Polyethylene Glycol and Polysorbate 80 Skin Tests in the Context of an Allergic Risk Assessment for Hypersensitivity Reactions to Anti-SARS-CoV-2 mRNA Vaccines.

Concern has arisen about hypersensitivity reactions in patients with allergic reactions to drugs containing polyethylene glycol (PEG) or polysorbate 80 (PS80), excipients of currently available anti-SARS-CoV-2 mRNA vaccines. However, the actual utility of PEG and PS80 skin allergy testing is currently still debated. We retrospectively analyzed all cases of patients on whom we performed allergometric skin tests for PEG and PS80 in the context of a pre-vaccination screening (for patients with multiple hypersensitivity reactions to drugs for which these excipients were among the suspected agents) or following suspected hypersensitivity reactions to anti-SARS-CoV-2 vaccines. A total of 134 tests were performed for PEG and PS80, eight of which produced uninterpretable results (due to dermographism or non-specific reactions). Of the remaining 126 cases (85 pre-vaccinal and 41 post-vaccine reactions), 16 (12.7%) were positive for PEG and/or PS80. Stratifying by clinical indication, there were no statistically significant differences in the proportion of positive tests between patients evaluated in the context of the pre-vaccination screening and those evaluated after a vaccine reaction (10.6% vs. 17.1%, respectively, p = 0.306). Allergometric skin tests for PEG and PS80 in our case series resulted positive in an unexpectedly high proportion of patients, suggesting that testing for allergy to these two excipients should not be ignored in case of reasonable clinical suspicion.

Updated Guidance Regarding The Risk ofAllergic Reactions to COVID-19 Vaccines and Recommended Evaluation and Management: A GRADE Assessment, and International Consensus Approach.

This guidance updates 2021 GRADE recomendations regarding immediate allergic reactions following COVID-19 vaccines and addresses re-vaccinating individuals with 1st dose allergic reactions and allergy testing to determine re-vaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 re-vaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommenations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the UK, and the US formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy, and re-vaccination after a prior immediate allergic reaction. We suggest against >15-minute post-vaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest re-vaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise, in a properly equipped setting. We suggest against pre-medication, split-dosing, or special precautions because of a comorbid allergic history.

Evaluation of pediatric patients with suspected polyethylene glycol and polysorbate allergy before mRNA SARS-CoV2 vaccination.

mRNA vaccines, particularly, have been associated with an increased risk of allergic reactions and rarely anaphylaxis. Although rare, vaccine reactions can cause significant anxiety and fear in the population, leading to indecision and vaccine refusal. This study aimed to retrospectively evaluate the role of polyethylene glycol (PEG) sensitivity in vaccination decision-making in pediatric patients at high risk of allergy or with suspected allergic reactions to the first dose of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccine. Seventeen enrolled patients were found to have decreased readiness to receive the Coronavirus Disease 2019 (COVID-19) vaccine after developing hypersensitivity to multiple and/or injectable drugs. Skin testing was performed. A basophil activation test with PEG-2000 and 4000 was performed on three patients who were ineligible for skin prick tests. Nine patients with negative tests received the vaccine without complications. One patient had urticarial angioedema despite negative tests. Three patients with positive tests did not agree to desensitization with the mRNA vaccine, and one of them was vaccinated with the inactivated COVID-19 vaccine. Four patients recurred despite negative tests. The general recommendation for patients describing severe reactions to drugs, foods, and allergens, such as toxins that do not contain the adjuvants of the SARS-CoV-2 vaccines, is to be routinely vaccinated with safety precautions. Excipients such as PEG and polysorbate-80 used in COVID-19 vaccines could be potential allergens, but this hypothesis is unclear. The predictive values of these adjuvants for skin testing and in vitro testing are controversial. Further research is needed on the hypersensitivity reactions of adjuvants, the predictive values of skin tests, and etiopathogenesis.

Allergology assessment prior to administration of COVID-19 vaccine in patients with allergy history

Background: The diagnosis of drug allergy requires a previous medical history suggestive of a Drug Hypersensitivity Reaction (DHR). DHRs caused by vaccines are rare (< 1/100.000 doses) and are mainly due to excipients. At the beginning of the COVID-19 vaccination, occasional cases of severe reactions were reported in patients with allergy history. This warning led to an increased demand for allergy testing to evaluate pre-vaccination risk assessment, especially due to the refusal of allergic patients to receive the vaccine. Method(s): Twenty patients were evaluated between May to July 2021, referred for allergology study prior to receiving the vaccine against COVID-19. All patients tested had allergy history. Skin tests were performed with the available excipients of the COVID-19 vaccine: polyethylene glycol (PEG-1500, 10% prick ROXALL), polysorbate 80 (tween 80 prick 0.04 -ID 0.004 mg/ml), and trometamol (prick 1 -ID 0.1 mg/ml). A telephone follow-up was subsequently performed to assess tolerance to the vaccine. Result(s): The median age of the patients was 54.5 years and ninety percent were female. (Table 1) The most frequent allergy history was adverse drug reactions (ADRs) in 18 patients (90%), followed by bronchial asthma (35%), rhinitis (25%), food allergy (25%), and dermatitis (15%). 12 patients (60%) had multiple allergic diseases. The drugs implicated in these ADRs were beta-lactam antibiotics (40%), NSAIDs (20%), radiographic contrast media (15%), and vaccines (15%). Skin tests with the excipients studied were negative in all cases. Subsequently, the COVID-19 vaccine was administered in 16 patients (80%). Six patients (30%) reported side effects expected from the vaccine and no DHRs were described. Although vaccination was recommended to all patients after the study, 4 patients (20%) refused the administration. Conclusion(s): Patients with atopic history do not require an allergology study prior to the administration of the COVID-19 vaccine. Exceptionally, it may be necessary if the patient has a history of suspected DHRs to the excipients involved. The previous allergology assessment did not prevent refusal of vaccination in 20% of the patients. (Table Presented).

