TY - JOUR AU - Bakos, Tamás AU - Mészáros, Tamás AU - Kozma, Gergely Tibor AU - Berényi, Petra AU - Facskó, Réka AU - Farkas, Henriette AU - Dézsi, László AU - Heirman, Carlo AU - de Koker, Stefaan AU - Schiffelers, Raymond AU - Glatter, Kathryn Anne AU - Radovits, Tamás AU - Szénási, Gábor AU - Szebeni, János TI - mRNA-LNP COVID-19 Vaccine Lipids Induce Complement Activation and Production of Proinflammatory Cytokines: Mechanisms, Effects of Complement Inhibitors, and Relevance to Adverse Reactions JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 25 PY - 2024 IS - 7 PG - 17 SN - 1661-6596 DO - 10.3390/ijms25073595 UR - https://m2.mtmt.hu/api/publication/34754128 ID - 34754128 AB - A small fraction of people vaccinated with mRNA–lipid nanoparticle (mRNA-LNP)-based COVID-19 vaccines display acute or subacute inflammatory symptoms whose mechanism has not been clarified to date. To better understand the molecular mechanism of these adverse events (AEs), here, we analyzed in vitro the vaccine-induced induction and interrelations of the following two major inflammatory processes: complement (C) activation and release of proinflammatory cytokines. Incubation of Pfizer-BioNTech’s Comirnaty and Moderna’s Spikevax with 75% human serum led to significant increases in C5a, sC5b-9, and Bb but not C4d, indicating C activation mainly via the alternative pathway. Control PEGylated liposomes (Doxebo) also induced C activation, but, on a weight basis, it was ~5 times less effective than that of Comirnaty. Viral or synthetic naked mRNAs had no C-activating effects. In peripheral blood mononuclear cell (PBMC) cultures supplemented with 20% autologous serum, besides C activation, Comirnaty induced the secretion of proinflammatory cytokines in the following order: IL-1α < IFN-γ < IL-1β < TNF-α < IL-6 < IL-8. Heat-inactivation of C in serum prevented a rise in IL-1α, IL-1β, and TNF-α, suggesting C-dependence of these cytokines’ induction, although the C5 blocker Soliris and C1 inhibitor Berinert, which effectively inhibited C activation in both systems, did not suppress the release of any cytokines. These findings suggest that the inflammatory AEs of mRNA-LNP vaccines are due, at least in part, to stimulation of both arms of the innate immune system, whereupon C activation may be causally involved in the induction of some, but not all, inflammatory cytokines. Thus, the pharmacological attenuation of inflammatory AEs may not be achieved via monotherapy with the tested C inhibitors; efficacy may require combination therapy with different C inhibitors and/or other anti-inflammatory agents. LA - English DB - MTMT ER - TY - CHAP AU - Szebeni, János ED - Stern, Stephan T. ED - Dobrovolskaia, Marina A. ED - Crist, Rachael M. ED - Clogston, Jeffrey D. TI - Evaluation of the Acute Anaphylactoid Reactogenicity of Nanoparticle-Containing Medicines and Vaccines Using the Porcine CARPA Model T2 - Characterization of Nanoparticles Intended for Drug Delivery PB - Springer US CY - New York, New York SN - 9781071637869 T3 - Methods in Molecular Biology, ISSN 1064-3745 ; 2789. PY - 2024 SP - 229 EP - 243 PG - 15 DO - 10.1007/978-1-0716-3786-9_23 UR - https://m2.mtmt.hu/api/publication/34754067 ID - 34754067 N1 - Export Date: 8 April 2024 LA - English DB - MTMT ER - TY - GEN AU - Bakos, Tamás AU - Mészáros, Tamás AU - Kozma, Gergely Tibor AU - Petra, Berényi AU - Facskó, Réka AU - Henriette, Farkas AU - Dézsi, László AU - Carlo, Heirman AU - Stefaan, de Koker AU - Raymond, Schiffelers AU - Kathryn, Anne Glatter AU - Radovits, Tamás AU - Szénási, Gábor AU - Szebeni, János TI - mRNA-LNP COVID-19 vaccine lipids induce low level complement activation and production of proinflammatory cytokines: Mechanisms, effects of complement inhibitors, and relevance to adverse reactions PY - 2024 SP - & UR - https://m2.mtmt.hu/api/publication/34521339 ID - 34521339 AB - Messenger RNA-containing lipid nanoparticles (mRNA-LNPs) enabled widespread COVID-19 vaccination with a small fraction of vaccine recipients displaying acute or sub-acute inflammatory symptoms. The molecular mechanism of these adverse events (AEs) remains undetermined. Here we report that the mRNA-LNP vaccine, Comirnaty, triggers low-level complement (C) activation and production of inflammatory cytokines, which may be key underlying processes of inflammatory AEs. In serum, Comirnaty and the control PEGylated liposome (Doxebo) caused