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• W4311304712 abstract "Novel messenger RNA (mRNA) vaccines have proven to be effective tools against coronavirus disease 2019, and they have changed the course of the pandemic. However, early reports of mRNA vaccine–induced anaphylaxis resulted in public alarm, contributing toward vaccine hesitancy. Although initial reports were concerning for an unusually high rate of anaphylaxis to the mRNA vaccines, the true incidence is likely comparable with other vaccines. These reactions occurred predominantly in young to middle-aged females, and many had a history of allergies. Although initially thought to be triggered by polyethylene glycol (PEG), lack of reproducibility of these reactions with subsequent dosing and absent PEG sensitization point away from an IgE-mediated PEG allergy in most. PEG skin testing has poor posttest probability and should be reserved for evaluating non–vaccine-related PEG allergy without influencing decisions for subsequent mRNA vaccination. Immunization stress–related response can closely mimic vaccine-induced anaphylaxis and warrants consideration as a potential etiology. Current evidence suggests that many individuals who developed anaphylaxis to the first dose of an mRNA vaccine can likely receive a subsequent dose after careful evaluation. The need to understand these reactions mechanistically remains critical because the mRNA platform is rapidly finding its way into other vaccinations and therapeutics. Novel messenger RNA (mRNA) vaccines have proven to be effective tools against coronavirus disease 2019, and they have changed the course of the pandemic. However, early reports of mRNA vaccine–induced anaphylaxis resulted in public alarm, contributing toward vaccine hesitancy. Although initial reports were concerning for an unusually high rate of anaphylaxis to the mRNA vaccines, the true incidence is likely comparable with other vaccines. These reactions occurred predominantly in young to middle-aged females, and many had a history of allergies. Although initially thought to be triggered by polyethylene glycol (PEG), lack of reproducibility of these reactions with subsequent dosing and absent PEG sensitization point away from an IgE-mediated PEG allergy in most. PEG skin testing has poor posttest probability and should be reserved for evaluating non–vaccine-related PEG allergy without influencing decisions for subsequent mRNA vaccination. Immunization stress–related response can closely mimic vaccine-induced anaphylaxis and warrants consideration as a potential etiology. Current evidence suggests that many individuals who developed anaphylaxis to the first dose of an mRNA vaccine can likely receive a subsequent dose after careful evaluation. The need to understand these reactions mechanistically remains critical because the mRNA platform is rapidly finding its way into other vaccinations and therapeutics. Anaphylaxis is a potentially life-threatening allergic reaction requiring immediate medical intervention. Vaccines are a rare cause of anaphylaxis; however, initial reports were concerning when a higher rate of coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccine–induced anaphylaxis was observed compared with other vaccine platforms. In the last 18 months, we have made significant progress in how to evaluate and manage individuals who have experienced allergic reactions to the COVID-19 mRNA vaccines. In this review, we discuss the evolution of current management strategies and highlight the gaps in our understanding to emphasize areas warranting additional research (Table I).Table IKnowns and unknowns of COVID-19 mRNA vaccine–induced anaphylaxisCurrent observations•Incidence of mRNA COVID-19 vaccine–induced anaphylaxis rate is estimated to be ∼5 (2.5-10) times higher compared with that of non–COVID-19 vaccines•More common in young to middle-aged individuals•Highly predominant in females•More common among those with a history of allergic reactions or anaphylaxis•Rapid onset (typically within 30 min of vaccine administration)•If appropriately managed, full recovery is highly likely•Premedication with oral antihistamines do not offer a clear benefit•ISRR, VCD, and other mimics likely contribute to a higher reported incidence•Most reactions are likely non–IgE-mediated•PEG or polysorbate skin testing is unlikely to predict an mRNA vaccine allergy•Skin testing to vaccine may have suboptimal predictability and should be used in selected cases with consideration for false positives and false negatives•Mastocytosis and HαT do not confer an increased propensity for COVID-19 vaccine–induced anaphylaxis•Most with first-dose immediate allergic reactions including anaphylaxis are likely to tolerate subsequent doses in appropriate settingsKnowledge gaps•What are the pathophysiological mechanisms underlying mRNA vaccine–induced anaphylaxis?