Polyethylene glycol sensitization in patients with recurrent urticaria: Something to consider before the administration of the mRNA COVID-19 vaccine

Background: Polyethylene glycol (PEG) and polysorbate are two commonly used excipients in cosmetics, therapeutics, and processed foods. They are used not just to stabilize and preserve but also to influence the pharmacokinetics and bioavailability of the active ingredients of these products. Numerous reports have described patients with recurrent urticaria self-reporting multiple unrelated products hypersensitivities. We aim to describe a case series of sensitization to PEG in patients with recurrent urticaria and its implications to the currently available COVID-19 vaccines in Malaysia. Method(s): Data of all patients during the peak vaccination period (March 2021 -May 2021) who had positive intradermal test to surrogate PEG and polysorbate 80 were retrieved and analyzed. They were tested with PEG 4000 (macrogol), PEG 400 (Systane Ultra eye drop) and polysorbate 80 (Tween 80). Result(s): A total of eight patients were skin test positive to PEG and/ or polysorbate 80. The mean age was 35.1 +/- 10.5 years. Only one patient was male. Everyone reported history of multiple product reactions with recurrent urticaria as the major symptom. Majority (75%) had multiple unrelated products hypersensitivities. Four of them had urticarial reactions after the first dose of mRNA vaccine. Two patients were skin test negative to the lower molecular weight PEG 400. Cross sensitization between PEG 4000 and polysorbate 80 was 100%. All patients were subsequently inoculated with two doses of inactivated virus COVID-19 vaccine without any serious sequalae. Conclusion(s): The validity of skin testing towards PEG is not yet clear. Nonetheless it is a promising tool in diagnosing PEG sensitization in selected patients reporting recurrent urticaria with multiple unrelated products. Pretesting of this select group may be considered before the inoculation of PEG-containing COVID-19 vaccine.

A case of anaphylaxis to the BNT162b2 mRNA COVID-19 vaccine in a patient with confirmed polyethylene glycol allergy

Case report The Food and Drug Administration (FDA) provided emergency use authorization (EUA) for the Pfizer/BioNTech (BNT162b2) COVID-19 vaccine in December 2020. Implementation of COVID-19 mass vaccination efforts were implemented soon after. However, following the FDAs EUA, COVID-19 vaccine allergic reactions were reported. These findings led to concerns about vaccine hesitancy and the possible avoidance of future doses. The Texas Children's Hospital COVID-19 Vaccine Hypersensitivity Clinic was established in December 2020 to help address these concerns and to evaluate both pediatric and adult patients with immediate allergic reactions to the COVID-19 vaccines, as well as evaluating patients with polyethylene glycol (PEG) or polysorbate (PS) allergy. We present the case of an 18yo female who experienced anaphylaxis following her second Pfizer mRNA COVID-19 vaccine. The patient developed symptoms of generalized hives, chest tightness and dyspnea 17 minutes after receiving the Pfizer mRNA COVID-19 vaccine. She was treated in the emergency department with IM prednisone and PO diphenhydramine. Of note, in 2018, she had a similar response to her HPV9 vaccine (containing PS 80). Tryptase wasn't obtained at the time of her COVID-19 or HPV9 vaccine reactions, but she did have a baseline that was normal around 4ng/mL. Skin testing was performed to the following: PEG 3350, PS 20 and PS 80. Skin testing (skin prick and intradermal) were negative for PS20 and PS80. PEG 3350 skin prick was negative but methylprednisone acetate (PEG 3350) was positive at the 4mg/mL intradermal testing strength. She underwent a Miralax (PEG 3350) oral challenge. Within 20 minutes of ingesting 0.17grams PEG 3350 she developed an itchy macular rash on neck and upper chest, nausea and a globus throat sensation. She was treated with PO cetirizine and symptoms improved. Tryptase level was obtained 30 min after the start of her reaction and was 4ng/mL. Given the patient's reaction, she was advised to avoid PEG containing products and will return to undergo a graded-step challenge to the Janssen (J&J) COVID-19 vaccine. The prevalence of COVID-19 mRNA vaccine anaphylaxis and PEG allergies is rare. However, allergy referral is warranted in cases of immediate reactions to the COVID-19 vaccine or history of PEG or polysorbate allergies.

