COVID-19 mRNA Vaccines: The Molecular Basis of Some Adverse Events

Vaccines, Год журнала: 2023, Номер 11(4), С. 747 - 747

Опубликована: Март 28, 2023

Each injection of any known vaccine results in a strong expression pro-inflammatory cytokines. This is the result innate immune system activation, without which no adaptive response to vaccines possible. Unfortunately, degree inflammation produced by COVID-19 mRNA variable, probably depending on genetic background and previous experiences, through epigenetic modifications could have made each individual tolerant or reactive subsequent stimulations.We hypothesize that we can move from limited condition conditions increasing cytokines culminate multisystem hyperinflammatory syndromes following (MIS-V). We graphically represented this idea hypothetical inflammatory pyramid (IP) correlated time factor after vaccines. Furthermore, placed clinical manifestations within IP, correlating them produced. Surprisingly, excluding possible presence an early MIS-V, complexity are inflammation: symptoms, heart disease

Язык: Английский

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A localizing nanocarrier formulation enables multi-target immune responses to multivalent replicating RNA with limited systemic inflammation

Molecular Therapy, Год журнала: 2023, Номер 31(8), С. 2360 - 2375

Опубликована: Июль 3, 2023

RNA vaccines possess significant clinical promise in counteracting human diseases caused by infectious or cancerous threats. Self-amplifying replicon (repRNA) has been thought to offer the potential for enhanced potency and dose sparing. However, repRNA is a potent trigger of innate immune responses vivo, which can cause reduced transgene expression dose-limiting reactogenicity, as highlighted recent trials. Here, we report that multivalent vaccination, necessitating higher doses total RNA, could be safely achieved mice delivering multiple repRNAs with localizing cationic nanocarrier formulation (LION). Intramuscular delivery LION resulted localized biodistribution accompanied significantly upregulated local induction antigen-specific adaptive absence systemic inflammatory responses. In contrast, delivered lipid nanoparticles (LNPs) showed generalized biodistribution, state, an increased body weight loss, failed induce neutralizing antibody composition. These findings suggest vivo platform technology safe effective vaccination through mechanisms distinct from LNP-formulated vaccines.

Язык: Английский

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Myocarditis: Etiology, Pathogenesis, and Their Implications in Clinical Practice

Biology, Год журнала: 2023, Номер 12(6), С. 874 - 874

Опубликована: Июнь 17, 2023

Myocarditis is an inflammatory disease of the myocardium caused by infectious or non-infectious agents. It can lead to serious short-term and long-term sequalae, such as sudden cardiac death dilated cardiomyopathy. Due its heterogenous clinical presentation course, challenging diagnosis limited evidence for prognostic stratification, myocarditis poses a great challenge clinicians. As it stands, pathogenesis etiology only partially understood. Moreover, impact certain features on risk assessment, patient outcomes treatment options not entirely clear. Such data, however, are essential in order personalize care implement novel therapeutic strategies. In this review, we discuss possible etiologies myocarditis, outline key processes governing summarize best available regarding state-of-the-art approaches.

Язык: Английский

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mRNA: Vaccine or Gene Therapy? The Safety Regulatory Issues

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(13), С. 10514 - 10514

Опубликована: Июнь 22, 2023

COVID-19 vaccines were developed and approved rapidly in response to the urgency created by pandemic. No specific regulations existed at time they marketed. The regulatory agencies therefore adapted them as a matter of urgency. Now that pandemic emergency has passed, it is consider safety issues associated with this rapid approval. mode action mRNA should classify gene therapy products (GTPs), but have been excluded agencies. Some tests undergone produced non-compliant results terms purity, quality batch homogeneity. wide persistent biodistribution mRNAs their protein products, incompletely studied due classification vaccines, raises issues. Post-marketing studies shown passes into breast milk could adverse effects on breast-fed babies. Long-term expression, integration genome, transmission germline, passage sperm, embryo/fetal perinatal toxicity, genotoxicity tumorigenicity be light events reported pharmacovigilance databases. potential horizontal (i.e., shedding) also assessed. In-depth vaccinovigilance carried out. We would expect these controls required for future outside context

