The conundrum of COVID-19 mRNA vaccine-induced anaphylaxis.

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.

Pseudolung Cancer Lymphadenopathy, Development of Idiopathic Tubulointerstitial Nephritis, and Dense Deposit Disease Following Pfizer-BioNTech COVID-19 Vaccination

Introduction: Despites reports of glomerulonephritis associated with COVID-19 mRNA vaccines, no study has reported about the dense deposit disease (DDD). Here we present a case of pseudolung cancer lymphadenopathy following COVID-19 mRNA vaccine, following which the patient developed idiopathic tubulointerstitial nephritis (TIN) and DDD. Case Description: A 74-year-old man received his second dose of the mRNA vaccine, and he developed fever, urticaria, and dyspnea. On further examination, he had pleural effusion and right hilar lymphadenopathies, which were improved with conservative therapy. On 48 days after the second vaccination, he developed renal dysfunction and new-onset hematuria. Light microscopy findings by a renal biopsy demonstrated apparent mesangial cell proliferation and diffuse inflammatory cell infiltration in the interstitium. Immunofluorescence analysis revealed 1+ positive results for IgG and IgM, negative results for IgA, and 2+ positive results for C3 with a garland pattern on the capillary walls. Electron microscopy detected that continuous and thickened highly dark-stained spotty dense deposits in the glomerular basement membrane. Based on the decrease in C3 and pathological findings, idiopathic TIN accompanied with DDD was diagnosed. Discussion(s): After vaccination acute allergic reaction, pseudolung cancer lymphadenopathy, hematuria, and hypocomplementemia were observed. Thus, both coincidental onset with DDD and TIN following acute allergic response that occurred about 7 weeks before made us think that each event or disease might be associated with COVID-19 mRNA vaccination as part of immunological reactions. In complement activation related pseudoallergy syndrome, it is recently recognized that several modernday therapeutic molecules may activate complements via the nonIgE mediated mechanism with the C3a and C5a anaphylatoxins binding to mast cells, triggering that the release of a number of several vasoactive mediators that cause the clinical features associated with hypersensitivity reactions. mRNA vaccine might have contributed to the development of lymphadenopathies, TIN and DDD in this case. Moreover, TIN and DDD might be associated with the activated alternative pathway induced by the mRNA vaccine.

Exposure of the Basophilic Cell Line KU812 to Liposomes Reveals Activation Profiles Associated with Potential Anaphylactic Responses Linked to Physico-Chemical Characteristics.

Lipidic nanoparticles (LNP), particularly liposomes, have been proven to be a successful and versatile platform for intracellular drug delivery for decades. Whilst primarily developed for small molecule delivery, liposomes have recently undergone a renaissance due to their success in vaccination strategies, delivering nucleic acids, in the COVID-19 pandemic. As such, liposomes are increasingly being investigated for the delivery of nucleic acids, beyond mRNA, as non-viral gene delivery vectors. Although not generally considered toxic, liposomes are increasingly shown to not be immunologically inert, which may have advantages in vaccine applications but may limit their use in other conditions where immunological responses may lead to adverse events, particularly those associated with complement activation. We sought to assess a small panel of liposomes varying in a number of physico-chemical characteristics associated with complement activation and inflammatory responses, and examine how basophil-like cells may respond to them. Basophils, as well as other cell types, are involved in the anaphylactic responses to liposomes but are difficult to isolate in sufficient numbers to conduct large scale analysis. Here, we report the use of the human KU812 cell line as a surrogate for primary basophils. Multiple phenotypic markers of activation were assessed, as well as the release of histamine and inflammasome activity within the cells. We found that larger liposomes were more likely to result in KU812 activation, and that non-PEGylated liposomes were potent stimulators of inflammasome activity (four-fold greater IL-1ß secretion than untreated controls), and a lower ratio of cholesterol to lipid was also associated with greater IL-1ß secretion ([Cholesterol:DSPC ratio] 1:10; 0.35 pg/mL IL-1ß vs. 5:10; 0.1 pg/mL). Additionally, PEGylation appeared to be associated with direct KU812 activation. These results suggest possible mechanisms related to the consequences of complement activation that may be underpinned by basophilic cells, in addition to other immune cell types. Investigation of the mechanisms behind these responses, and their impact on use in vivo, are now warranted.

Polyethylene glycol (PEG): The nature, immunogenicity, and role in the hypersensitivity of PEGylated products.