Polyethylenglycol and polysorbate evaluation for COVID vaccines in two patients with multiple drug allergies

Background: Covid 19 is a global epidemic. One of the most important steps in the fight against this epidemic is vaccination. mRNA vaccines are used in vaccination in our country. Among the additives in the vaccine, the substance with the highest allergenic risk is polyethylene glucose (PEG). There are different molecular weights of PEG. Another additive that has a high risk of cross-reaction with PEG as an additive is POLISORBAT 80. Skin tests with drugs containing PEG and POLISORBAT 80 and, if available, tests with vaccines are instructive. Among the drugs containing PEG: Moxifloxacin tablet, ciprofloxacin tablet, Amoxicillin clavulanic acid tablet;Medicines containing polysorbate include: Omalizumab vaccine, Mepolizumab vaccine. The results of the skin test with PEG-containing methylprednisolone (DEPO-MEDROL) and POLYSORBAT-containing triamcinolone (KENACORT-A) in order to be evaluated in terms of vaccine in our 2 patients who had multiple drug sensitivities before were shared. Method(s): Case 1: 33 y, F *There are diagnoses of urticaria and angioedema. Urticaria 30 minutes after taking aspirin, levofloxacin, cefdinir tablet;5 minutes after taking ciprofloxacin tablets, he has anaphylaxis. *Applies before Biontec vaccine. *The patient had a history of anaphylaxis with PEG-containing ciprofloxacin. In the skin tests performed with DEPO-MEDROL and KENACORT-A, 1/100 intradermal test was positive. *The patient for whom Biontec vaccine was not recommended received Synovac vaccine without any problems. Case 2: 52 years, F * He has a diagnosis of urticaria. 5 minutes after general anesthesia and local anesthesia;The patient who had cardiac arrest 3 times was evaluated. The patient, who had Synovac for 2 times without any problems, wanted to have the 3rd dose of Biontec vaccine. *Tested with general -local anesthetic agents. *Ciprofloxacin skin tests are negative;Urticaria plaques developed after 30 minutes of 1/4 tb in oral provocation. In the skin tests performed with DEPO-MEDROL and KENACORT-A, 1/100 intradermal test was positive. *Biontec vaccine is not recommended. Result(s): A safer vaccination is ensured by testing with additives in Covid 19 vaccines. Conclusion(s): Drug additives should also be kept in mind in patients with multiple drug allergies.

Characteristics of immune response profile in patients with immediate allergic and autoimmune urticarial reactions induced by COVID-19 vaccines

Allergic and hypersensitivity reactions induced by COVID-19 vaccines are increasingly reported and some patients may develop prolonged urticarial reactions following COVID-19 vaccination. Herein, we investigated the risk factors and immune mechanisms for patients with COVID-19 vaccines-induced immediate allergy and chronic urticaria (CU). We prospectively recruited and analyzed 129 patients with COVID-19 vaccine-induced immediate allergic and urticarial reactions as well as 115 COVID-19 vaccines-tolerant individuals from multiple medical centers during 2021-2022. The clinical manifestations included acute urticaria, anaphylaxis, and delayed to chronic urticaria developed after COVID-19 vaccinations. The serum levels of histamine, IL-2, IL-4, IL-6, IL-8, IL-17A, TARC, and PARC were significantly elevated in allergic patients comparing to tolerant subjects (P-values=4.5x10-5-0.039). Ex vivo basophil revealed that basophils from allergic patients could be significantly activated by COVID-19 vaccine excipients (polyethylene glycol 2000 and polysorbate 80) or spike protein (P-values from 3.5x10-4 to 0.043). Further BAT study stimulated by patients' autoserum showed positive in 81.3% of patients with CU induced by COVID-19 vaccination (P=4.2x10-13), and the reactions could be attenuated by anti-IgE antibody. Autoantibodies screening also identified the significantly increased of IgE-anti-IL-24, IgG-anti-FceRI, IgG-anti-TPO, and IgG-anti-thyroid-related proteins in COVID-19 vaccines-induced CU patients comparing to SARS-COV-2 vaccines-tolerant controls (P-values= 4.6x10-10-0.048). Patients with COVID-19 vaccines-induced recalcitrant CU patients could be successfully treated with anti-IgE therapy. In conclusion, our results revealed that multiple vaccine components, inflammatory cytokines, and autoreactive IgG/IgE antibodies contribute to COVID-19 vaccine-induced immediate allergic and autoimmune urticarial reactions (Minor revision in Journal of Autoimmunity [IF=14.551]).Copyright © 2023

