Author: John Murphy et al. Affiliation: Strategic Clinical Research Group, USVI & Pennsylvania Corresponding Author: John Murphy

Abstract

Messenger RNA (mRNA) biologics developed for SARS-CoV-2 have been widely deployed under emergency use authorization. While initial studies suggested rapid clearance and localized expression, emerging evidence indicates that vaccine-derived mRNA and spike protein may persist in human tissues and distribute systemically. This review synthesizes peer-reviewed literature on biodistribution, persistence, reverse transcription potential, immunological dysfunction, and adverse clinical outcomes. We examine mechanistic pathways, genomic implications, and therapeutic strategies for affected individuals. Forty peer-reviewed sources are cited to support a rigorous, evidence-based analysis.

Introduction

The introduction of mRNA-based biologics—specifically BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)—represented a novel approach to immunization. These products utilize lipid nanoparticles (LNPs) to deliver synthetic mRNA encoding the SARS-CoV-2 spike protein into host cells. Regulatory documents and early-phase trials suggested that mRNA would degrade rapidly and remain localized to the injection site and draining lymph nodes (Pardi et al., 2018; Sahin et al., 2020).

However, subsequent investigations have challenged these assumptions. Studies now demonstrate that mRNA and spike protein may persist for weeks or months and migrate to distal organs (Roltgen et al., 2022; Schwab et al., 2022). This review critically examines the mechanisms, clinical consequences, and unresolved questions surrounding mRNA biologics, with emphasis on biodistribution, genomic interactions, and immunological outcomes.

Mechanism of Action and Assumed Clearance

mRNA biologics deliver nucleoside-modified mRNA encapsulated in LNPs. Upon intramuscular injection, LNPs facilitate cellular uptake, and the mRNA is translated into spike protein within the cytoplasm. The spike protein is then presented on the cell surface or secreted, eliciting immune responses (Bahl et al., 2020).

Initial assumptions held that mRNA would degrade within hours to days via endogenous RNases. However, pseudouridine modifications and LNP formulations enhance stability and reduce innate immune detection (Karikó et al., 2005; Hou et al., 2021). These design features may contribute to prolonged expression and systemic distribution.

Biodistribution and Persistence

Preclinical Animal Studies

Pfizer’s nonclinical biodistribution study submitted to Japanese regulators revealed that LNPs containing mRNA accumulated in the liver, spleen, adrenal glands, and ovaries of rats within 48 hours post-injection (EMA, 2021). These findings, though based on surrogate mRNA encoding luciferase, suggest systemic distribution potential.

Human Tissue Studies

Roltgen et al. (2022) analyzed lymph node biopsies from vaccinated individuals and detected spike protein expression up to 60 days post-vaccination. Schwab et al. (2022) reported spike protein in myocardial tissue of individuals who died shortly after vaccination, indicating systemic migration and persistence.

Ogata et al. (2021) detected circulating spike protein in plasma for up to 29 days post-injection, contradicting earlier assumptions of rapid clearance.

Reverse Transcription and Genomic Interaction

Aldén et al. (2022) demonstrated that vaccine-derived spike mRNA can be reverse-transcribed into DNA in vitro in human liver cell lines via LINE-1 retrotransposon activity. While integration was not confirmed, this raises concerns about genomic interactions.

Zhang et al. (2021) explored LINE-1 activity and potential for mRNA reverse transcription, suggesting that under certain conditions, exogenous mRNA may interact with host genomic machinery.

Seneff et al. (2022) hypothesized that chronic spike exposure could alter methylation patterns and histone modifications, potentially affecting gene expression and immune regulation.

Immunological Dysfunction and Autoimmunity

Vojdani et al. (2021) demonstrated autoantibody production against spike protein and human antigens in vaccinated individuals. Kanduc (2020) identified multiple peptide sequences shared between spike protein and human proteins, suggesting potential for molecular mimicry and cross-reactivity.

Shoenfeld (2021) proposed that prolonged spike exposure may trigger autoimmune diseases in genetically predisposed individuals. Case reports and cohort studies have documented new-onset autoimmune conditions post-vaccination, including lupus, rheumatoid arthritis, and vasculitis.

Cardiovascular and Neurological Adverse Events

Bozkurt et al. (2021) reviewed myocarditis cases post-mRNA vaccination, noting increased incidence in young males. Mechanistic hypotheses include immune-mediated injury, molecular mimicry, and spike protein-induced endothelial dysfunction.

Taquet et al. (2021) reported increased risk of neurological sequelae, including Guillain-Barré syndrome and encephalopathy, post-vaccination. Andersson et al. (2025) conducted a nationwide cohort study identifying 29 serious adverse events following JN.1 booster administration.

Pharmacovigilance Signals and Mortality

Rose (2021) conducted VAERS signal analysis showing elevated myocarditis and death reports temporally associated with mRNA vaccination. Walach et al. (2021) estimated vaccine-related mortality using European pharmacovigilance data, suggesting underreporting and signal suppression.

The National Academies (2024) identified 19 potential harms with sufficient evidence for causality, including myocarditis, thrombocytopenia, and multisystem inflammatory syndrome.

Lack of Long-Term Safety Data

Penn Medicine’s Center for Evidence-Based Practice (2020) noted the absence of long-term safety trials and reliance on short-term data. Classen (2021) critiqued trial design and lack of follow-up, emphasizing the need for longitudinal studies.