different rises of C split products, C5a, sC5b-9, Bb and C4d, indicating stimulation of the classical pathway of C activation mainly by the liposomes, while a stronger stimulation of the alternative pathway was equal with the vaccine and the liposomes. Spikevax had similar C activation as Comirnaty, but viral or synthetic mRNAs had no such effect. In autologous serum-supplemented peripheral blood mononuclear cell (PBMC) cultures, Comirnaty caused increases in the levels of sC5b-9 and proinflammatory cytokines in the following order: IL-1α < IFN-γ < IL-1β < TNF-α < IL-6 < IL-8, whereas heatinactivation of serum prevented the rises of IL-1α, IL-1β, and TNF-α. Clinical C inhibitors, Soliris and Berinert, suppressed vaccine-induced C activation in serum but did not affect cytokine production when applied individually. These findings suggest that the PEGylated lipid coating of mRNA-LNP nanoparticles can trigger C activation mainly via the alternative pathway, which may be causally related to the induction of some, but not all inflammatory cytokines. While innate immune stimulation is essential for the vaccine’s efficacy, concurrent production of C- and PBMC-derived inflammatory mediators may contribute to some of the AEs. Pharmacological attenuation of harmful cytokine production using C inhibitors likely requires blocking the C cascade at multiple points. LA - English DB - MTMT ER - TY - GEN AU - Szénási, Gábor AU - Bakos, Tamás AU - Őrfi, Erik AU - Mészáros, Tamás AU - Hricisák, László AU - Rosivall, László AU - Hamar, Péter AU - Benyó, Zoltán AU - Szebeni, János AU - Dézsi, László TI - COMPARISON OF LIPOSOMAL DRUG-INDUCED BLOOD PRESSURE CHANGES IN MICE AND RATS PY - 2023 SP - 73 EP - 73 PG - 1 UR - https://m2.mtmt.hu/api/publication/34747635 ID - 34747635 AB - Introduction: Liposomal drugs administered intravenously (i.v.) can induce IgEindependent side effects known as infusion reaction, and also termed as complement activation-related pseudoallergy (CARPA). Aim: We aimed to reveal the basic mechanisms of blood pressure changes after i.v. injection of amphotericin B-containing liposomes (Abelcet, rats: 10 mg/kg; mice: 30 mg/kg). Methods: Male NMRI mice, and wild type or thromboxane prostanoid receptor deficient (TP KO) mice on C57Bl/6 background, as well as male Wistar rats (anesthetized with pentobarbital) were used (n=6-8/group). Mean arterial blood pressure was continuously monitored. Blood was collected at 0, 1, 3 10 and 30 min in rats, and from separate groups of mice at 3-5 min after treatment. Plasma C3a and thromboxane B2 (TXB2) concentrations were assayed using ELISA. Blood count was obtained using a hematology analyzer (Abacus Vet5). Results: Abelcet caused transient hypertension in mice (10-15 min) and transient hypotension in rats (20-40 min). Abelcet resulted in leucopenia and thrombocytopenia, and increased plasma complement C3a and TXB2 concentrations in both species. Complement depletion with cobra venom factor (CVF) lengthened the hypertensive effect in mice and abolished the hypotensive effect in rats. Pretreatment with DF2593A (10 mg/kg, i.v.), a C5a receptor (C5aR) antagonist, lengthened the hypertensive effect of Abelcet in mice and elicited a small decrease in the hypotensive effect in rats. Inhibition of C3a receptors with SB290157 (10 mg/kg) attenuated the hypertension in mice and enhanced the hypotension in rats, but both effects were rather small. Macrophage depletion with clodronate liposomes in mice lengthened the hypertensive effect similarly to CVF. Pre-treatment with GdCl3 to inhibit macrophages slightly attenuated the hypotensive effect of Abelcet in rats. Inhibition of mast cell activation by cromolyn or C48/80, decreased the hypotensive response in rats, but induced delayed hypotension in mice, respectively. Inhibition of platelet activation using eptifibatide, a platelet glycoprotein IIb/IIIa (GPIIb/IIIa) receptor inhibitor, lengthened the hypertensive effect in mice, but hardly affected the responses in rats. Abelcet did not change blood pressure in TP KO mice and led to a delayed hypertension after pretreatment with CVF. Conclusion: Our results suggest that complement activation has a small contribution to liposomal drug-induced hypotension, and both macrophages and mast cells contribute to the release of vasoactive mediators in rats. The early hypertensive effect of TXA2 release in mice wasindependent from complement