Management of adverse reactions to COVID-19 vaccines by a Portuguese centre

Background: Since the introduction of COVID-19 vaccines, many reports have focused on adverse reactions. However, there is no global agreement on how to manage those patients. We aim to assess the management of adverse reactions by an immunoallergology department and its outcomes. Method(s): Retrospective analysis of the patients sent to our centre from January to October 2021 for adverse reactions to a COVID-19 vaccine, and who were considered ineligible for a 2nd dose by general practitioners. We collected data on the reported reactions, allergological study and outcomes. Result(s): 123 patients with adverse reactions were included (77% women, n = 95), mean age 55 years-old (min 12;max 92). Pfizer/ BioNTech Vaccine was inoculated in 64 patients (52%);Moderna in 15 (12%);AstraZeneca in 44 (36%). 65 patients (53%) presented symptoms compatible with allergic reactions: 86% (n = 56) with mucocutaneous symptoms, mainly urticaria-like lesions and/or angioedema;17% (n = 11) with suspected anaphylaxis and 5% (n = 3) with Steven-Johnson Syndrome. 19 patients performed skin testing with: PEG2000 (n = 17);polysorbate 80 (n = 15);COVID-19 vaccines (n = 21). Four patients had at least one positive test. 58 patients (47%) presented with non-allergic reactions. They showed great variability of symptoms. Most mild: 47% reported non-specific symptoms (such as malaise, headache, myalgia, fever, or fatigue) and 26% reported local reactions on the inoculation site. Some severe: 6 with deep vein or pulmonary thrombosis, 4 with myocarditis, 2 with stroke or myocardial infarction, and 1 with VITT. Patients with positive skin tests or severe previous reactions (n = 36, 29%) were referred for an alternative vaccine. Those with suspected allergic reaction but negative skin tests were premedicated with antihistamines before the 2nd dose. Follow-up showed: of the 81 patients (66%) who received an additional dose, 25% (n = 20) reported an adverse reaction, which was mild, and no case of anaphylaxis was reported. 16 (13%) refused a 2nd dose, and for 26 (21%) the information could not be obtained. Conclusion(s): The intervention of an allergologist had a significant positive impact on vaccination rates, with 2/3 of patients being reclassified as eligible for a 2nd dose. Allergological study and intervention identified vaccine-allergic patients and guided the decision on vaccine change and premedication, which resulted in a considerably lower number of adverse reactions to the 2nd dose, or at least its severity.

Immune response and allergenic components of COVID-19 vaccines induced delayed cutaneous reactions

Background: Delayed-type cutaneous adverse reactions (DCARs) are potential adverse reactions induced by COVID-19 vaccinations. Objective(s): To investigate the immune pathomechanism of COVID-19 vaccination-related DCARs. Method(s): We conducted a prospective observational study on patients with COVID-19 vaccine-DCARs and tolerant subjects. Serum immune molecules and high-parameter blood cell analysis were analyzed.In vitro lymphocyte activation test (LAT) was performed to evaluate the causative allergens of COVID-19 vaccines for DCARs. Result(s): We enrolled 103 patients with COVID-19 vaccine-DCARs. Patients suffered from DCARs mainly after the first vaccination dose (75.7%). Compared to the tolerant controls, patients with DCARs showed significantly higher serum levels of IL-4, IL-6, IL-8, IL-17A, IL-18, IFN-gamma, IP-10, MIG, granulysin, PARC and TARC(P=3.40x10-5-0.028). High-parameter flow cytometric analysis revealed significant increased CD4+Th2, CD4+Th17, CD4+Th22, CD4+LAG-3+, CD4+CD103+Trm, Tfr, CD8+CXCR3+, CD8+Tc2, CD8+Tc17 and CD8+CTLA4+cell populations relative to total DCARs and specific phenotypes(P=0.001-0.042). In vitro LAT assays measuring IFN-gamma, granulysin, and granzyme B showed that patients with AZD1222-DCARs were significantly reactive to polysorbate 80 and spike protein;BNT162b2-DCARs were significantly reactive to polyethene glycol(PEG) 2000, and spike protein;while mRNA-1273-DCARs were significantly reactive to PEG 2000, tris and spike protein(P<0.05). Conclusion(s): We demonstrated a distinct immune response related to variable clinical phenotypes involved in the immune mechanism of COVID-19 vaccines-DCARs. In vivo LAT assays showed that COVID-19 vaccines excipients and spike protein were potential major components related to the COVID-19 vaccines-induced DCARs.Copyright © 2023

Central Nervous System Distribution of the Ataxia-Telangiectasia Mutated Kinase Inhibitor AZD1390: Implications for the Treatment of Brain Tumors

Effective drug delivery to the brain is critical for the treatment of glioblastoma (GBM), an aggressive and invasive primary brain tumor that has a dismal prognosis. Radiation therapy, the mainstay of brain tumor treatment, works by inducing DNA damage. Therefore, inhibiting DNA damage response (DDR) pathways can sensitize tumor cells to radiation and enhance cytotoxicity. AZD1390 is an inhibitor of ataxia-telangiectasia mutated kinase, a critical regulator of DDR. Our in vivo studies in the mouse indicate that delivery of AZD1390 to the central nervous system (CNS) is restricted due to active efflux by P-glycoprotein (P-gp). The free fraction of AZD1390 in brain and spinal cord were found to be low, thereby reducing the partitioning of free drug to these organs. Coadministration of an efflux inhibitor significantly increased CNS exposure of AZD1390. No differences were observed in distribution of AZD1390 within different anatomic regions of CNS, and the functional activity of P-gp and breast cancer resistance protein also remained the same across brain regions. In an intracranial GBM patient-derived xenograft model, AZD1390 accumulation was higher in the tumor core and rim compared with surrounding brain. Despite this heterogenous delivery within tumor-bearing brain, AZD1390 concentrations in normal brain, tumor rim, and tumor core were above in vitro effective radiosensitizing concentrations. These results indicate that despite being a substrate of efflux in the mouse brain, sufficient AZD1390 exposure is anticipated even in regions of normal brain. SIGNIFICANCE STATEMENT Given the invasive nature of glioblastoma (GBM), tumor cells are often protected by an intact blood-brain barrier, requiring the development of brain-penetrant molecules for effective treatment. We show that efflux mediated by P-glycoprotein (P-gp) limits central nervous system (CNS) distribution of AZD1390 and that there are no distributional differences within anatomical regions of CNS. Despite efflux by P-gp, concentrations effective for potent radiosensitization are achieved in GBM tumor-bearing mouse brains, indicating that AZD1390 is an attractive molecule for clinical development of brain tumors.Copyright © 2022 American Society for Pharmacology and Experimental Therapy. All rights reserved.

