BREAKING! mRNA-LNP COVID-19 Vaccine Lipids Induce Complement Activation And Adverse Proinflammatory Issues Similar To Actual Infections!

COVID-19 News: The advent of mRNA–lipid nanoparticle (mRNA-LNP)-based COVID-19 vaccines marked a pivotal moment in the fight against the SARS-CoV-2 virus. While there have been unsubstantiated claims that Pfizer-BioNTech's Comirnaty and Moderna's Spikevax vaccines have demonstrated significant efficacy in preventing severe illness and mortality associated with COVID-19, the number of adverse effects and people actually suffering the after effects of these vaccines are growing day by day!


mRNA-LNP COVID-19 Vaccine Lipids Induce Complement Activation And Adverse Proinflammatory Issues Similar To Actual Infections. Complement activation by Comirnaty, Spikevax, and SARS-CoV-2 mRNA (A) and synthetic, virus-irrelevant mRNAs (B) in human serum. The experiments were similar to those in Figure 2A, except that the blood donors were different. In A, the final mRNA concentrations in the Comirnaty, Spikevax, and SARS-CoV-2 samples were 20 μg/mL. The lipids in Comirnaty are (((4-hydroxybutyl) azanediyl) bis (hexane-6,1-diyl)bis(2-hexyldecanoate))(ALC-0315), (2-((polyethylene glycol)-2000)-N,N-ditetradecylacetamide) (ALC-0159), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and cholesterol (total lipids: 2.57 mg mL−1). The relative amounts of these Comirnaty ingredients are specified in Table S1. The lipids in Spikevax are heptadecan-9-yl 8-((2-hydroxyethyl) (6-oxo-6-(undecyloxy)hexyl)amino) octanoate (SM-102), polyethylene glycol-2000-dimyristoyl glycerol (PEG-DMG), DSPC, and cholesterol (total lipids: 3.86 mg mL−1). In B, the mRNAs tested were codings for the proteins CD40L, Luciferase, and Cre-recombinase, transcribed from the moCD40L, rstsFluc, and Cre-recombinase genes. Their sequences are shown in Tables S3–S5, and the nucleotide numbers are on top of the bars. The abscissa shows the concentrations of these mRNAs added to serum: ZYM, zymosan. Mean ± SEM, n = 5 different sera. *, **, significant differences compared with PBS at p < 0.05 and p < 0.01
 
Though, like all medical interventions, these vaccines are not without their share of adverse events (AEs), a growing fraction of vaccinated individuals have reported acute or subacute inflammatory symptoms, raising questions about the underlying mechanisms triggering these reactions.
 
In this comprehensive study covered in this COVID-19 News report, conducted by a collaborative team from various prestigious institutions including Semmelweis University in Budapest, Hungary, SeroScience in Budapest, Hungary, Etherna Biopharmaceuticals in Belgium, University Medical Center in Utrecht, The Netherlands, Gratz College in Philadelphia, USA, Miskolc University in Hungary, and Sungkyunkwan University in the Republic of Korea, the researchers delve into the intricate immunological responses induced by mRNA-LNP vaccines. The study aims to elucidate the molecular mechanisms behind complement activation and proinflammatory cytokine release triggered by these vaccines, shedding light on potentia l pathways leading to adverse reactions.
 
Background and Significance
The mRNA-LNP vaccines have been hailed as a breakthrough in vaccine technology due to their ability to induce robust immune responses against the SARS-CoV-2 virus. However, concerns have emerged regarding rare adverse events observed post-vaccination, some of which mimic symptoms seen in actual COVID-19 infections. These "special interest" severe adverse events (SAEs) have prompted intense scrutiny and investigation into the immunological effects of mRNA-LNP vaccines.
 
Previous studies have highlighted the role of complement activation and proinflammatory cytokine release in the pathogenesis of severe COVID-19. Complement activation, a fundamental defense mechanism, and the subsequent release of inflammatory cytokines are intricately linked processes that contribute to the hyperinflammatory state observed in severe cases of COVID-19. Understanding how mRNA-LNP vaccines modulate these immune responses is crucial for optimizing vaccine safety and efficacy.
 
Study Objectives
The primary objectives of this study were:
 
-To analyze the mechanisms of complement activation induced by Comirnaty and Spikevax mRNA-LNP vaccines.
 
-To investigate the relationship between complement activation and proinflammatory cytokine production in response to mRNA-LNP vaccines.
 
-To assess the efficacy of clinical complement inhibitors in mitigating vaccine-induced immune responses.
 
Methods and Experimental Design
The study employed a combination of in vitro assays using human serum-supplemented peripheral blood mononuclear cell (PBMC) cultures and complement activation assays. The vaccines tested included Pfizer-BioNTech's Comirnaty and Moderna's Spikevax, along with controls such as PEGylated liposomes (Doxebo) and zymosan as a gold standard for complement activation.

Complement activation was assessed by measuring biomarkers such as sC5b-9, C5a, C4d, and Bb in serum samples following vaccine incubation. Proinflammatory cytokine production in PBMC cultures was quantified using ELISA assays, focusing on cytokines including IL-1α, IL-1β, IL-6, IL-8, IFN-γ, and TNF-α.
 
Results and Findings
-Complement Activation: Both Comirnaty and Spikevax induced significant complement activation, primarily through the alternative pathway. The level of activation was higher for Comirnaty compared to Spikevax, indicating vaccine-specific differences in complement modulation.
 
-Cytokine Production: Exposure to Comirnaty resulted in the secretion of proinflammatory cytokines, with IL-6, IL-8, and TNF-α showing the highest levels of induction. Heat inactivation of complement in serum reduced the production of certain cytokines, suggesting a link between complement activation and cytokine release.
 
-Efficacy of C Inhibitors: Clinical complement inhibitors such as Soliris and Berinert demonstrated partial inhibition of complement activation induced by mRNA-LNP vaccines. However, they did not suppress cytokine production, indicating complex interactions between complement and cytokine pathways.
 
Discussion and Implications
The findings from this study provide valuable insights into the immunological effects of mRNA-LNP COVID-19 vaccines. The observed complement activation and cytokine release shed light on potential mechanisms underlying vaccine-induced adverse events. The study also underscores the challenges in mitigating these immune responses solely through complement inhibition, highlighting the need for multifaceted approaches to vaccine safety.
 
From a public health perspective, understanding the immunological profiles of mRNA-LNP vaccines can inform strategies to improve their safety profiles and mitigate rare adverse events. The study's findings contribute to ongoing discussions on vaccine safety and pave the way for further research into optimizing vaccine design and administration protocols.
 
Conclusion
In conclusion, this study represents a comprehensive analysis of the immunological effects of mRNA-LNP COVID-19 vaccines, focusing on complement activation, proinflammatory cytokine production, and the efficacy of complement inhibitors.

The results highlight the complex interplay between innate immune responses and vaccine-induced adverse events, emphasizing the need for tailored approaches to enhance vaccine safety and efficacy. Future research directions may explore novel strategies to modulate immune responses and minimize rare adverse events associated with mRNA-LNP vaccines, ultimately advancing global efforts to combat infectious diseases effectively.
 
The study findings were published in the peer reviewed International Journal of Molecular Sciences.
https://www.mdpi.com/1422-0067/25/7/3595
 
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