Язык: Английский

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COVID-19 mRNA Vaccines: Lessons Learned from the Registrational Trials and Global Vaccination Campaign

Cureus, Год журнала: 2024, Номер unknown

Опубликована: Янв. 24, 2024

Our understanding of COVID-19 vaccinations and their impact on health mortality has evolved substantially since the first vaccine rollouts. Published reports from original randomized phase 3 trials concluded that mRNA vaccines could greatly reduce symptoms. In interim, problems with methods, execution, reporting these pivotal have emerged. Re-analysis Pfizer trial data identified statistically significant increases in serious adverse events (SAEs) group. Numerous SAEs were following Emergency Use Authorization (EUA), including death, cancer, cardiac events, various autoimmune, hematological, reproductive, neurological disorders. Furthermore, products never underwent adequate safety toxicological testing accordance previously established scientific standards. Among other major topics addressed this narrative review are published analyses harms to humans, quality control issues process-related impurities, mechanisms underlying (AEs), immunologic basis for inefficacy, concerning trends based registrational data. The risk-benefit imbalance substantiated by evidence date contraindicates further booster injections suggests that, at a minimum, should be removed childhood immunization program until proper studies conducted. Federal agency approval blanket-coverage population-wide had no support an honest assessment all relevant commensurate consideration risks versus benefits. Given extensive, well-documented unacceptably high harm-to-reward ratio, we urge governments endorse global moratorium modified questions pertaining causality, residual DNA, aberrant protein production answered.

Язык: Английский

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Determinants of COVID-19 vaccine-induced myocarditis

Therapeutic Advances in Drug Safety, Год журнала: 2024, Номер 15

Опубликована: Янв. 1, 2024

Background: Following the roll-out of Pfizer-BioNTech BNT162b2, Moderna mRNA-1273, and Janssen Ad26.COV2.S coronavirus disease 2019 (COVID-19) injections in United States, millions individuals have reported adverse events (AEs) using vaccine reports system (VAERS). The objective this analysis is to describe myocarditis data VAERS COVID-19 vaccines as potential determinants myocarditis. Methods: We used examine frequency reporting since beginning mass vaccination campaign compared with historical values administration from Our World Data database. examined context sex, age, dose. Statistical was done Student’s t-test determine statistically significant differences between ages among chi-square test relationships categorical variables statistical significance. Results: found number after 2021 223 times higher than average all combined for past 30 years. This represented a 2500% increase absolute first year when comparing prior 2021. Demographic revealed that occurred most youths (50%) males (69%). A total 76% cases resulted emergency care hospitalization. Of reports, 92 died (3%). Myocarditis more likely dose 2 ( p < 0.00001) less years age were older acquire 0.00001). Conclusion: strongly associated serious safety signal myocarditis, particularly children young adults resulting hospitalization death. Further investigation into underlying mechanisms vaccine-induced imperative create effective mitigation strategies ensure programs across populations.

Язык: Английский

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Long‐lasting, biochemically modified mRNA, and its frameshifted recombinant spike proteins in human tissues and circulation after COVID‐19 vaccination

Pharmacology Research & Perspectives, Год журнала: 2024, Номер 12(3)

Опубликована: Июнь 1, 2024

Abstract According to the CDC, both Pfizer and Moderna COVID‐19 vaccines contain nucleoside‐modified messenger RNA (mRNA) encoding viral spike glycoprotein of severe acute respiratory syndrome caused by corona virus (SARS‐CoV‐2), administered via intramuscular injections. Despite their worldwide use, very little is known about how nucleoside modifications in mRNA sequences affect breakdown, transcription protein synthesis. It was hoped that resident circulating immune cells attracted injection site make copies while injected degrades within a few days. also originally estimated recombinant proteins generated would persist body for weeks. In reality, clinical studies now report modified SARS‐CoV‐2 routinely up month from can be detected cardiac skeletal muscle at sites inflammation fibrosis, may over half year blood. Vaccination with 1‐methylΨ (pseudouridine enriched) elicit cellular immunity peptide antigens produced +1 ribosomal frameshifting major histocompatibility complex‐diverse people. The translation using liquid chromatography tandem mass spectrometry identified nine peptides derived frame. These products impact on off‐target host T cell include increased production new B far reaching consequences. As an example, highly significant increase heart 18‐flourodeoxyglucose uptake vaccinated patients (180 days). This review article focuses medical biochemistry, proteomics deutenomics principles explain persisting phenomenon circulation organ‐related functional damage even asymptomatic individuals. Proline hydroxyproline residues emerge as prominent deuterium (heavy hydrogen) binding structural robust isotopic stability resists not only enzymatic but virtually all (non)‐enzymatic cleavage mechanisms chemistry.

