Lipid nanoparticle library towards development next generation genomic medicines

Ionizable amino lipids are a major constituent of the lipid nanoparticles for delivering nucleic acid therapeutics (e.g., DLin-MC3-DMA in ONPATTRO , ALC-0315 in Comirnaty , SM-102 in Spikevax ). Scarcity of lipids that are suitable for cell therapy, vaccination, and gene therapies continue to be a problem in advancing many potential diagnostic/therapeutic/vaccine candidates to the clinic. Herein, we describe the development of novel ionizable lipids to be used as functional excipients for designing vehicles for nucleic acid therapeutics/vaccines in vivo or ex vivo use in cell therapy applications. We first studied the transfection efficiency (TE) of LNP-based mRNA formulations of these ionizable lipid candidates in primary human T cells and established a workflow for engineering of primary immune T cells. We then adapted this workflow towards bioengineering of CAR constructs to T cells towards non-viral CAR T therapy. Lipids were also tested in rodents for vaccine applications using self-amplifying RNA (saRNA) encoding various antigens. We have then evaluated various ionizable lipid candidates and their biodistribution along with the mRNA/DNA translation exploration using various LNP compositions. Further, using ionizable lipids from the library, we have shown gene editing of various targets in rodents. We believe that these studies will pave the path to the advancement in nucleic acid based therapeutics and vaccines, or cell gene therapy agents for early diagnosis and detection of cancer, and for targeted genomic medicines towards cancer treatment and diagnosis.

Vaccination

The importance of global vaccines for various infectious agents has been emphasized through our experience with the current COVID-19 vaccine. Physicians trained in allergy and immunology are considered experts in vaccines and adverse reactions from vaccines. This chapter will emphasize how to approach vaccines for various populations, including immunodeficient patients, how to determine best paths for patients who miss vaccine doses, and how to address adverse reactions to vaccines, as noted in Case 2, where the patient experienced an anaphylactic reaction to the measles, mumps, and rubella (MMR) vaccine. In addition, mechanisms behind adverse vaccine reactions are discussed. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

Exploring the authentication of COVID-19 vaccines using Surface-enhanced handheld Raman spectroscopy (SERS) equipped with orbital Raster scattering and machine learning

COVID-19 is a novel coronavirus first emerging in Wuhan, China in December 2019 and has since spread rapidly across the globe escalating into a worldwide pandemic causing millions of fatalities. Emergency response to the pandemic included social distancing and isolation measures as well as the escalation of vaccination programmes. The most popular COVID-19 vaccines are nucleic acid-based. The vast spread and struggles in containment of the virus has allowed a gap in the market to emerge for counterfeit vaccines. This study investigates the use of handheld Raman spectroscopy as a method for nucleic acid-based vaccine authentication and utilises machine learning analytics to assess the efficacy of the method. Conventional Raman spectroscopy requires a large workspace, is cumbersome and energy consuming, and handheld Raman systems show limitations with regards to sensitivity and sample detection. Surface Enhanced Raman spectroscopy (SERS) however, shows potential as an authentication technique for vaccines, allowing identification of characteristic nucleic acid bands in spectra. SERS showed strong identification potential through Correlation in Wavelength Space (CWS) with all vaccine samples obtaining an r value of approximately 1 when plotted against themselves. Variance was observed between some excipients and a selected number of DNA-based vaccines, possibly attributed to the stability of the SERS colloid where the colloid-vaccine complex had been measured over different time intervals. Further development of the technique would include optimisation of the SERS method, stability studies and more comprehensive analysis and interpretation of a greater sample size. © 2023 IEEE.

Identifying and Managing Those at Risk for Vaccine-Related Allergy and Anaphylaxis.