•What component in the vaccine is triggering these reactions?•Why are the reactions more common with first dose compared with subsequent doses?•What are the negative and positive predictive values of skin testing to excipients and vaccine?•Are there other in vivo biomarkers or in vitro tests such as BAT that may aid in diagnosis?•Do certain demographic, genetic, or environmental factors or underlying medical conditions place individuals at high risk for developing these reactions?•Why are these reactions so female-predominant?•Are currently used criteria such as Brighton Collaboration criteria or NIAID anaphylaxis criteria specific enough to distinguish anaphylaxis from mimics?•Is there a need for a more robust scoring system for vaccine-induced reactions to account for ISRR or other mimics?•How does the immune response in those incompletely or discordantly vaccinated compare with individuals fully vaccinated at recommended intervals?•Would a nationally synchronous, multidisciplinary approach to assess and manage vaccine-associated reactions in mass vaccination settings reduce vaccine hesitancy?HαT, Hereditary α-tryptasemia; NIAID, National Institute of Allergy and Infectious Diseases; VCD, vocal cord dysfunction. Open table in a new tab HαT, Hereditary α-tryptasemia; NIAID, National Institute of Allergy and Infectious Diseases; VCD, vocal cord dysfunction. In December 2020, at a time when deaths from COVID-19 in the United States had surpassed 0.3 million, 2 novel mRNA-based COVID-19 vaccines, Pfizer-BioNTech (Comirnaty) and Moderna (Spikevax), received emergency use authorization from the US Food and Drug Administration, having demonstrated 95% and 94% efficacy, respectively, in preventing COVID-19.1Piret J. Boivin G. Pandemics throughout history.Front Microbiol. 2020; 11: 631736Crossref PubMed Scopus (225) Google Scholar, 2CDC museum COVID-19 timeline. Atlanta, GA: Centers for Disease Control and Prevention; 2022.https://www.cdc.gov/museum/timeline/covid19Date accessed: May 26, 2022Google Scholar, 3Polack F.P. Thomas S.J. Kitchin N. Absalon J. Gurtman A. Lockhart S. et al.Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.N Engl J Med. 2020; 383: 2603-2615Crossref PubMed Scopus (8459) Google Scholar, 4Baden L.R. El Sahly H.M. Essink B. Kotloff K. Frey S. Novak R. et al.Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.N Engl J Med. 2021; 384: 403-416Crossref PubMed Scopus (5763) Google Scholar Subsequently, an adenovirus vector–based COVID-19 vaccine, Janssen, was granted emergency use authorization in February 2021. The emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with enhanced transmissibility has contributed to persistently high infection rates in the population. As of May 19, 2022, 5 variants of concern have been identified. Collectively, COVID-19 has affected more than 524 million individuals globally and resulted in the loss of 6.2 million lives.5WHO coronavirus (COVID-19) dashboard. Geneva, Switzerland: World Health Organization; 2020. Available at: https://covid19.who.int/. Accessed May 26, 2022.Google Scholar In the United States alone, it has infected more than 83 million individuals (ie, a quarter of the US population) and caused the demise of more than 1 million people, which is 50% more than what the flu pandemic of 1919 had caused.6The deadliest flu: the complete story of the discovery and reconstruction of the 1918 pandemic virus. Atlanta, GA: Centers for Disease Control and Prevention; 2020.https://www.cdc.gov/flu/pandemic-resources/reconstruction-1918-virusDate accessed: May 26, 2022Google Scholar,7COVID data tracker. Atlanta, GA: Centers for Disease Control and Prevention; 