activation, and wasreversed with some delay mainly by the activation of C5aR. Both macrophages and platelets are substantially implicated in the latter effect. LA - English DB - MTMT ER - TY - JOUR AU - Bakos, Tamás AU - Kozma, Gergely Tibor AU - Szebeni, János AU - Szénási, Gábor TI - Eculizumab suppresses zymosan-induced release of inflammatory cytokines IL-1α, IL-1β, IFN-γ and IL-2 in autologous serum-substituted PBMC cultures: Relevance to cytokine storm in Covid-19 JF - BIOMEDICINE & PHARMACOTHERAPY J2 - BIOMED PHARMACOTHER VL - 166 PY - 2023 PG - 8 SN - 0753-3322 DO - 10.1016/j.biopha.2023.115294 UR - https://m2.mtmt.hu/api/publication/34095902 ID - 34095902 N1 - Export Date: 24 April 2024 CODEN: BIPHE Correspondence Address: Szénási, G.; Institute of Translational Medicine, Nagyvárad tér 4, Hungary; email: szenasi.gabor@med.semmelweis-univ.hu LA - English DB - MTMT ER - TY - JOUR AU - Szebeni, János AU - Kiss, Bálint AU - Bozó, Tamás AU - Turjeman, Keren AU - Levi-Kalisman, Yael AU - Barenholz, Yechezkel AU - Kellermayer, Miklós TI - Insights into the Structure of Comirnaty Covid-19 Vaccine: A Theory on Soft, Partially Bilayer-Covered Nanoparticles with Hydrogen Bond-Stabilized mRNA–Lipid Complexes JF - ACS NANO J2 - ACS NANO VL - 17 PY - 2023 IS - 14 SP - 13147 EP - 13157 PG - 11 SN - 1936-0851 DO - 10.1021/acsnano.2c11904 UR - https://m2.mtmt.hu/api/publication/34058342 ID - 34058342 N1 - Nanomedicine Research and Education Center, Department of Translational Medicine, Semmelweis University, Budapest, 1089, Hungary Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health Sciences, Miskolc University, Miskolc, 2880, Hungary School of Chemical Engineering and Translational Nanobioscience Research Center, Sungkyunkwan University, Suwon, 16419, South Korea Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, 1094, Hungary Hungarian Centre of Excellence for Molecular Medicine (HCEMM), In Vivo Imaging Advanced Core Facility, Budapest, 1094, Hungary ELKH-SE Biophysical Virology Research Group, Budapest, 1094, Hungary The Laboratory of Membrane and Liposome Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, 9112102, Israel Institute of Life Sciences and the Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, 9190401, Israel Export Date: 19 October 2023 Correspondence Address: Szebeni, J.; Nanomedicine Research and Education Center, Hungary; email: jszebeni2@gmail.com LA - English DB - MTMT ER - TY - JOUR AU - Kozma, Gergely Tibor AU - Mészáros, Tamás AU - Berényi, Petra AU - Facskó, Réka AU - Patkó, Zsófia Panna AU - Oláh, Csaba Zsolt AU - Nagy, Adrienne AU - Fülöp, Tamás Gyula AU - Glatter, Kathryn Anne AU - Radovits, Tamás AU - Merkely, Béla Péter AU - Szebeni, János TI - Role of anti-polyethylene glycol (PEG) antibodies in the allergic reactions to PEG-containing Covid-19 vaccines: Evidence for immunogenicity of PEG JF - VACCINE J2 - VACCINE VL - 41 PY - 2023 IS - 31 SP - 4561 EP - 4570 PG - 10 SN - 0264-410X DO - 10.1016/j.vaccine.2023.06.009 UR - https://m2.mtmt.hu/api/publication/34039197 ID - 34039197 N1 - Funding Agency and Grant Number: Materials and Nanotechnology, Center of Excellence, Miskolc University, Miskolc, Hungary Funding text: The financial support by the European Union Horizon 2020 projects 825828 (Expert) and 952520 (Biosafety) are acknowledged. This project was supported by a grant from the National Research, Development, and Innovation Office (NKFIH) of Hungary (2020-1.1.6-JOEV}O-2021-00013). JS thanks the logistic support by the Applied & nbsp;Materials and Nanotechnology, Center of Excellence, Miskolc University, Miskolc, Hungary.r Materials and Nanotechnology, Center of Excellence, Miskolc University, Miskolc, Hungary. LA - English DB - MTMT ER - TY - GEN AU - Barta, András Bálint AU - Radovits, Tamás AU - Dobos, Attila Balázs AU - Kozma, Gergely Tibor AU - Mészáros, Tamás AU - Berényi, Petra AU - Facskó, Réka AU - Fülöp, Tamas Gyula AU - Merkely, Béla AU - Szebeni, János TI - The COVID-19 mRNA vaccine Comirnaty induces anaphylactic shock in an anti-PEG hyperimmune large animal model: Role of complement activation in cardiovascular, hematological and inflammatory mediator changes PY - 2023 SP - 541479 UR - https://m2.mtmt.hu/api/publication/33993634 ID - 33993634 LA - English DB - MTMT ER - TY - JOUR AU - Unterweger, Harald AU - Janko, Christina AU - Folk, Tamara AU - Cicha, Iwona AU - Stelczerné Kovács, Noémi