Immediate hypersensitivity reactions to vaccines, the most severe of which is anaphylaxis, are uncommon events occurring in fewer than 1 in a million doses administered. These reactions are infrequently immunoglobulin E-mediated. Because they are unlikely to recur, a reaction to a single dose of a vaccine is rarely a contraindication to redosing. This narrative review article contextualizes the recent knowledge we have gained from the coronavirus 2019 (COVID-19) pandemic rollout of the new mRNA platform with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines within the much broader context of what is known about immediate reactions to other vaccinations of routine and global importance. We focus on what is known about evidence-based approaches to diagnosis and management and what is new in our understanding of mechanisms of immediate vaccine reactions. Specifically, we review the epidemiology of immediate hypersensitivity vaccine reactions, differential diagnosis for immune-mediated and nonimmune reaction clinical phenotypes, including how to recognize immunization stress-related responses. In addition, we highlight what is known about mechanisms and review the rare but important contribution of excipient allergies and specifically when to consider testing for them as well as other key features that contribute to safe evaluation and management.

Delayed type hypersensitivity reaction to oral intake of trometamol

Case report Trometamol (tromethamine, tris(hydroxymethyl)aminomethane (TRIS)) is an excipient frequently used as buffer in fluids and semisolid agents, including many drugs such as antibiotics, iodinated contrast agents and the COVID-19 vaccine mRNA-1273. Here, we report the first case of a delayed-type hypersensitivity after oral intake of trometamol. A 64-year- old female patient presented to our emergency department with generalized erythematous rash, pruritus and swelling of the face five hours after the intake of one tablet of fosfomycin trometamol for a urinary tract infection. Further medical history revealed a previous erythematous rash five to six hours after administration of the iodinated contrast agent iopromide. We performed skin prick and intradermal tests with trometamol, fosfomycin trometamol and various iodinated contrast agents, including iopromide, iomeprol, iobitridol, iopamidol and iodixanol. These tests showed no reactions initially. However, 48 hours after intradermal testing, macular erythematous lesions developed at the sites tested with trometamol 0.1%, trometamol 0.01% and all sites tested with iodinated contrast agents. Furthermore, when we performed a lymphocyte transformation test with trometamol, fosfomycin trometamol and iopromide, we recorded a positive reaction with cytokine release after stimulating T cells with trometamol and iopromide. In contrast, basophil activation testing showed a negative result for these agents. Based on these results and our patient's history, we diagnosed a clinically relevant type IV sensitization to trometamol. There are only a few case reports about immediate-type allergic reactions to gadolinium contrast agents caused by the excipient trometamol. There are some published cases which report contact dermatitis after topical administration of trometamol-containing agents. To our knowledge, ours is the first case to report a delayed hypersensitivity reaction to oral administration of trometamol. Excipients are indispensable for drugs, vaccines and other products since they stabilize and preserve the active agents. Nevertheless, excipients should always be considered during an allergy workup, especially if the patient reports prior drug reactions that cannot be explained by a chemical cross-reaction. In our case, we diagnosed delayed-type hypersensitivity to the excipient trometamol. This is a consequential diagnosis for the patient, because trometamol is contained in many drugs and in the COVID-19 vaccine mRNA-1273.

Chronic spontanous urticaria following anti-covid 19 vaccine: Is there a link?