Second-dose COVID-19 vaccines are well tolerated in patients with allergic reactions to the first dose -A single center experience

Background: COVID-19 vaccines contain additives such as Polyethylenglycol-2000 (PEG2000;mRNA vaccines) or Polysorbat 80 (vector vaccines), which have been described previously as culprits for anaphylactic events. Method(s): This retrospective study included 46 individuals, who were referred to the Allergy Center at the Depart. of Dermatology, University Hospital Linz with suspected allergic reactions to the first COVID-19 vaccine dose with either mRNA or vector-based vaccines. Patients underwent detailed anamnesis, clinical examination and in most cases skin prick testing using pure additive substances (PEG -different molecular weights, Polysorbate 80). Result(s): Out of 46, 7 patients' reactions were classified as possibly anaphylactic and graded according to Ring & Messmer. Forty patients out of 46 were assessed with skin prick tests for potential allergens in COVID-19 vaccines. Only one patient showed an immediate positive prick test to PEG2000. Second-dose vaccination with mRNA or vector-based vaccines were tolerated well in all patients, including the individual with a positive skin prick test against PEG2000. Conclusion(s): The currently available COVID-19 vaccines have an overall low allergic potential and may be administered safely in patients with suspected allergic reactions to the first dose.

Desensitization to Pfizer-BioNTech Covid-19 mRNA-based vaccine in patients with severe hypersensitivity to PolyEthylene Glycol and/or Polysorbate 80

Background: Covid-19 viral infection affects strongly the populations in the world by the level of morbidity, mortality and the economic impact. A worldwide vaccination program was developed since the end of 2020 to limit the propagation of the virus and the development of variants. In USA and Europe the risk of an allergic reaction is estimated to be 1.31 (95 % CI, 0.90-1.84) per million vaccine dose. The excipients are considered to be the most probable cause of IgE-mediated allergic reactions: PolyEthylene Glycol (PEG) for the Moderna and the Pfizer-BioNTech vaccines and Polysorbate 80 (P80) for the Astra Zeneca and the Johnson & Johnson. P80 presents clinical cross-reactivity with PEG. Patients with a history of severe allergic reaction to PEG or P80 should avoid the vaccination. However, some of them strongly wanted to be vaccinated because their accumulated risk factors for severe infection. Method(s): To 4 severely PEG/P80 allergic patients (grade 3 of anaphylaxis), we proposed a desensitization protocol (7 steps in 90 min + 60 min of observation) with the Pfizer-BioNTech vaccine. Each injection was performed alternately in the deltoid muscle (SC for 2 treated by apixaban) every 15 min. Two patient received all the injections in the same arm due to insufficient lymphatic drainage post mastectomy. The protocol was repeated 1 month and once again 6 months later for the second and the booster doses respectively. One patient didn't received the last one because she was meanwhile moved in palliative treatment. We followed the modification of their immunological status. All patients took a premedication with bilastine 20 mg and montelukast 10 mg (without PEG/P80) 24 h and 3 h before each protocol. Result(s): No patient developed adverse nor allergic reaction after the successive vaccinations. Conclusion(s): We c an p ropose adesensitization protocol to the COVID-19 Pfizer-BioNTech vaccine to patients with severe hypersensitivity to PEG/P80. The desensitization is well tolerated and followed by an increase of specific antibodies and an evolution of antibody level like patients who received the total dosis (0.3 ml) in one injection. (Figure Presented).

Desensitization protocol for anti-SARS- CoV- 2 vaccines in allergic patients: A case series