2020.https://covid.cdc.gov/covid-data-tracker/Date accessed: May 26, 2022Google Scholar At the same juncture, 18 months after public vaccination for COVID-19 began, a total of 258 million individuals (77.8% of the total and 82.7% of the eligible US population, ie, age ≥ 5 years) have received at least 1 dose. Comparatively, 221 million individuals have been fully vaccinated (66.6% of the total and 70.8% of the eligible US population, ie, age ≥ 5 years), and 103 million have received their first booster (46.6% of the total and 48.4% of the eligible US population, ie, age ≥ 12 years). These numbers indicate that a significant proportion of the population is incompletely vaccinated. More than 11% of those who received the first dose of a COVID-19 mRNA vaccine have not received a second dose. Furthermore, of the individuals fully vaccinated and eligible for a booster dose, more than 22% are yet to receive their first booster dose. Of the approved COVID-19 vaccines in the United States, a total of 586 million vaccine doses have been administered, which included 346 million doses of Pfizer-BioNTech (59%), 221 million doses of Moderna (38%), and 19 million doses of Janssen (3%).7COVID data tracker. Atlanta, GA: Centers for Disease Control and Prevention; 2020.https://covid.cdc.gov/covid-data-tracker/Date accessed: May 26, 2022Google Scholar Pfizer-BioNTech and Moderna vaccines used a novel mRNA-based platform, each encoding for distinctly modified SARS-CoV-2 spike protein (Table II).8DailyMed. Moderna COVID-19 vaccine (cx-024414) injection, suspension. Nih.gov. Last Updated: October 17, 2022. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo. Accessed May 26, 2022.Google Scholar,9DailyMed - PFIZER-BIONTECH COVID-19 VACCINE- bnt162b2 injection, suspension. Last Updated: December 12, 2022. Nih.gov. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo. Accessed May 26, 2022.Google Scholar Lipid nanoparticles (LNPs) were used as vehicles to deliver the mRNA intracellularly. LNPs stabilize the vaccine, maintain its efficacy during storage, and potentially act as an immunologic adjuvant. LNPs comprise an external shell composed of (a) lipid-conjugated polyethylene glycol 2000 (PEG-2000) (Pfizer and Moderna have different lipid residues conjugated to PEG), (b) cholesterol residues, and (c) neutral lipid (1,2-distearoyl sn-glycero-3-phosphocholine). This shell prevents aggregation of LNPs and premature extracellular release of the mRNA. Inside the shell, LNPs contain cationic ionizable lipid (Pfizer-BioNTech: ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate); Moderna: proprietary SM-102) along with active mRNA. This ionizable lipid remains neutral at physiologic pH but assumes cationic charge intracellularly to facilitate mRNA trafficking to its destination. Although the precise mechanism has not been demonstrated in human studies, presumptively once injected, the LNP-mRNA complexes are rapidly endocytosed by nearby leukocytes (such as antigen-presenting cells) and then disintegrated in endosomes. The mRNA escapes into the cytosol through the endosomal membrane, a process facilitated by the ionizable lipid, and then traffics to the rough endoplasmic reticulum for translation. The subsequent MHC II–based antigenic loading results in maturation and proliferation of antigen-specific CD4+ T cells as well as activation of humoral immune responses (Fig 1). Preexisting antibodies to PEG may potentially enhance initial uptake of the vaccine and allow for more effective intracellular delivery.10Ndeupen S. Qin Z. Jacobsen S. Bouteau A. Estanbouli H. Igyarto B.Z. The mRNA-LNP platform’s lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory.iScience. 2021; 24: 103479Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar, 11Szebeni J. Storm G. Ljubimova J.Y. Castells M. Phillips E.J. Turjeman K. et al.Applying lessons learned from nanomedicines to understand rare hypersensitivity reactions to mRNA-based SARS-CoV-2 vaccines.Nat Nanotechnol. 2022; 17: 337-346Crossref PubMed Scopus (40) Google Scholar, 12Risma K.A. Edwards K.M. Hummell D.S. Little F.F. Norton A.E. Stallings A. et al.Potential mechanisms of anaphylaxis to COVID-19 mRNA vaccines.J Allergy Clin Immunol. 