Background: Urticarial reactions following Covid-19 vaccine were rarely reported and have a short self-limited resolution. However only one case of chronic spontaneous urticaria (CSU) after mRNA vaccine was observed (1). Herein, we describe an original case series of patients who exhibited a CSU after Sars-Cov- 2 vaccination. Method(s): It was a retrospective case series of patients referred to the department of Clinical pharmacology of the University of Monastir for exploration of urticaria after Covid-19 vaccination., between January 2021 and January 2022. Result(s): Eight patients (8 F /5M) were included in this study. The median patient age was 36.5 years. None of them had a medical history of CSU. Urticaria was reported in 4 patients following mRNA vaccine (BNT162b2 and Moderna). Viral vector vaccine (Oxford/ AstraZeneca) was offended in 2 cases and inactivated virus vaccine (Sinovac, CoronaVac) was reported in 2 others cases. The mean time interval between vaccination and the onset of urticaria was 28.5 hours. The first shot of vaccine was the mostly offended dose (n = 6). Urticaria was associated with angioedema in 5 patients after Oxford/AstraZenecavaccine (n = 2) and following mRNA vaccine (n = 2). One case of urticaria was associated with angioedema and dyspnea after the CoronaVac administration. Blood tests showed polynuclear leucocytosis in 37% of patients. Positive anti-thyroperoxidase antibodies, and elevated polyclonal hypergammaglobulinemia were present in one patient 3 months after receiving BNT162b2 vaccine. Total serum IgE were high in 25% of patients following BNT162b2 and CoronaVac. All patients required antihistamines and 4 cases required intravenous betametasone. The median time to symptom resolution was 3 days but urticaria rapidly reccured throughout the entire body inspite the regular use of full dose of antihistamine. Intradermal test for the vaccine excipient as well as the offended Covid-19 vaccine was carried out in 5 patients, and were negative in all of them.Currently, all patients still has the pruritic rash daily. Conclusion(s): These cutaneous reactions seem to be particularly prolonged despite the use of symptomatic drugs, as compared with of drug induced-urticaria. Consequently, careful monitoring of urticaria over an extended period of time is needed.

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).

Is an allergic study to trometamol necessary before the administration of the SARS-CoV- 2 vaccines including this excipient?

Background: Trometamol is an excipient present in radiological contrast media, antibiotic drugs such as fosfomycin, and some NSAIDs formulations (namely ketorolac and desketoprofen). Patients with previous hypersensitivity reactions to these drugs could be at a higher risk after the administration of a SARS-CoV- 2 vaccine formulation including trometamol (SARS/Trometamol vaccine) Method: Patients with a previous history of hypersensitivity reactions to drugs including trometamol as excipient, were sent to our Department for assessment, before receiving a SARS/Trometamol vaccine from December 2021 to January 2022 Allergic study included prick-tests with SARS/Trometamol vaccine and trometamol. According to skin-tests results, a controlled administration of SARS/ Trometamol vaccine was performed. Result(s): A total of 59 patients, 42 women (71.2%) and 17 men (28.8%), were included in our study, with a mean age of 57.3 years. Nineteen patients (32.2%) reported a previous history of hypersensitivity reactions to radiological contrast media, thirty-five patients (59.3%) had reacted to NSAIDS, and five patients had suffered reactions to both drug groups (8.5%) None of the studied patients showed a positive skin-test to neither SARS/Trometamol vaccine nor trometamol. Corresponding SARS/Trometamol vaccine doses were administered to all the patients, and no hypersensitivity reactions were observed. Conclusion(s): According to our results, a previous history of hypersensitivity reactions to drugs including trometamol does not seem to increase the allergic risk after the administration of a SARS-CoV- 2 vaccine formulation containing trometamol. Thus, it would not be necessary to perform an allergic study routinely previous to the vaccination of this kind of patients. However, since trometamol allergy is rather rare, more patients should be studied before this conclusion can be generalized.

Allergological study in patients referred for adverse reactions to the SARS CoV2 vaccine: Our experience