Язык: Английский

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Inflammation in the COVID-19 airway is due to inhibition of CFTR signaling by the SARS-CoV-2 spike protein

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Июль 23, 2024

Abstract SARS-CoV-2-contributes to sickness and death in COVID-19 patients partly by inducing a hyper-proinflammatory immune response the host airway. This state involves activation of signaling NFκB, unexpectedly, ENaC, epithelial sodium channel. Post-infection inflammation may also contribute "Long COVID"/PASC. Enhanced NFκB ENaC marks airway suffering from cystic fibrosis, life-limiting proinflammatory genetic disease due inactivating mutations CFTR gene. We therefore hypothesized that might similarly be inhibition SARS-CoV-2 spike protein, both signaling. used western blot electrophysiological techniques, an organoid model normal epithelia, differentiated on air–liquid-interface (ALI). found protein expression cAMP-activated chloride channel activity were lost when epithelium was exposed proteins. As hypothesized, absence led TNFα/NFκB α γ ENaC. had previously shown cardiac glycoside drugs digoxin, digitoxin ouabain blocked interaction ACE2. Consistently, addition 30 nM concentrations drugs, prevented loss activity. ACE2 co-immunoprecipitate basal cells epithelia. Thus spike-dependent involve as bridge between Spike CFTR. In addition, exposure epithelia resulted failure endosomal recycling return plasma membrane. Thus, recovery mechanism for Finally, we authentic virus infection induced which rescued ouabain. Based experiments with this small comparisons 16HBE14o- other cell types expressing CFTR, predict mediated thus fibrosis-like clinical phenotype. To our knowledge is first time has been experimentally traced subjects contribution

Язык: Английский

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Vaccination-Associated Myocarditis and Myocardial Injury

Circulation Research, Год журнала: 2023, Номер 132(10), С. 1338 - 1357

Опубликована: Май 11, 2023

SARS-CoV-2 vaccine–associated myocarditis/myocardial injury should be evaluated in the contexts of COVID-19 infection, other types viral myocarditis, and vaccine-associated cardiac disorders. myocardial can caused by an inflammatory immune cell infiltrate, but etiologies such as microvascular thrombosis are also possible. The clinical diagnosis is typically based on symptoms magnetic resonance imaging. Endomyocardial biopsy confirmatory for may not show infiltrate because rapid resolution or a non-inflammatory etiology. Myocarditis associated with SARS-COVID-19 vaccines occurs primarily mRNA platform vaccines, which most effective. In persons aged >16 >12 years myocarditis estimated crude incidences after first 2 doses BNT162b2 mRNA-1273 approximately 1.9 3.5 per 100 000 individuals, respectively. These rates equate to excess above control populations 1.2 (BNT162b2) (mRNA-1273) persons, lower than rate smallpox higher that influenza vaccines. studies have included vaccine measured same methodology, incidence was increased 3.5-fold over compared 1.5-fold 6.2-fold mRNA-1273. However, mortality major morbidity less recovery faster infection. reasons this include having young adults adolescents, no involvement organs comparisons non-COVID inherently more benign course.

Язык: Английский

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Shedding Light on Mechanisms of Myocarditis With COVID-19 mRNA Vaccines

Circulation, Год журнала: 2023, Номер 147(11), С. 877 - 880

Опубликована: Фев. 16, 2023

yocarditis is recognized as a rare complication of coronavirus disease 2019 (COVID-19) vaccinations, especially in young adult men and adolescent boys. 1,2Incidence approximatel 1 to 5 cases among 100 000 the general population, 20 those16 30 years age. 2 Cases most often occur days after second vaccine dose are usually mild self-limited.

Язык: Английский

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