2021; 147: 2075-2082.e2Abstract Full Text Full Text PDF PubMed Scopus (94) Google ScholarTable IIComposition of mRNA-based COVID-19 vaccinesPfizer-BioNTech (Comirnaty)Moderna (Spikevax)DosePrimary and booster adult dose: 0.3 mLPrimary adult dose: 0.5 mLBooster adult dose: 0.25 mLIngredients•Active100 μg/mL of nucleoside-modifiedmRNA encoding SARS-CoV-2 viral spike (S) glycoprotein•Active200 μg/mL of nucleoside-modified mRNAencoding SARS-CoV-2 prefusion stabilized spike(S) glycoprotein•Lipids(a)((4-Hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate)(b)2-(Polyethylene glycol 2000)-N,N-ditetradecylacetamide(c)Cholesterol(d)1,2-Distearoyl sn-glycero-3-phosphocholine•Lipids(a)SM-102 (proprietary)(b)Dimyristoyl glycerol polyethylene glycol 2000(c)Cholesterol(d)1,2-Distearoyl sn-glycero-3-phosphocholine•Buffers and other excipients(a)Potassium chloride(b)Monobasic potassium phosphate(c)Sodium chloride(d)Dibasic sodium phosphate dihydrate(e)SucroseSterile 0.9% sodium chloride is used as a diluent.•Buffers and other excipients(a)Tromethamine(b)Tromethamine hydrochloride(c)Acetic acid(d)Sodium acetate trihydrate(e)SucroseNote. Neither vaccine contains any preservatives. For both vaccines, the vial stoppers are not made of natural rubber latex. Open table in a new tab Note. Neither vaccine contains any preservatives. For both vaccines, the vial stoppers are not made of natural rubber latex. The mechanisms underlying allergic reactions to the COVID-19 mRNA vaccines are poorly understood. IgE-mediated allergic reaction is a well-characterized aberrant immunologic reaction caused by allergen-induced cross-linking of specific IgE bound to the high-affinity IgE receptor on the surface of mast cells. This cross-linking results in release of preformed mediators (histamine, tryptase, chymase, carboxypeptidase, and TNF-α) and synthesis of new mediators (prostaglandins, leukotrienes, and cytokines) that are responsible for the clinical presentation of a classic allergic reaction.13Lieberman P. Mechanisms of anaphylaxis beyond classically mediated antigen- and IgE-induced events.Ann Allergy Asthma Immunol. 2017; 118: 246-248Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Some non-mRNA vaccine–associated allergic reactions have been attributed to inactive components, including gelatin, latex, egg protein, yeast, preservatives (thimerosal, aluminum, and phenol), and polysorbate-80.14McNeil M.M. DeStefano F. Vaccine-associated hypersensitivity.J Allergy Clin Immunol. 2018; 141: 463-472Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 15Stone Jr., C.A. Rukasin C.R.F. Beachkofsky T.M. Phillips E.J. Immune-mediated adverse reactions to vaccines.Br J Clin Pharmacol. 2019; 85: 2694-2706Crossref PubMed Scopus (123) Google Scholar, 16Badiu I. Geuna M. Heffler E. Rolla G. Hypersensitivity reaction to human papillomavirus vaccine due to polysorbate 80.BMJ Case Rep. 2012; 2012bcr0220125797Crossref PubMed Scopus (71) Google Scholar However, the mRNA vaccines do not contain any of these and instead contain another excipient, lipid-conjugated PEG-2000, which is not used in any other vaccine. PEG is ubiquitously present as an excipient in various medications, and health care and lifestyle products, and in the last 2 decades, it has been increasingly recognized as a cause of anaphylaxis.17Wenande E. Garvey L.H. Immediate-type hypersensitivity to polyethylene glycols: a review.Clin Exp Allergy. 2016; 46: 907-922Crossref PubMed Scopus (247) Google Scholar,18Stone Jr., C.A. Liu Y. Relling M.V. Krantz M.S. Pratt A.L. Abreo A. et al.Immediate hypersensitivity to polyethylene glycols and polysorbates: more common than we have recognized.J Allergy Clin Immunol Pract. 2019; 7: 1533-1540.e8Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar The molecular weight of PEG included in common products can range from 200 to 35,000 g/mol, and although the exact threshold for weight-based reactivity is not clearly known, generally lower-molecular-weight PEGs are well tolerated and most reactions are reported for moderate-sized PEGs such as PEG-3350 (used as laxative or bowel preparation) or PEG-5000 (pegaspargase and PEG-adenosine deaminase). Studies have shown that skin testing is effective in identifying IgE-mediated PEG hypersensitivity in non–vaccine-related PEG anaphylaxis as well as cross-reactivity with structurally similar polysorbates.19Sellaturay P. Nasser S. Ewan P. Polyethylene glycol-induced systemic allergic reactions (anaphylaxis).J Allergy Clin Immunol Pract. 