age and older. 1. It is the second vaccine to BOF 196 cases were evaluated for the efficacy analysis of which 185 cases of COVID-19 were observed in the placebo group versus 11 in the mRNA-1273 group. The secondary endpoint involved the assessment of severe cases of COVID-19 and included 30 individuals. All of the severe cases occurred in the placebo group and none in the mRNA-1273 vaccinated group. 5. The RA stated that the potential benefits of mRNA-1273 outweigh the potential risks. 1 Serious allergic reactions to the active components of the vaccine itself, or to other components, are one of the potential risks of every vaccination product. According to the Local News Agency. 6. On the 25Dec a physician in (withheld) developed an anaphylactic reaction to mRNA-1273 soon after vaccination started in "PRIVATE". He used his own adrenaline autoinjector, carried for his shellfish allergy, and recovered well. On the 10Jan2021, 4,041,396 people had received the first dose of the mRNA-1273 vaccine and 1266 adverse events had been reported. A total of 10 cases were determined as being anaphylaxis, all of which recovered. 7 Anaphylactic reactions to BNT162b2 were also reported in the "PRIVATE", "PRIVATE", and "PRIVATE". 8. 9 Allergic reactions to vaccines including severe anaphylaxis are generally IgE-mediated.10,11 They usually occur within the first 30 min after vaccination and can be fatal. The symptoms include urticarial rashes, generalized pruritus, erythema, wheezing, coughing, dyspnea, throat, tongue, or eye swelling (angioedema), hypotension, dizziness, and vomiting. Furthermore, IgG- and complement-mediated anaphylaxis-like reactions have been described.12,13 Clinical symptoms of this non-IgE-mediated hypersensitivity include, among others, hypo- and hypertension as well as airway obstruction with dyspnea.14 Severe anaphylactic reactions to vaccines are rare, and the rate has been estimated at 1.31 (95% CI, 0.90-1.84) per million vaccine doses.15 The frequency of allergic reactions to BNT162b2 was nearly the same in both the verum and placebo groups (0.6% vs. 0.5%). 16 Allergic reactions to the mRNA-1273 vaccine have not been reported in detail. During the phase I trial of the mRNA-1273 vaccine, one case of transient urticaria in the verum group treated with a vaccine dose of 25 ug was reported after the first injection. The total number of participants in this phase I trial was 45. 17 Both BioNTech/Pfizer and Moderna excluded individuals with a history of allergic reaction to vaccines or their components from the phase III trials. The exclusion criteria for mRNA-1273 state: History of anaphylaxis, urticaria, or other significant adverse reaction requiring medical intervention after receipt of a vaccine.18 The anaphylactic reactions to the BioNTech/Pfizer vaccine during the routine vaccination prompted the Regulatory Agency in "PRIVATE" to issue an alert stating that individuals with a history of severe allergic reactions to vaccines, medicines, food, or to any component of these particular vaccines should be advised against their administration and that a second dose should not be given to anyone having experienced anaphylaxis after the first dose. 19 Currently, the RA only CARPA is partly attributed to the binding of preexisting anti-PEG IgM to the liposomes with subsequent complement activation. 40 Clinical symptoms of this non-IgE-mediated hypersensitivity have been described as hypo- and hypertension, airway obstruction with dyspnea, and other anaphylaxis symptoms shortly after the intravenous administration of liposome-containing drugs.12,33,34,41,42 Independent of PEGylation, liposomes have the potential to activate complement, non-specifically depending on their different surface structures and charge. 12,- 36 Complement products C3a, C4a, and C5a (anaphylatoxins) are considered to be particularly important mediators. In addition to basophils, neutrophils and macrophages are also considered to be relevant effector cells that can be activated via immune complex receptors (CD16, CD32, and CD64, respectively). 9,12,13,35 Anaphylatoxins are liberated during complement activation. 38,43 Possible sensitization to PEG by previous use of cosmetics or drugs containing PEG is conceivable. Little is known about the prevalence of anti-PEG antibodies in the population. Certain reports state that as much as 72% of the population have at least some IgG or IgM antibodies against PEG, 44 while others report high levels in healthy people and even in those without documented treatment with PEGylated products.37,45,46 However, there is no evidence for allergy or anaphylaxis depending on IgG in man. Evidence for a possible role of IgE in triggering PEGI induced hypersensitivity is also being discussed. 47-49 Allergic reactions following the use of PEG as an excipient in a variety of products have been described. This is also referred to as a hidden allergen. 47-50 Similar to BNT162b2, the mRNA-1273 COVID-19 vaccine is a messenger ribonucleic acid (mRNA) vaccine encoding the viral spike (S) glycoprotein of SARS-CoV-2. The list of excipients of both vaccines shares certain components but also differs in others. Interestingly, PEG-2000 can also be found as an excipient in the mRNA-1273 COVID-19 vaccine (Figure 1). It should be noted that PEGs have never been used in any vaccine and that both Pfizer BioNTech and Moderna are the first to apply this substance. PEG is a hydrophilic polyether compound used as an additive in medical products and cosmetics. 51 It is branded under different names, for example, macrogol. The molecular weight of the different PEG excipients varies from 300 to 10,000 g/mol or higher. Furthermore, hypersensitivity reactions may occur to the PEG of all molecular weights, with a higher rate of reaction to molecular weights of between 3350 and 6000 g/mol.47 However, it has been suggested that the molecular weight threshold for PEG immediate reactions is still undetermined.48,52 Cross-reactivity between PEG and its derivatives that is, structurally related polymers such as polysorbate exists due to shared moieties (=CH2CH2 and =CH2CH2OH). 