Background: Adverse reaction's reported after COVID 19 vaccination had a negative impact on public opinion. These adverse reactions may be or may be not be mediated by hypersensibility reactions. The proper assesment and the manegament of adverse reactions are crucial in order to offer a safer inmunitation and also to reduce the misinformation and the growing rejection to COVID 19 vaccination. Objective(s): To describe clinical characteristics and the allergological study done in different patients who had an adverse event right after COVID 19 vaccine administration Method: Descriptive study in patients who have experienced an adverse event after one single dose of the SARS CoV2's vaccine. Sex, age, atopy, drug allergies, anaphylaxis reaction (according to EEACI), syntoms, timing, vaccine and dose are described on this study. Skin test were done in every patient (Prick-Test and intradermo reaction) with ARN vaccine samples (Pfizer and Moderna), Adenovirus vaccine extract (Astrazeneca) and a battery of excipients (Polietilenglicol, Polisorbato80 and Trometamol). Result(s): The study included 44 patients with an average of 48,76 +/- 12,23 years, (93% women-29% atopic). 29% of the patients reported to be allergic to other drugs (AINES especially). The most frequent reaction according to EEACI anaphilaxy's classification was Grade 1 with a 61%. Grade 2: 18%, Grade 3: 21%. Urticaria and/or angioedema were the most frequent syntoms (60%) followed by disnea (20%) and being late syntoms (50%) the most usual ones. Pfizer was the most implicated vaccine (64%) with the first dose (84%). Skin tests with Polietilenglicol, Trometamol and Polisorbato80 at different concentrations were negative in all patients but two, one positive to Polisorbato80 0.004mg/ml with a previous sensitization to Prontosan (contains Polisorbato) and another one positive to Trometamol 0.1mg/ml. Conclusion(s): Allergists play a main role to offer the maximum befenits to their patients and to improve the vaccine's safety. Skin tests were the most efective tool to diagnose hypersensibility reactions. The 93,17% of the patients with a negative test result tolerated the second dose. The others did not get the second dose due to their own will. Avoiding the COVID 19 vaccine was recommended in those patients with a hypersensibility to the vaccine components diagnose.

Insights from a COVID-19 in-person vaccination program operated in an Allergy department over 13 months

Background: The Spanish COVID-19 vaccination program commenced in December 2020. Some patients were excluded due to background pathologies, ever changing vaccination protocols and the risk of the secondary effects. Some were allergy patients with previous non-vaccine- related anaphylactic episodes, mastocytosis, and food or drug allergies. There were concerns that patients with secondary effects after the first or second doses would be reluctant to have further doses. The Allergy department at the Hospital Universitario Central de Asturias created a COVID-19 pre-and post-vaccination in-person program in which allergy excipient testing and vaccination were carried out when necessary. As far as we are aware, this is the first ever allergy-led testing and vaccination centre protocol of this kind. Method(s): 110 consecutive patients received at least one vaccine dose under the program in the Allergy Department from January 2021 to February 2022. Result(s): Females were more likely to be referred to the Allergy Department (90% of the total). The mean patient age was 53 years and ranged from 18 to 92 years. 27% were existing patients referred internally by the Allergy department, with the remainder from elsewhere. Angioedema (9%), mastocytosis (4%) and anaphylaxis (17%) were some of the patients' preconditions. A third of patients had two or more doses administered in the department. 61% of patients who received one dose of vaccine in the Allergy department went on to complete the full vaccination course as per national Spanish protocol. Only 16% could not continue with immunizations due to a severe allergic reaction to their first or second doses. None of the patients in the Allergy department program required emergency care after vaccination. Conclusion(s): The majority of patients at high risk of secondary effects were able to complete their vaccination course after the Allergy department input. The Allergy department can work as a successful vaccination centre when required.

