Guillain-Barré syndrome associated with SARS-CoV-2 vaccination: how is it different? a systematic review and individual participant data meta-analysis

Reddy, Yerasu Muralidhar; Murthy, Jagarlapudi MK; Osman, Syed; Jaiswal, Shyam Kumar; Gattu, Abhinay Kumar; Pidaparthi, Lalitha; Boorgu, Santosh Kumar; Chavan, Roshan; Ramakrishnan, Bharadwaj; Yeduguri, Sreekanth Reddy

doi:10.7774/cevr.2023.12.2.143

Cited by 4 publications

(1 citation statement)

References 76 publications

(79 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Table 1 lists the AEs reported or claimed for COVID-19 mRNA vaccines, categorized by the organ systems affected. Importantly, myocarditis/pericarditis [5][6][7][8][9][10][11][12], HSRs/anaphylaxis [13][14][15][16], autoimmune diseases [17], thrombosis, thrombocytopenia and other coagulation disorders [18][19][20][21], skin [22][23][24][25] and ocular inflammations [26][27][28], Guillain-Barré syndrome [29][30][31][32][33][34][35], and other neurologic problems [36,37] can all be linked to acute or chronic inflammatory processes that are also characteristic of SARS-CoV-2 infections.…”

Section: Introductionmentioning

confidence: 99%

mRNA-LNP COVID-19 Vaccine Lipids Induce Complement Activation and Production of Proinflammatory Cytokines: Mechanisms, Effects of Complement Inhibitors, and Relevance to Adverse Reactions

Bakos,

Mészáros,

Kozma

et al. 2024

IJMS

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

mRNA-LNP COVID-19 Vaccine Lipids Induce Complement Activation and Production of Proinflammatory Cytokines: Mechanisms, Effects of Complement Inhibitors, and Relevance to Adverse Reactions

Bakos,

Mészáros,

Kozma

et al. 2024

IJMS

View full text Add to dashboard Cite

show abstract

Pooled rates and demographics of POTS following SARS-CoV-2 infection versus COVID-19 vaccination: Systematic review and meta-analysis

Yong,

Halim,

Liu

et al. 2023

Autonomic Neuroscience

View full text Add to dashboard Cite

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

Bakos,

Mészáros,

Kozma

et al. 2024

Preprint

View full text Add to dashboard Cite

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.

show abstract

Guillain-Barré syndrome associated with SARS-CoV-2 vaccination: how is it different? a systematic review and individual participant data meta-analysis

Cited by 4 publications

References 76 publications

mRNA-LNP COVID-19 Vaccine Lipids Induce Complement Activation and Production of Proinflammatory Cytokines: Mechanisms, Effects of Complement Inhibitors, and Relevance to Adverse Reactions

mRNA-LNP COVID-19 Vaccine Lipids Induce Complement Activation and Production of Proinflammatory Cytokines: Mechanisms, Effects of Complement Inhibitors, and Relevance to Adverse Reactions

Pooled rates and demographics of POTS following SARS-CoV-2 infection versus COVID-19 vaccination: Systematic review and meta-analysis

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

Contact Info

Product

Resources

About