47 Severe allergic reactions to PEG, although rare, have been described after the administration of medications that contain this excipient. PEG has even been described as the high-risk hidden allergen, since it is difficult to detect as a possible cause of allergic reaction. 30,47,48,52,53 PEGylation is used successfully for drug delivery to protect the drug from any damage (concentration 1:1) followed by intradermal testing with dilutions of trometamol from 1:1000 to 1:10.55,59 Although allergic reactions tomRNA-1273 components such as PEG and trometamol have not been frequently reported, the fact that the COVID-19 vaccines will be extensively administrated worldwide to a high proportion of the population should caution health care providers of the potential allergic reactions that may occur in individuals previously sensitized to the components of the vaccines, especially to PEG and PEG analogues as well as to trometamol in the case of mRNA-1273 granted an EUA by local regulators after the authorization received by Pfizer-BioNTech on the 11Dec2020 for the use of the BNT162b2 vaccine.2 The authorization of mRNA-1273 was based on early-phase trials 3,4 and on the revision of the results of an ongoing phase III trial that involved 33,000 adult subjects, randomized 1:1 to receive them RNA-1273 vaccine in a two-dose regimen or placebo. The assessment performed by the RA demonstrated that the vaccine was 94.1% effective for the prevention of COVID-19 as determined 14 days after the administration of the second dose. 1 A total excludes those with a hypersensitivity to the active substance or to any of the excipients of the approved vaccines. Individuals having had a hypersensitive reaction to the first dose should not receive the second dose. For the PEG-containing vaccines, a warning was also issued for individuals hypersensitive to polysorbates, due to a potential cross-reactivity.20-22 The RA and the FDA both have the same recommendations for the BioNTech/Pfizer and Moderna vaccines. 23-27 Although the culprit trigger has yet to be determined, initial reports pointed at the excipient polyethylene glycol 2000 (PEG2000) contained in the vaccine as a PEG micellar carrier system as the potential cause of the anaphylactic reactions. 8,28 PEGylated microsomes used as the carrier of the vaccine can cause anaphylactic reactions in individuals with preexisting PEG allergies, as has been previously observed for PEGylated drugs used in cancer therapy and treatment of chronic diseases.8,29,30 PEG is also used as an excipient in other medicinal products as well as in everyday products, such as depo-steroids, tablets, toothpaste, cosmetics, shampoos, and some biologicals. 31 Lipid nanoparticles are similar to liposomes, which have been in use pharmaceutically for many years as carriers for drugs. Some of the approved liposome/LNP-containing drugs also contain a PEGylated lipid (e.g., in Caelyx pegylated liposomal or Onpattro). The PEG chains on the surface form a hydrate shell around the liposome/LNP. This increases stability and prevents opsonization, that is, the mechanism by which the surface of foreign cells (e.g., bacteria, viruses) that have invaded the body is covered with antibodies and factors of the complement system. In addition, the stability and half-life of the lipid particles are increased. PATHOPHYSIOLOGY: Allergic reactions to such PEGylated lipids are IgE-mediated.10,11 However, non-IgE-mediated reactions should also be considered. 32-34 IgE activates mast cells and basophilic granulocytes via crosslinks of high-affinity IgE receptors, which is indirectly measurable in an increased expression of surface markers (CD63, CD203c) on basophils. 9,35 The symptoms of anaphylactic reactions are particularly caused by mediators released mainly from mast cells and basophilic granulocytes such as histamine, prostaglandins, leukotrienes (LTB4, LTC4, and LTD4), tryptase, platelet-activating factor (PAF), heparin, proteases, serotonin, and cytokines.9,35 Besides IgE, other antibody classes may trigger similar symptomatology or amplify an IgE-mediated re action.9,35 Possible non-IgE-mediated reactions include complement activation-related pseudo allergy (CARPA) and have been described in the context of liposomes.36-38 Updating the Gell and Coombs scheme of type I-IV hypersensitivity reactions (HSRs),39 CARPA may be regarded as an independent category within type I reactions, representing receptor-mediated mast cell activations. 38 by the immune system and to deliver it to the targeted location. In addition, PEG is an additive in cosmetics and shampoos. Both a primary cutaneous sensitization pathway and sensitization after systemic administration are possible. 48 Additionally, and unlike the Pfizer-BioNTech vaccine, mRNA1273 contains tromethamine, also called trometamol (molecular formula: C4H11NO3), an organic amine that is widely used in several medications for topical, enteral, or parenteral administration. Tromethamine/trometamol is also used in cosmetic products as an emulsifier, and contact sensitization and allergy to this compound have been described. 54 Recently, the first case of anaphylaxis to trometamol as an excipient in a gadolinium-based contrast agent (GBCA) was reported.55 The reaction occurred immediately after the GBCA injection in a 23-year-old woman, and IgE-mediated trometamol allergy was detected in this patient. 55. No follow-up attempts are possible. No further information is expected. Sender's Comments: Based on the information available and a close temporal association a possible contributory role of the suspect BNT162B2 cannot be excluded for the reported events. The impact of this report on the benefit/risk profile of the Pfizer product is evaluated as part of Pfizer procedures for safety evaluation, including the review and analysis of aggregate data for adverse events. Any safety concern identified as part of this review, as well as any appropriate action in response, will be promptly notified to regulatory authorities, Ethics Committees, and Investigators, as appropriate