Background: Vaccination has proven to be the best viable tool for preventing the spread of SarsCov2 infection. The fear of adverse events represents one of the limits of this vaccination campaign. As Allergists, we had a fundamental role evaluating the allergological risks and performing specific tests. The only absolute contraindication to SARS-CoV- 2 vaccination is hypersensitivity to its components. When an individual is allergic to an indispensable medication, it is possible to resort to desensitization. Given the lack of a standardized scheme, the aim of our study is to propose a desensitization protocol for anti-SARS- CoV- 2 vaccines. Method(s): The desensitization protocol we developed consists in the fractioned administration of the entire vaccine dose into 5 separate injections of increasing quantity, through a 2-hour period. Premedication with antihistamines and chromones was administrated. Between January 2021 and January 2022, 23 patients referred to our Unit were deemed with a high risk of hypersensitivity reactions to the vaccines and underwent the desensitization protocol. We here describe 23 consecutive cases of patients who underwent desensitization to anti-SARS- CoV- 2 vaccine. Result(s): 4/23 had positive allergy skin test to Polysorbate and underwent desensitization for their entire vaccination cycle. 19/23 had a previous hypersensitivity reaction to an anti-SARS- CoV- 2 vaccine (18 after the first dose and 1 after the second one). Among 4 patients with sensitization to Polysorbate none developed hypersensitivity reactions after fractionated administration of BNT162b2 vaccine. Among 19 patients that underwent desensitization because of hypersensitivity reactions after I or II dose of vaccine, 15 experienced a reaction following vaccination with BNT162b2, 4 with mRNA-1273 and 4 with ChAdOx1-S recombinant. Furthermore, we categorized their reactions according to WAO score per systemic reactions: 15/19 (79%) grade1, 2/19 (10.5%) grade2, 2/19 (10.5%) grade3. No severe late hypersensitivity reactions were observed. All but one of this 19 patients had no hypersensitivity reactions after vaccination through the desensitization protocol. 1 patient experienced anaphylaxis during desensitization with BNT162b2 vaccine (WAO grade4). No late hypersensitivity reactions were observed. Overall, 22/23 (95.6%) patients that underwent anti-SARS- CoV- 2 vaccination through the desensitization protocol did not experience hypersensitivity reactions. Conclusion(s): Our results suggest that desensitization can be implemented to extend the vaccination to currently ineligible individuals. Larger studies are needed to prove the safety and efficacy of this approach.

Immediate hypersensitivity reaction to COVID-19 vaccines: What's the value of skin tests?

Background: Most of adverse reactions (ARs) caused by COVID-19 vaccines are self-limited and benign, such as localized cutaneous injection-site reactions, fatigue, headache. However, IgE-mediated hypersensitivity reactions (HSR) to COVID-19 vaccines are considered extremely rare. These HSR are either attributed to the vaccine itself or its excipients. Method(s): We carried out a retrospective study including all cases of suspected immediate HSR induced by COVID-19 vaccination and notified to the pharmacovigilance department of Monastir (Tunisia). Skin tests (Prick and intradermal tests (IDR)) to vaccines and their respective excipients were performed. Result(s): Among 339 ARs following COVID-19 vaccination, only 10 cases were related to suspected immediate HSR (7 females/3 males) with an average age of 46 years old. Clinical manifestations were urticaria in 7 cases, anaphylactic reaction grade 3 in 2 cases and grade 2 in one case. The median delay to the onset of symptoms was 3 hours (few seconds to 24 hours). All immediate HSR were secondary to the first dose of vaccine administration. Suspected Covid-19 vaccines were Vaxzevria in 6 cases, Moderna in 2 cases, COMIRNATY and CoronaVac in one case, each of them. Skin tests (Prick test/ IDR10-1/ undiluted IDR) were performed for all patients. Only 2 patients, who presented urticaria and anaphylactic 0.0shock, had a positive result to the culprit vaccine Vaxzevria. Skin test (Prick test/IDR10-1) to the excipient (Polysorbate 80) was negative. Among patients with negative skin tests (n = 8), six underwent vaccination with the same vaccine with antihistaminic premedication, without recurrence of the HSR. In the two remaining patients, culprit vaccines were contraindicated in view of the severity of the reaction Conclusion(s): Hypersensitivity reactions to COVID-19 vaccines are unpredictable and can vary from a localized reaction to life-threatening anaphylaxis. Skin tests can be helpful in the diagnosis of authentic IgE mediated HSR. However, their sensitivity remains to be determined in a large scale population.

Evaluation of patients with history of vaccine allergies prior to mRNA-based Coronavirus Disease 2019 (COVID-19) vaccination

Background: During the initial rollout of COVID-19 vaccination in Singapore, the Ministry of Health (MOH) issued recommendations that patients with a history of any previous vaccine allergy be referred to an allergist for further review on suitability to proceed with mRNA-based COVID-19 vaccines. We review the evaluation of these patients with suspected vaccine allergies prior to receiving mRNA-based COVID-19 vaccines. Method(s): Between 8 April and 22 September 2021, 304 patients were evaluated prior to receiving the COVID-19 vaccinations. Of these, 63 (20.7%) patients with suspected immediate hypersensitivity reactions to non-COVID polysorbate-containing vaccines proceeded to have skin prick test (SPT) and Intradermal test (IDT) to polyethylene glycol (PEG)-3350, polysorbate 80 and polysorbate 20 containing products. Another 62 (20.4%) who reported delayed hypersensitivity reactions to polysorbate-containing vaccines proceeded to have direct inoculation (DI) of the Pfizer BNT162b2 vaccine under the supervision of an allergist. The remaining 242 (76.6%) finally assessed not allergic polysorbate-or tolerated previous non-polysorbate- containing vaccines were recommended to proceed with COVID-19 vaccinations at the community vaccination sites. 99 patients in the SPT/IDT and DI group completed a questionnaire-based survey to report any post vaccination reactions. (Figure 1) Results: Of 63 patients who underwent SPT/IDT, 2 (3.2%) with equivocal IDT tolerated both doses of the BNT162b2 vaccine without major allergic reactions. 61 (6.8%) patients with negative SPT/IDT and 62 (100%) in the DI group completed both doses of BNT162b2 vaccination without major reactions. Among those who completed the questionnaire survey, 13 (13%) reported reactions including non-specific rashes and mild urticaria/angioedema post first dose vaccine. All subsequently completed the second dose of the BNT162b2 vaccine following allergist review;with 8 (61.5%) reporting similar mild skin reactions. Conclusion(s): Majority of those with suspected reactions to polysorbate containing vaccines are able to tolerate the BNT162n2 vaccine which contains PEG-2000. Skin tests prior to mRNA COVID-19 vaccination is unnecessary. Those who report mild potentially allergic reactions after the first dose are able to tolerate the second dose of the BNT162b2 vaccine.