Polyethylene glycol (PEG) is a versatile polymer that is widely used as an additive in foods and cosmetics, and as a carrier in PEGylated therapeutics. Even though PEG is thought to be less immunogenic, or perhaps even non-immunogenic, with a variety of physicochemical properties, there is mounting evidence that PEG causes immunogenic responses when conjugated with other materials such as proteins and nanocarriers. Under these conditions, PEG with other materials can result in the production of anti-PEG antibodies after administration. The antibodies that are induced seem to have a deleterious impact on the therapeutic efficacy of subsequently administered PEGylated formulations. In addition, hypersensitivity to PEGylated formulations could be a significant barrier to the utility of PEGylated products. Several reports have linked the presence of anti-PEG antibodies to incidences of complement activation-related pseudoallergy (CARPA) following the administration of PEGylated formulations. The use of COVID-19 mRNA vaccines, which are composed mainly of PEGylated lipid nanoparticles (LNPs), has recently gained wide acceptance, although many cases of post-vaccination hypersensitivity have been documented. Therefore, our review focuses not only on the importance of PEGs and its great role in improving the therapeutic efficacy of various medications, but also on the hypersensitivity reactions attributed to the use of PEGylated products that include PEG-based mRNA COVID-19 vaccines.

Safety of Therapy with Tocilizumab and Other Interleukin Inhibitors

Monoclonal antibodies directed against interleukin and interleukin receptors have been successfully used for the treatment of rheumatic diseases since 2001, and since 2020 they have been used as part of complex therapy for patients with severe COVID-19. This raises the question of safety of these products, especially when used for new indications. The aim of the study was to analyse data on potential adverse reactions to tocilizumab and other interleukin inhibitors in order to increase the safety of pharmacotherapy of systemic connective tissue diseases, as well as of severe COVID-19. Literature data suggest that the most frequent adverse reactions to tocilizumab and other interleukin inhibitors are infections, hypercholesterolemia, leukopenia, neutropenia, thrombocytopenia, and increased liver enzyme activity. Hypersensitivity and acute infusion reactions, manifested as pseudoallergic reactions, also pose serious health risks and can even be fatal. However, the identification of undesirable reactions to interleukin inhibitors is challenging, due to their prolonged intake and long intervals between injections. Besides, they are often used in combination with other medicines, such as methotrexate or glucocorticosteroids, which complicates establishment of a reliable correlation between an adverse reaction and a particular medicine. At present, the safety of tocilizumab and other interleukin inhibitors for the treatment of severe COVID-19 has not been studied properly and needs further research with an increased number of participants and a careful analysis of the risk/benefit ratio of these medicines when used for COVID-19 treatment.

Anaphylaxis to additives in vaccines.

Anaphylaxis in connection with the administration of vaccines occurs only very rarely. Triggers of immunoglobulin IgE-mediated and non-IgE-mediated anaphylaxis-in addition to the active ingredient itself-may be excipients contained in the vaccine due to their special properties. Some of the excipients in medicinal products are the same compounds used as additives in food. Furthermore, residues from the manufacturing process (e.g., chicken egg white, casein, antibiotics, formaldehyde) or contaminants (e.g., from the primary packaging material) may be potential triggers of anaphylaxis in vaccines. This review article provides an overview of ingredients in vaccines that pose an allergenic risk potential. The components of COVID-19 vaccines approved and marketed in Germany are discussed with regard to their potential for triggering anaphylaxis and possible pathophysiological mechanisms involved.

A naturally hypersensitive porcine model may help understand the mechanism of COVID-19 mRNA vaccine-induced rare (pseudo) allergic reactions: complement activation as a possible contributing factor.

A tiny fraction of people immunized with lipid nanoparticle (LNP)-enclosed mRNA (LNP-mRNA) vaccines develop allergic symptoms following their first or subsequent vaccinations, including anaphylaxis. These reactions resemble complement (C) activation-related pseudoallergy (CARPA) to i.v. administered liposomes, for which pigs provide a naturally oversensitive model. Using this model, we injected i.v. the human vaccination dose (HVD) of BNT162b2 (Comirnaty, CMT) or its 2-fold (2x) or 5-fold (5x) amounts and measured the hemodynamic changes and other parameters of CARPA. We observed in 6 of 14 pigs transient pulmonary hypertension along with thromboxane A2 release into the blood and other hemodynamic and blood cell changes, including hypertension, granulocytosis, lymphopenia, and thrombocytopenia. One pig injected with 5x CMT developed an anaphylactic shock requiring resuscitation, while a repeat dose failed to induce the reaction, implying tachyphylaxis. These typical CARPA symptoms could not be linked to animal age, sex, prior immune stimulation with zymosan, immunization of animals with Comirnaty i.v., or i.m. 2 weeks before the vaccine challenge, and anti-PEG IgM levels in Comirnaty-immunized pigs. Nevertheless, IgM binding to the whole vaccine, used as antigen in an ELISA, was significantly higher in reactive animals compared to non-reactive ones. Incubation of Comirnaty with pig serum in vitro showed significant elevations of C3a anaphylatoxin and sC5b-9, the C-terminal complex. These data raise the possibility that C activation plays a causal or contributing role in the rare HSRs to Comirnaty and other vaccines with similar side effects. Further studies are needed to uncover the factors controlling these vaccine reactions in pigs and to understand their translational value to humans.