e-Article
mRNA-LNP COVID-19 Vaccine Lipids Induce Complement Activation and Production of Proinflammatory Cytokines: Mechanisms, Effects of Complement Inhibitors, and Relevance to Adverse Reactions.
Document Type
Academic Journal
Author
Bakos T; Nanomedicine Research and Education Center, Department of Translational Medicine, Semmelweis University, 1085 Budapest, Hungary.; Mészáros T; Nanomedicine Research and Education Center, Department of Translational Medicine, Semmelweis University, 1085 Budapest, Hungary.; SeroScience LCC., 1089 Budapest, Hungary.; Department of Cardiology, Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary.; Department of Surgical Research and Techniques, Heart and Vascular Center, Semmelweis University, 1089 Budapest, Hungary.; Kozma GT; Nanomedicine Research and Education Center, Department of Translational Medicine, Semmelweis University, 1085 Budapest, Hungary.; SeroScience LCC., 1089 Budapest, Hungary.; Berényi P; Nanomedicine Research and Education Center, Department of Translational Medicine, Semmelweis University, 1085 Budapest, Hungary.; SeroScience LCC., 1089 Budapest, Hungary.; Facskó R; Nanomedicine Research and Education Center, Department of Translational Medicine, Semmelweis University, 1085 Budapest, Hungary.; SeroScience LCC., 1089 Budapest, Hungary.; Department of Cardiology, Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary.; Department of Surgical Research and Techniques, Heart and Vascular Center, Semmelweis University, 1089 Budapest, Hungary.; Farkas H; Hungarian Center of Reference and Excellence, Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary.; Dézsi L; Nanomedicine Research and Education Center, Department of Translational Medicine, Semmelweis University, 1085 Budapest, Hungary.; Heirman C; Etherna Biopharmaceuticals, 2845 Niel, Belgium.; de Koker S; Etherna Biopharmaceuticals, 2845 Niel, Belgium.; Schiffelers R; Division of Laboratories and Pharmacy, University Medical Center, 3584 CX Utrecht, The Netherlands.; Glatter KA; Department of Education, Gratz College, Philadelphia, PA 19027, USA.; Radovits T; Department of Cardiology, Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary.; Department of Surgical Research and Techniques, Heart and Vascular Center, Semmelweis University, 1089 Budapest, Hungary.; Szénási G; Nanomedicine Research and Education Center, Department of Translational Medicine, Semmelweis University, 1085 Budapest, Hungary.; Szebeni J; Nanomedicine Research and Education Center, Department of Translational Medicine, Semmelweis University, 1085 Budapest, Hungary.; SeroScience LCC., 1089 Budapest, Hungary.; Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health Sciences, Miskolc University, 3530 Miskolc, Hungary.; Translational Nanobioscience Research Center, Sungkyunkwan University, Suwon 06351, Republic of Korea.
Source
Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
Subject
Language
English
Abstract
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.