2021; 9: 670-675Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar,20Bruusgaard-Mouritsen M.A. Jensen B.M. Poulsen L.K. Duus Johansen J. Garvey L.H. Optimizing investigation of suspected allergy to polyethylene glycols.J Allergy Clin Immunol. 2022; 149: 168-175.e4Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Furthermore, anti-PEG IgE was found to be positive in 6 cases of PEG-induced anaphylaxis compared with controls.21Zhou Z.H. Stone Jr., C.A. Jakubovic B. Phillips E.J. Sussman G. Park J. et al.Anti-PEG IgE in anaphylaxis associated with polyethylene glycol.J Allergy Clin Immunol Pract. 2021; 9: 1731-1733.e3Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar Given these findings, PEG was initially targeted as the culprit antigen responsible for reactions to the COVID-19 mRNA vaccines, and a few weeks after initial reports of anaphylaxis, an expert panel in the United States recommended skin testing with PEG- and polysorbate-containing medications in high-risk patients (those with history of IgE-mediated potential PEG allergy or an allergic reaction to the COVID-19 mRNA vaccines).22Banerji A. Wickner P.G. Saff R. Stone Jr., C.A. Robinson L.B. Long A.A. et al.mRNA vaccines to prevent COVID-19 disease and reported allergic reactions: current evidence and suggested approach.J Allergy Clin Immunol Pract. 2021; 9: 1423-1437Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar At the time, this strategy was instituted to encourage vaccination in individuals with allergies unrelated to PEG or mRNA vaccines and to identify individuals at highest risk. A case report proposed IgE-mediated hypersensitivity to PEG as a cause of mRNA vaccine–induced anaphylaxis in a patient with previously unconfirmed medication allergies who developed anaphylaxis to the Pfizer-BioNTech vaccine. This patient had a positive skin prick test result to PEG-4000 (1% wt/vol concentration) that elicited an anaphylactic reaction requiring treatment with epinephrine. Of note, skin testing result to all other excipients including PEG-2000 and the Pfizer-BioNTech and AstraZeneca vaccines was negative.19Sellaturay P. Nasser S. Ewan P. Polyethylene glycol-induced systemic allergic reactions (anaphylaxis).J Allergy Clin Immunol Pract. 2021; 9: 670-675Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar However, several subsequent studies have found PEG and polysorbate skin testing result to have a poor correlation and predictive value.23Pitlick M.M. Sitek A.N. D’Netto M.E. Dages K.N. Chiarella S.E. Gonzalez-Estrada A. et al.Utility and futility of skin testing to address concerns surrounding messenger RNA coronavirus disease 2019 vaccine reactions.Ann Allergy Asthma Immunol. 2022; 128: 153-160Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 24Greenhawt M. Abrams E.M. Shaker M. Chu D.K. Khan D. Akin C. et al.The risk of allergic reaction to SARS-CoV-2 vaccines and recommended evaluation and management: a systematic review, meta-analysis, GRADE assessment, and international consensus approach.J Allergy Clin Immunol Pract. 2021; 9: 3546-3567Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 25Wolfson A.R. Robinson L.B. Li L. McMahon A.E. Cogan A.S. Fu X. et al.First-dose mRNA COVID-19 vaccine allergic reactions: limited role for excipient skin testing.J Allergy Clin Immunol Pract. 2021; 9: 3308-3320.e3Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 26Krantz M.S. Bruusgaard-Mouritsen M.A. Koo G. Phillips E.J. Stone Jr., C.A. Garvey L.H. Anaphylaxis to the first dose of mRNA SARS-CoV-2 vaccines: don’t give up on the second dose!.Allergy. 2021; 76: 2916-2920Crossref PubMed Scopus (53) Google Scholar Refresh Tears eye drops, which was initially proposed to test for polysorbate-80 allergy, was noted to cause frequent irritant reactions in controls.25Wolfson A.R. Robinson L.B. Li L. McMahon A.E. Cogan A.S. Fu X. et al.First-dose mRNA COVID-19 vaccine allergic reactions: limited role for excipient skin testing.J Allergy Clin Immunol Pract. 