AU - Gyebnár, Gyula AU - Horváth, Ildikó AU - Máthé, Domokos AU - Zheng, Kang H. AU - Coolen, Bram F. AU - Stroes, Erik AU - Szebeni, János AU - Alexiou, Christoph AU - Dézsi, László AU - Lyer, Stefan TI - Comparative in vitro and in vivo Evaluation of Different Iron Oxide-Based Contrast Agents to Promote Clinical Translation in Compliance with Patient Safety JF - INTERNATIONAL JOURNAL OF NANOMEDICINE J2 - INT J NANOMED VL - 18 PY - 2023 SP - 2071 EP - 2086 PG - 16 SN - 1176-9114 DO - 10.2147/IJN.S402320 UR - https://m2.mtmt.hu/api/publication/33856424 ID - 33856424 N1 - ENT-Department, Section of Experimental Oncology und Nanomedicine (SEON), Universitätsklinikum Erlangen, Erlangen, Germany Hungarian Centre of Excellence for Molecular Medicine, Semmelweis University, Budapest, Hungary Medical Imaging Centre, Semmelweis University, Budapest, Hungary Department Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, Netherlands Department of Biomedical Engineering and Physics, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, Netherlands Nanomedicine Research and Education Center, Institute of Translational Medicine, Semmelweis University, Budapest, Hungary SeroScience Ltd, Budapest, Hungary Export Date: 1 June 2023 Correspondence Address: Unterweger, H.; Universitätsklinikum Erlangen, Glueckstr. 10a, Germany; email: harald.unterweger@uk-erlangen.de AB - Introduction: One of the major challenges in the clinical translation of nanoparticles is the development of formulations combining favorable efficacy and optimal safety. In the past, iron oxide nanoparticles have been introduced as an alternative for gadolinium-containing contrast agents; however, candidates available at the time were not free from adverse effects.Methods: Following the development of a potent iron oxide-based contrast agent SPIONDex, we now performed a systematic comparison of this formulation with the conventional contrast agent ferucarbotran and with ferumoxytol, taking into consideration their physicochemical characteristics, bio-and hemocompatibility in vitro and in vivo, as well as their liver imaging properties in rats.Results: The results demonstrated superior in vitro cyto-, hemo-and immunocompatibility of SPIONDex in comparison to the other two formulations. Intravenous administration of ferucarbotran or ferumoxytol induced strong complement activation-related pseu-doallergy in pigs. In contrast, SPIONDex did not elicit any hypersensitivity reactions in the experimental animals. In a rat model, comparable liver imaging properties, but a faster clearance was demonstrated for SPIONDex.Conclusion: The results indicate that SPIONDex possess an exceptional safety compared to the other two formulations, making them a promising candidate for further clinical translation. LA - English DB - MTMT ER - TY - JOUR AU - Koller, Ákos AU - Szebeni, János TI - Covid-19 vaccines elicit effective IgG responses in an elderly thymus cancer patient with chemotherapy JF - HUMAN VACCINES & IMMUNOTHERAPEUTICS J2 - HUM VACC IMMUNOTHER VL - 19 PY - 2023 IS - 1 PG - 6 SN - 2164-5515 DO - 10.1080/21645515.2023.2188035 UR - https://m2.mtmt.hu/api/publication/33760499 ID - 33760499 N1 - Institute of Translational Medicine, Eötvös Loránd Research Network-SU Cerebrovascular and Neurocognitive Disorders Research Group and Department of Morphology & Physiology, Semmelweis University, Research Center for Sport Physiology, Hungarian University of Sports Science, Budapest, Hungary Department of Physiology, New York Medical College, Valhalla, NY, United States Nanomedicine Research and Education Center, Institute of Translational Medicine Semmelweis University, Budapest, Hungary Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary Translational Nanobioscience Research Center, Sungkyunkwan University, South, Suwon, South Korea Cited By :1 Export Date: 6 September 2023 Correspondence Address: Koller, A.; Institute of Translational Medicine, Üllői út. 26, Hungary; email: akos.koller@gmail.com Chemicals/CAS: etoposide, 33419-42-0, 433304-61-1; gamma interferon, 82115-62-6; immunoglobulin G, 97794-27-9, 308067-58-5; immunoglobulin M, 9007-85-6; tozinameran, 2417899-77-3; macrogol, 25322-68-3; Antibodies, Viral; BNT162 Vaccine; COVID-19 Vaccines; Etoposide; Immunoglobulin G; Polyethylene Glycols Tradenames: Quantiferon, Qiagen, Germany Manufacturers: Abbott, Germany; Qiagen, Germany LA - English DB - MTMT ER -