Skin testing for exploration of hypersensitivity to SARS-Cov- 2 vaccines or its excipients: A retrospective monocentric cohort of pediatric and adult patients

Background: National guidelines recommend that patients with high risk of allergic reactions to COVID-19 vaccinations must undergo allergological evaluation before authorizing vaccination. To date, allergological testing to COVID-19 vaccines and its excipients is not standardized. There is a need to provide more data on skin testing (ST) to COVID-19 vaccines. In this study, we aimed to evaluate the performance of skin testing with SARS-CoV- 2 vaccines and their excipients in our cohort of adult and pediatric patients. Method(s): All patients evaluated for a suspicion of allergy to any of the vaccine components (polyethylene glycols (PEGs) and polysorbate (PS)), or with a history of immediate or delayed reaction to a first injection of an mRNA vaccine were included. Evaluated patients received the following ST: *PEG 400 and 4000 (100 mg/ml), prick (PT) 1:1 and intradermal tests (IDR) 1:100,000, 1:10,000, 1:1000, 1:100, 1:10. *PS80 (0.4 mg/ml), PT 1:1, IDR 1:1000, 1:100, 1:10. *Tozinameran (Comirnaty) vaccine (30 mug/0.3 ml), PT 1:1 and IDR 1:10. ST readings were performed after 20 minutes for immediate reaction and 24 hours for delayed reaction. Patients were systematically contacted by phone after vaccination to assess side effects including anaphylaxis. Result(s): Between February 1st and October 31st 2021, 83 patients underwent allergological testing, with a majority of female (83.1%). Age (mean +/- SD) was 51 +/- 18 years old (yo) (range: 12-91 yo). Among those patients, 35 were tested following a reaction to the SARS-CoV- 2 vaccine and 48 for a suspected allergy to an excipient. No patients reported anaphylactic reaction after a COVID vaccine. Among them, 13 had positive ST (1 patient to PS80 IDR, 1 patient to PS80 PT and vaccine IDR, 11 patients to vaccine: 5 delayed IDR, 5 immediate IDR, 1 doubtful IDR). Eleven patients were vaccinated, well tolerated. We have no information about COVID vaccination for 2 patients. Out of the 70 patients with negative ST, 5 chose not to be vaccinated and 54 (77.1%) got vaccinated (11 (15.7%) did not respond to the phone call). No anaphylactic reactions were reported. Conclusion(s): In our cohort, vaccinations do not lead to hypersensitivity reactions, regardless of test results. We did not find real IgE mediated allergy. Vaccine IDR seemed too irritating and did not contribute to the diagnosis of vaccine hypersensitivity. The clinical context and skin tests results are helpful in authorizing vaccination.

Development of research use only specific IgE immunoassays for PEG

Background: Polyethylene glycols (PEGs) are hydrophilic polyethers widely used in pharmaceutical, cosmetic, food, and household products. PEG is usually safe and allergic reactions are rare, however according to literature, hypersensitivity is most likely underestimated and mild to life-threatening immediate-type hypersensitivity to PEG have been reported. PEG 2000 is an ingredient in some of the COVID-19 vaccines and is a possible cause of rare cases of adverse reactions to the vaccines that have been reported*. PEG hypersensitivity seems to depend on molecular weight (MW) and higher MW PEGs appear to be more allergenic. Based on this, we developed two ImmunoCAP PEG tests with different MW:s of PEG for measurement of anti-PEG specific IgE (sIgE) and specific IgG antibodies. Method(s): ImmunoCAP PEG 2000 and PEG 10000 Research Use Only (RUO) tests were developed according to conventional methods. As PEG is structurally related to polysorbates, a specific polysorbate 20 free washing solution was developed. The analytical characteristics of the ImmunoCAP PEG tests have been determined and an accelerated stability study has been performed. Result(s): The developed RUO ImmunoCAP PEG 2000 and PEG 10000 tests fulfilled internal standard RUO specifications using the polysorbate 20 free washing solution. Intra-and inter assay performance were evaluated at three concentrations from low to high on the sIgE measuring range (0-100 kUA/L). Overall results for intra-and inter assay performance were <=6.0 %CV and <=9.5 %CV, respectively. Anti-PEG IgG have been reported in human plasma samples with levels reaching up to 6.5 mug/mL (median 49.3 ng/mL). No anti-PEG IgG interference could be detected for these PEG tests when assayed with an anti-PEG IgG positive control in concentrations up to 6.5 mug/mL. An accelerated stability study indicated a shelf-life of two years for both PEG tests. Conclusion(s): Two ImmunoCAP PEG tests have been developed. These tests have been used as a complementary research tool to evaluate the risk for hypersensitivity reactions to PEG and to determine sIgE sensitization pattern in patient serum. In addition, studies have shown sIgE levels >0.1 kUA/L using these ImmunoCAP PEG tests for patients with a history of reactions to PEG together with positive skin prick testing. *It is important to understand that these reactions are extremely rare and should not discourage the general public from vaccination.