2021; 9: 3308-3320.e3Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar In a study by Warren et al,27Warren C.M. Snow T.T. Lee A.S. Shah M.M. Heider A. Blomkalns A. et al.Assessment of allergic and anaphylactic reactions to mRNA COVID-19 vaccines with confirmatory testing in a US regional health system.JAMA Netw Open. 2021; 4: e2125524Crossref PubMed Scopus (83) Google Scholar all 17 patients with confirmed anaphylaxis to their first dose of a COVID-19 mRNA vaccine tested negative for PEG-2000 and polysorbate-80 by skin testing, and only 1 patient had a positive skin test result to the same mRNA vaccine that caused the initial reaction. Intriguingly, 100% (11 of 11) had a positive basophil activation test (BAT) result to the mRNA vaccine and 91% (10 of 11) had a positive BAT result to PEG-2000. None of these individuals had detectable anti-PEG IgE, but all had positive anti-PEG IgG, raising the possibility of a non-IgE pathway as the mechanism for these reactions. Several case series have described individuals with known histories of PEG allergies to paclitaxel, docetaxel, pegaspargase, and other PEG- or polysorbate-containing medications who have tolerated the COVID-19 mRNA vaccines without reaction or increased propensity for anaphylaxis.28Banerji A. Wolfson A.R. Robinson L.B. McMahon A.E. Cogan A.S. Saff R.R. et al.COVID-19 vaccines tolerated in patients with paclitaxel and docetaxel allergy.Allergy. 2022; 77: 1048-1051Crossref PubMed Scopus (7) Google Scholar, 29Koo G. Anvari S. Friedman D.L. Zarnegar-Lumley S. Szafron V. Kahwash B.M. et al.mRNA COVID-19 vaccine safety in patients with previous immediate hypersensitivity to pegaspargase.J Allergy Clin Immunol Pract. 2022; 10: 322-325Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 30Mark C. Gupta S. Punnett A. Upton J. Orkin J. Atkinson A. et al.Safety of administration of BNT162b2 mRNA (Pfizer-BioNTech) COVID-19 vaccine in youths and young adults with a history of acute lymphoblastic leukemia and allergy to PEG-asparaginase.Pediatr Blood Cancer. 2021; 68: e29295Crossref PubMed Scopus (30) Google Scholar, 31Otani I.M. Tsao L.R. Tang M. COVID-19 vaccine administration in patients with reported reactions to polyethylene glycol- and polysorbate-containing therapeutics.Ann Allergy Asthma Immunol. 2022; 29: 88-94.e1Abstract Full Text Full Text PDF Scopus (8) Google Scholar, 32Picard M. Drolet J.P. Masse M.S. Filion C.A. AlMuhizi F. Fein M. et al.Safety of COVID-19 vaccination in patients with polyethylene glycol allergy: a case series.J Allergy Clin Immunol Pract. 2022; 10: 620-625.e1Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 33Brockow K. Mathes S. Fischer J. Volc S. Darsow U. Eberlein B. et al.Experience with polyethylene glycol allergy-guided risk management for COVID-19 vaccine anaphylaxis.Allergy. 2022; 77: 2200-2210Crossref PubMed Scopus (35) Google Scholar Furthermore, the fact that many individuals without known PEG sensitization have reacted to the first dose, the nonreproducibility of these reactions with subsequent dosing, and the minimal to no correlation between reactions and positive skin testing result and anti-PEG IgE, all suggest that IgE-mediated PEG allergy is an unlikely explanation for these reactions and reinforce that most individuals with PEG allergies can safely receive these vaccines. The Moderna vaccine contains another excipient, tromethamine, which has been previously implicated in delayed-type reactions to gadolinium contrast magnetic resonance imaging and has occasionally been suspected to cause IgE-mediated reactions.34Lukawska J. Mandaliya D. Chan A.W.E. Foggitt A. Bidder T. Harvey J. et al.Anaphylaxis to trometamol excipient in gadolinium-based contrast agents for clinical imaging.J Allergy Clin Immunol Pract. 2019; 7: 1086-1087Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Tromethamine is not found in the Pfizer vaccine. Rama et al35Rama T.A. Coutinho R.M. Mota D. Moreira A. Cernada J. Hypersensitivity to the Moderna COVID-19 vaccine caused by tromethamine: PEG is not always the culprit excipient.J Investig Allergol Clin Immunol. 