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 - 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 - Kökény, Gábor AU - Bakos, Tamás AU - Barta, Bálint András AU - Nagy, Georgina Viktória AU - Mészáros, Tamás AU - Kozma, Gergely Tibor AU - Szabó, András AU - Szebeni, János AU - Merkely, Béla Péter AU - Radovits, Tamás TI - Zymosan Particle-Induced Hemodynamic, Cytokine and Blood Cell Changes in Pigs: An Innate Immune Stimulation Model with Relevance to Cytokine Storm Syndrome and Severe COVID-19 JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 2 PG - 18 SN - 1661-6596 DO - 10.3390/ijms24021138 UR - https://m2.mtmt.hu/api/publication/33548672 ID - 33548672 N1 - MTA Bolyai János Kutatási Ösztöndíj AB - Hemodynamic disturbance, a rise in neutrophil-to-lymphocyte ratio (NLR) and release of inflammatory cytokines into blood, is a bad prognostic indicator in severe COVID-19 and other diseases involving cytokine storm syndrome (CSS). The purpose of this study was to explore if zymosan, a known stimulator of the innate immune system, could reproduce these changes in pigs. Pigs were instrumented for hemodynamic analysis and, after i.v. administration of zymosan, serial blood samples were taken to measure blood cell changes, cytokine gene transcription in PBMC and blood levels of inflammatory cytokines, using qPCR and ELISA. Zymosan bolus (0.1 mg/kg) elicited transient hemodynamic disturbance within minutes without detectable cytokine or blood cell changes. In contrast, infusion of 1 mg/kg zymosan triggered maximal pulmonary hypertension with tachycardia, lasting for 30 min. This was followed by a transient granulopenia and then, up to 6 h, major granulocytosis, resulting in a 3–4-fold increase in NLR. These changes were paralleled by massive transcription and/or rise in IL-6, TNF-alpha, CCL-2, CXCL-10, and IL-1RA in blood. There was significant correlation between lymphopenia and IL-6 gene expression. We conclude that the presented model may enable mechanistic studies on late-stage COVID-19 and CSS, as well as streamlined drug testing against these conditions. LA - English DB - MTMT ER - TY - GEN 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 - Gyula Fülöp, Tamás AU - Anne Glatter, Kathryn AU - Radovits, Tamás AU - Merkely, Béla Péter AU - Szebeni, János TI - Role of anti-polyethylene glycol (PEG) antibodies in the allergic reactions and immunogenicity of PEG-containing Covid-19 vaccines PY - 2022 UR - https://m2.mtmt.hu/api/publication/33209367 ID - 33209367 AB - The polyethylene-glycol (PEG)-containing Covid-19 vaccines can cause hypersensitivity reactions (HSRs), or rarely, life-threatening anaphylaxis. A causal role of anti-PEG antibodies (Abs) has been proposed, but not yet proven in humans. The 191 blood donors in this study included 10 women and 5 men who displayed HSRs to Comirnaty or Spikevax Covid-19 vaccines with 3 anaphylaxis. 118 donors had pre-vaccination anti-PEG IgG/IgM values as measured by ELISA, of which >98% were over background regardless of age, indicating the presence of these Abs in almost everyone. Their values varied over 2-3 orders of magnitude and displayed strong left-skewed distribution with 3-4% of subjects having >15-30-fold higher values than the respective median. First, or booster injections with both vaccines led to significant rises of anti-PEG IgG/IgM with >10-fold rises in about ∼10% of Comirnaty, and all Spikevax recipients, measured at different times after the injections. The anti-PEG Ab levels measured within 4-months after the HSRs were significantly higher than those in nonreactors. Serial testing of plasma (n=361 tests) showed the SARS-CoV-2 neutralization IgG to vary over a broad range, with a trend for biphasic dose dependence on anti-PEG Abs. The highest prevalence of anti-PEG Ab positivity in human blood reported to date represents new information which can most easily be rationalized by daily exposure to common PEG-containing medications and/or household items. The significantly higher, HSR-non-coincidental blood level of anti-PEG Abs in hypersensitivity reactor vs. non-reactors, taken together with relevant clinical and experimental data in the literature, suggest that anti-PEG Ab supercarrier people might be at increased risk for HSRs to PEG-containing vaccines, which themselves can induce these Abs via bystander immunogenicity. Our data also raise the possibility that anti-PEG Abs might also contribute to the reduction of these vaccines’ virus neutralization efficacy. Thus, screening for anti-PEG Ab supercarriers may identify people at risk for HSRs or reduced vaccine effectiveness. LA - English DB - MTMT ER - TY - JOUR AU - Dézsi, László AU - Mészáros, Tamás AU - Kozma, Gergely Tibor AU - H-Velkei, Mária AU - Oláh, Csaba Zsolt AU - Szabó, Miklós AU - Patkó, Zsófia Panna AU - Fülöp, Tamás AU - Hennies, Mark AU - Szebeni, Miklós AU - Barta, Bálint András AU - Merkely, Béla Péter AU - Radovits, Tamás AU - Szebeni, János TI - 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 JF - GEROSCIENCE: OFFICIAL JOURNAL OF THE AMERICAN AGING ASSOCIATION (AGE) J2 - GEROSCIENCE VL - 44 PY - 2022 IS - 2 SP - 597 EP - 618 PG - 22 SN - 2509-2715 DO - 10.1007/s11357-021-00495-y UR - https://m2.mtmt.hu/api/publication/32666145 ID - 32666145 N1 - Tamás Radovits and János Szebeni contributed equally to the article. AB - 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. LA - English DB - MTMT ER - TY - CHAP AU - Szebeni, János AU - Barenholz, Y.C. TI - Complement Activation, Immunogenicity, and Immune Suppression as Potential Side Effects of Liposomes T2 - Advances in Clinical Immunology, Medical Microbiology, COVID-19, and Big Data PB - Jenny Stanford Publishing SN - 9789814877848 T3 - Advances in Clinical Immunology, Medical Microbiology, COVID-19, and Big Data PY - 2021 SP - 55 EP - 75 PG - 21 UR - https://m2.mtmt.hu/api/publication/33881414 ID - 33881414 LA - English DB - MTMT ER - TY - JOUR AU - Németh, Csaba AU - Tóth, Adrienn AU - Lelbach, Ádám Antal AU - Póti, Péter AU - Hidas, Karina Ilona AU - Friedrich, László Ferenc TI - A nagy hidrosztatikus nyomású technológia tojásfehérjére gyakorolt hatásai optimális fehérje termékek előállítása az időskorúak számára JF - IDŐSGYÓGYÁSZAT J2 - IDŐSGYÓGYÁSZAT VL - 6 PY - 2021 IS - 1-2 SP - 37 EP - 47 PG - 11 SN - 2498-8057 UR - https://m2.mtmt.hu/api/publication/33130509 ID - 33130509 LA - Hungarian DB - MTMT ER -