Symptoms compatible with hypersensitivity reactions after receipt of the first and second dose of COVID-19 vaccine

Background: Until January 2022, 8.975.458 cases of COVID-19 have been reported in Spain. In December of 2020, the European Union authorized the first mRNA vaccines against SARS-COV- 2, developed by Pfizer-BioNTech and Moderna, with two doses separated by 21 and 28 days, respectively. Reports of severe allergic reactions, including anaphylaxis, have prompted concern that the new mRNA vaccine platform has the potential to cause allergic reactions (including anaphylaxis) at a greater rate than other vaccines. Method(s): Immunization process started at Hospital Ramon y Cajal (Madrid, Spain) in January 2021. The hospital provided a form to report any adverse effect after the first or second dose of the vaccine. Until today, in our Allergy Department, we have received more than 500 patients with suspected adverse reaction to the vaccine, although the data in this publication are collected from January 2021 to September 2021. All of them were referred from different services (Occupational Risk Prevention Department, Preventive Medicine Department, General Practitioners and other specialties) by telephone, e-mail or personally at our service. Result(s): Out of the 139 vaccinated patients who reported adverse effects, 131 had a reaction with the first dose, of whom 65% were women. 51% were local reactions and 49% systemic, of which 62% were immediate reactions. We performed diagnostic tests in 55% of the patients: prick test (with macrogol, triamcinolone, dexketoprofen, methylprednisolone acetate, PEG), ID test (with triamcinolone, dexketoprofen, methylprednisolone acetate) with immediate reading and delayed reading in case of delayed reactions, epicutaneous tests (with PEG and polysorbate 80) and blood tests in systemic reactions. All diagnostic tests showed negative results. 82% of patients that reported adverse effects after the first dose tolerated the second dose of the vaccine without incidents. Only one patient had a reaction to the first and second dose despite a negative study, a 58-year- old woman who presented an urticarial rash 24 hours after administration. 8 patients, all of them women, were referred for reaction after the second dose, 87% of whom had tolerated the first dose. Conclusion(s): This single-center experience suggests that most patients who had mild reactions to the first dose of mRNA vaccines have received the second dose uneventfully or with only mild repeat reactions.

Allergist coorporation, the COVID-19 vaccination's keystone

Background: The French vaccination campaign against COVID-19 was accompanied by an overwhelming increase in allergists work load highlighting our key role in the stratification of the allergy risk prior to vaccination. Method(s): In order to describe our triage and testing experience for the COVID-19 vaccination all requests were analysed in a standardized way prospectively. Our final goal was to filter the requests and avoid any delay in the vaccination process. We first set up and validated locally a questionnaire (completed by the requesting practitioner) allowing to evaluate the risk of allergy to the vaccine, based on the clinical history of the patient. Questionnaire-based allergy advices were delivered (regular vaccination or allergy testing prior to vaccination). Result(s): From January 2021 to January 2022, we addressed 1047 requests. Forty-one patients (4%) were tested. 96% had allergies to other compounds, not increasing the risk of reacting to the covid vaccines and were vaccinated safely. Half of the tested patients experienced an immediate reaction to the vaccine and the other half had a history of allergy to the vaccine's components. We identified 3 groups of patients: -Suspicions of polyethylene glycol (PEG) containing laxative allergy comprised 8 patients (26%), including 2 cases with proven IgE-mediated allergy to PEG. They were 63% (5) women, 63% (5) atopic (average age of 49 +/-10 yrs). Two thirds (63%, 5 patients) had an immediate reaction to PEG, including 3 and 2 patients with anaphylaxis with and without shock, respectively. The two allergic patients refused vaccination and received a certificate of contraindication to PEG-containing vaccines (as per French law). -Reactions to the covid vaccine comprised 21 patients: most were women (86%, 18 patients) and 29% (6) were atopic (average age was 51 +/-19 yrs). Three quarters (76%, 16 patients) presented a reaction within 1 hour after the vaccination, considered as potential anaphylaxis in 12 patients (8 patients with and 5 without shock). 100% (21 patients) were tested negative. Twenty patients (95%) were further vaccinated without reaction. One required H1 antihistamine. -Suspicions of allergy to PEG or polysorbate as excipients included 12 patients (29%). Most clinical histories were anaphylactic (42% without and 33% with shock). Following negative excipient skin testing, regular vaccination was authorized. Conclusion(s): Overall, only 4% of the initial requests were deemed eligible for allergy testing. We did not diagnose any allergy in patients who reacted to the vaccines and we delivered two certificates of contraindication to mRNA COVID-19 PEG-containing vaccines in two cases of confirmed IgE-mediated allergy to PEG.