2022; 32: 414-415Crossref PubMed Scopus (6) Google Scholar reported a case of acute urticaria after Moderna vaccination in a patient who later had a positive skin test result to tromethamine-containing gadolinium contrast. This individual tolerated the Pfizer-BioNTech vaccine. Thus, although tromethamine may potentially explain some cases of anaphylaxis because of the Moderna vaccine only, more research is needed to establish a direct causal relationship. In addition to IgE, mast cells can be activated by a wide range of chemical, physical, and other triggers that lead to signs and symptoms clinically indistinguishable from IgE-mediated anaphylaxis. PEG has also been implicated in these pseudoallergic or anaphylactoid reactions via a pathway known as complement activation–related pseudoallergy (CARPA). CARPA can occur following activation of any of the 3 complement pathways (classical, lectin, or alternative) and has been previously described following administration of pegylated liposomes, including pegylated doxorubicin. PEG-reactive IgM and IgG can trigger the classical pathway and generation of the anaphylatoxins C3a and C5a, which then induce mast cell degranulation. In the study by Warren et al,27Warren C.M. Snow T.T. Lee A.S. Shah M.M. Heider A. Blomkalns A. et al.Assessment of allergic and anaphylactic reactions to mRNA COVID-19 vaccines with confirmatory testing in a US regional health system.JAMA Netw Open. 2021; 4: e2125524Crossref PubMed Scopus (83) Google Scholar PEG-specific IgG antibodies were thought to be responsible for positive BAT assays in patients who experienced anaphylactic reactions to the COVID-19 mRNA vaccines. However, anti-PEG IgM and IgG antibodies have been observed in up to 40% of healthy people potentially because of prior exposure to PEG.11Szebeni J. Storm G. Ljubimova J.Y. Castells M. Phillips E.J. Turjeman K. et al.Applying lessons learned from nanomedicines to understand rare hypersensitivity reactions to mRNA-based SARS-CoV-2 vaccines.Nat Nanotechnol. 2022; 17: 337-346Crossref PubMed Scopus (40) Google Scholar,12Risma K.A. Edwards K.M. Hummell D.S. Little F.F. Norton A.E. Stallings A. et al.Potential mechanisms of anaphylaxis to COVID-19 mRNA vaccines.J Allergy Clin Immunol. 2021; 147: 2075-2082.e2Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar,36Kozma G.T. Shimizu T. Ishida T. Szebeni J. Anti-PEG antibodies: properties, formation, testing and role in adverse immune reactions to PEGylated nano-biopharmaceuticals.Adv Drug Deliv Rev. 2020; 154-155: 163-175Crossref PubMed Scopus (250) Google Scholar,37Szebeni J. Complement activation-related pseudoallergy: a stress reaction in blood triggered by nanomedicines and biologicals.Mol Immunol. 2014; 61: 163-173Crossref PubMed Scopus (263) Google Scholar It is unclear why this mechanism would trigger a severe allergic reaction in only a small subset of individuals who harbor these antibodies. In addition to PEG-containing LNPs, mRNA and expressed SARS-CoV-2 spike protein have been proposed to have the ability to trigger complement activation via the alternative and lectin pathways, respectively.11Szebeni J. Storm G. Ljubimova J.Y. Castells M. Phillips E.J. Turjeman K. et al.Applying lessons learned from nanomedicines to understand rare hypersensitivity reactions to mRNA-based SARS-CoV-2 vaccines.Nat Nanotechnol. 2022; 17: 337-346Crossref PubMed Scopus (40) Google Scholar,38Yu J. Yuan X. Chen H. Chaturvedi S. Braunstein E.M. Brodsky R.A. Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition.Blood. 2020; 136: 2080-2089Crossref PubMed Google Scholar Unlike IgE-mediated reactions, CARPA can cause anaphylactic reactions on first exposure, with lack of recurrence following subsequent doses, a pattern also observed in pegylated medication–induced hypersensitivity reactions.37Szebeni J. Complement activation-related pseudoallergy: a stress reaction in blood triggered by nanomedicines and biologicals.Mol Immunol. 2014; 61: 163-173Crossref PubMed Scopus (263) Google Scholar Platelet-activating factor (PAF) release has been increasingly recognized as a contributing m" @default.
• W4311304712 created "2022-12-25" @default.
• W4311304712 creator A5057200060 @default.
• W4311304712 creator A5057968453 @default.
• W4311304712 date "2023-02-01" @default.
• W4311304712 modified "2023-10-18" @default.
• W4311304712 title "The conundrum of COVID-19 mRNA vaccine–induced anaphylaxis" @default.
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• W4311304712 doi "https://doi.org/10.1016/j.jacig.2022.10.003" @default.
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