Online medical consultations and Covid-19 Vaccines in allergic patients

Background: Anaphylaxis reports after Covid-19 vaccination caused concerns regarding adverse effects. Many allergic patients demanded assurances by their allergists. Online Medical Consultations (OMC) are a communication tool between Primary Care and Allergy Department in Navarre. We assessed the impact of allergists' advice regarding Covid-19 vaccination in allergic patients, defined by vaccination status after OMC, and compared reported allergy severity between vaccinated and non-vaccinated. Method(s): Retrospective review of Allergy OMC and vaccination records of patients attended between 2020th September and 2021th August. We screened Covid-19 related OMC and selected those related with possible contraindications/specific recommendations before vaccination (BV).We analysed demographics, vaccination status, allergic diseases (green: non-anaphylactic allergy;yellow: anaphylaxis/ severe drug allergy;red: severe allergy to Covid-19 vaccine or related drug/excipients;blue: non-immunologic symptoms) and OMC replies (contraindication or other recommendations) Results: We received 1438 OMC, 422 due to Covid-19 vaccine and analysed 302 (71.6%), concerning BV. Demographics: Age (median, P25-P75) 61 (46.7-72.25) years. Sex: Female 221 (73.2%);Male 81 (26.8%). Vaccination: 275 (91.1%) completed vaccination (CV) (2 doses), 11 (3.6%) received 1 (IC) and 16 patients (5.3%) none (NC). Specific preparations were contraindicated in 28 (9.4%) (Pfizer-Biontech : 17, Astra-Zeneca 3 and Moderna: 8 cases). Recommendations: 30-minute observation 18.2%;45-minute observation 14.6%;antihistamines 2.6%;time interval with other injectables 1%;alternative vaccine 2.3%;other modifications 1%;premedication and observation period (2.3%). Ten patients (3.3%) required another OMC after adverse events during vaccination. Allergy severity was different according to sex (Male: green 59.2%, yellow 38.2%, red 0%;blue 2.46%;Female: green: 60.2%, yellow 31.8%, red 9.9%, blue: 4.5% (p = 0.025)). Comparison of allergies between groups: CV (Green: 60.7%, yellow: 33.4%, red: 2.9%, blue: 1%);IC (Green: 27%;yellow: 63.6% red: 0%, blue: 9%);NC (Green: 68.75%, yellow: 12.5%, red: 0%, blue: 18.75% (p = 0.03)) Conclusion(s): Adherence to OMC recommendations has been excellent in these patients. Differences in the number of OMC according to sex appear related to previous allergy diagnosis. Observed differences in past allergic diseases according to vaccination status are not related to real contraindications.

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

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

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).

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.

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.

Anaphylactic shock induced by a depot corticosteroid: Reflections on a clinical case

Introduction (contexte de la recherche): IgE-mediated reactions to systemic corticosteroids (CSs) are rare. Hydrocortisone and methylprednisolone succinate ester are the most frequent elicitors. Excipients of depot corticosteroids (like carmellose or macrogol) may also be involved. The involvement of the dipropionate form of betamethasone (present in the depot Diprostene) has not been studied. Objectif: To describe the case of a 40-year-old woman, who presented an anaphylactic shock reaction upon intra-articular administration of Diprostene (Betamethasone sodium phosphate and betamethasone dipropionate), associated with an iodinated radiocontrast media (ICM, Xenetix). Methodes: An allergy work-up was performed, according to recommendations for severe immediate reactions. Nine months after the reaction [hypotension (7/5 mmHg), erythema and desaturation at 94%, treated with adrenalin, methylprednisolone hemisuccinate, dexchlorpheniramine] the patient underwent skin prick tests (SPT) and intradermal tests (IDT) with ICM, bethamethasone and Diprostene (commercial molecules). Latex and chlorexidine were also studied. Resultats: The tests resulted negative for ICM, latex and chlorexidine (including serum specific IgE ImmunoCAP ThermoFisher Scientific), bethametasone phosphate (IDT 0.4 mg/mL) and carmellose (IDT 0.5 mg/mL). SPT elicited a positive reaction towards Diprostene in immediate reading, (for 5, 0.5, 0.05 mg/mL) with an erythema (10, 8, 5 mm respectively) and a wheal (of at least 3 mm for each SPT). We performed an oral drug challenge to bethametasone phosphate for a total of 8 mg and it was well tolerated. The basal tryptase was 5.5 microg/mL. Tryptasemia 30 minutes after the reaction was 26.8 microg/mL. Conclusion(s): We describe an anaphylactic reaction to Diprostene, proven by positive ST. The hypothesis of allergy to betamethasone dipropionate is under investigation. The hypothesis of allergy to macrogol, the other excipient of (which was not tested separately) is less likely, since the patient received Commirnaty SARS-CoV-2 vaccine 3 months after the reaction. The allergy work-up is ongoing (tests are programmed for betamethasone dipropionate alone).Copyright © 2023

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.

Anaphylaxis to trometamol excipient in Moderna COVID-19 vaccine: A case report

Case report The first approved COVID-19 vaccines include BNT162B2 Pfizer-BioNTech and mRNA-1273 Moderna mRNA vaccines. Some severe allergic reactions to these vaccines have been report, and even though there is a lack of robust evidence, IgE-mediated hypersensitivity to excipients may be the cause of several. The excipient polyethylene glycol (PEG) is present in both, whilst Moderna further contains trometamol (or tromethamine), a buffer additive present in drug formulations and contrast media. We report the case of a 40 year-old woman, with controlled allergic rhinitis and asthma, who was referred to our Immunoallergology Department due to an anaphylactic reaction to Moderna COVID-19 vaccine. She described an episode of cervical and facial pruritus 5 minutes after receiving the first dose of vaccine, which rapidly evolved to generalized urticaria. She was promptly given intravenous (IV) clemastine with improvement of symptoms. However, 1h later she developed respiratory symptoms (dry cough, shortness of breath and wheezing). IV hydrocortisone was also given, and the patient was kept under medical supervision for 6h, after which she was discharged home. The following day, she had urticaria that resolved with oral deflazacort (60 mg). She denies exercise practice, alcohol consumption or outset of new drugs prior to vaccination. During investigation, the patient described two similar reactions in the past, 5 minutes after the administration of trometamol-containing contrast media (10 years before with an iodinated contrast and 2 years ago with a gadolinium contrast, both with trometamol). A week after the reaction all laboratory evaluation were within normal limits, including tryptase level. Skin tests were performed, 2 months after, with contrast media that contain trometamol (iopromide, iomeprol, iodixanol, ioversol, gadobutrol) and that do not (ioxitalamate, amidotrizoate, gadoterate meglumine), in accordance with the EAACI/ENDA guidelines. Iopromide and iodixanol were positive on intradermal testing (1:10 dilution), suggesting trometamol as the culprit excipient. She was advised not to receive the 2nd dose of Moderna vaccine. She received Pfizer-BioNTech vaccine at the hospital, without any reactions. This case demonstrates that an IgE-mediated reaction to trometamol may be an underlying mechanism for immediate hypersensitivity to mRNA Moderna vaccine. The risk of an allergic reaction to it increases when a previous history of hypersensitivity to contrast media exists.

The importance of a comprehensive study in allergic reactions

Background: Polyethylene glycol (PEG) is a condensed polymer of ethylene glycol used as excipient in over 1000 commonly medicines, as well as for industrial products or cosmetics (shampoo, toothpaste.) where it can act as thickener, solvent, softener or humectant. In relation to the recently developed COVID-19 vaccines and their excipients some questions have arisen in our consultations. Method(s): A 48-year- old woman came to our clinic with doubts about the administration of COVID-19 vaccine. 8 years ago, after rectal administration of a healing suppository for an anal fissure she immediately presented a dry cough and a generalized urticaria which subsided spontaneously without attend to the emergency department. 5 years ago, with the application of an hemorrhoid cream se presented an immediate reaction consisting of cough, difficulty breathing and generalized urticaria. The symptoms subsided spontaneously after 30-45 minutes. The patient reported previous tolerance to both drugs. She has avoided them ever since. All these medicines have in common PEG as an excipient. We performed several studies to find out if PEG was the culprit. Result(s): *Prick test with Casenlax (which contains 10 grams of PEG 4000): negative. *Oral provocation test with Casenlax: we started with the intake of 2.5 grams of Casenlax and after 5 minutes she started with oropharyngeal pruritus, dry cough, feeling of shortness of breath and desaturation (since 98% to 92-90%). The patient was monitored and administered intramuscular adrenaline (0.3 ml), methylprednisolone 60 mg and dexchlorpheniramine 5 mg. The symptoms were controlled after 15-30 minutes. *COVID-19 AstraZeneca vaccine was administered without incident. Conclusion(s): Given the high incidence of reactions to the excipients accompanying the drugs, this should be taken into account when taking the patient's medical history and in the subsequent pharmacological study.