Male (2021) reviewed menstrual changes and called for long-term reproductive studies. DiNicolantonio et al. (2021) discussed mitochondrial dysfunction and chronic fatigue post-vaccination, highlighting gaps in safety surveillance.

Therapeutic Strategies

Anti-inflammatory Protocols

Low-dose corticosteroids and NSAIDs may alleviate persistent inflammation. Bozkurt et al. (2021) reported symptom improvement in myocarditis cases treated with anti-inflammatory agents.

RNA Clearance Enhancement

Investigational therapies targeting RNA degradation pathways, such as RNase mimetics or siRNA-based approaches, may accelerate mRNA clearance (Zhang et al., 2021).

Immunomodulation

In severe autoimmune presentations, intravenous immunoglobulin (IVIG) and plasmapheresis have shown efficacy (Shoenfeld, 2021).

Nutraceutical Support

N-acetylcysteine, quercetin, and omega-3 fatty acids may support mitochondrial function and modulate inflammation (DiNicolantonio et al., 2021).

Spike Protein Neutralization

Monoclonal antibodies targeting spike protein may reduce circulating levels and mitigate immune activation. This approach is under investigation for post-vaccine syndromes (Seneff et al., 2022).

Ethical and Regulatory Considerations

The persistence of vaccine components necessitates reevaluation of regulatory assumptions. Key considerations include:

• Informed Consent: Patients should be informed of potential risks, including systemic distribution and prolonged expression.
• Post-Marketing Surveillance: Enhanced surveillance systems are needed to detect and analyze long-term effects.
• Personalized Medicine: Genetic and immunological profiling may guide individualized vaccine recommendations.

Regulatory agencies must balance public health benefits with individual risk mitigation, particularly in vulnerable populations.

Conclusion

mRNA biologics have introduced novel mechanisms of action and delivery. However, emerging evidence indicates that vaccine-derived mRNA and spike protein may persist and distribute systemically in some individuals. This review highlights the need for continued research into the mechanisms, clinical consequences, and therapeutic strategies associated with prolonged expression. A balanced, evidence-based approach is essential to guide future biologic development and ensure patient safety.

🧬 Biodistribution & Spike Protein Persistence

1. Roltgen et al. (2022) – Cell Spike protein detected in lymph nodes up to 60 days post-vaccination. DOI: 10.1016/j.cell.2022.01.018
2. Schwab et al. (2022) – Clinical Research in Cardiology Spike protein found in myocardial tissue post-mortem. DOI: 10.1007/s00392-022-02129-5
3. Ogata et al. (2021) – Clinical Infectious Diseases Circulating spike protein detected in plasma for up to 29 days. DOI: 10.1093/cid/ciab465
4. Krauson et al. (2023) – npj Vaccines mRNA detected in myocardium and lymph nodes up to 30 days post-vaccination. DOI: 10.1038/s41541-023-00742-7
5. Yonker et al. (2023) – Circulation Spike protein found in myocarditis patients post-mRNA vaccination. DOI: 10.1161/CIRCULATIONAHA.122.061025
6. Patterson et al. (2025) – Human Vaccines & Immunotherapeutics S1 spike protein detected in CD16+ monocytes up to 245 days post-vaccination. DOI: 10.1080/21645515.2025.2494934
7. Rong et al. (2024) – Brain Pathology Spike protein persistence at skull-meninges-brain axis. Link
8. Fehrer et al. (2025) – Journal of Clinical Medicine Serum spike protein persistence post-COVID and vaccination. DOI: 10.3390/jcm14041086

🧠 Immunological Dysfunction & Autoimmunity

9. Vojdani et al. (2021) – Journal of Autoimmunity Autoantibodies against spike and human proteins post-vaccination. DOI: 10.1016/j.jaut.2020.102489
10. Kanduc (2020) – Autoimmunity Reviews Molecular mimicry between spike protein and human peptides. DOI: 10.1016/j.autrev.2020.102591
11. Wallukat et al. (2021) – Frontiers in Cardiovascular Medicine Functional autoantibodies in long COVID and post-vaccine syndromes. Link
12. Mantovani et al. (2024) – Biomedicines Autoantibodies targeting GPCRs and RAS-related molecules in PACVS. DOI: 10.3390/biomedicines12122852
13. Tang et al. (2023) – Frontiers in Immunology Autoimmune diseases following COVID-19 and vaccination. Link

🧬 Genomic & Reverse Transcription Concerns

14. Aldén et al. (2022) – Current Issues in Molecular Biology In vitro reverse transcription of spike mRNA in liver cells. DOI: 10.3390/cimb44010059
15. Zhang et al. (2021) – Journal of Biological Chemistry LINE-1 activity and mRNA reverse transcription potential. DOI: 10.1016/j.jbc.2021.100682
16. Seneff et al. (2022) – Food and Chemical Toxicology Epigenetic and oncogenic risks from persistent spike protein. DOI: 10.1016/j.fct.2022.113008
17. Cari et al. (2023) – Vaccines Real-world expression levels of spike protein post-mRNA vaccination. DOI: 10.3390/vaccines11040879

🫀 Cardiovascular & Neurological Adverse Events

18. Bozkurt et al. (2021) – Circulation Myocarditis mechanisms and clinical presentation post-vaccination. DOI: 10.1161/CIRCULATIONAHA.121.056135
19. Taquet et al. (2021) – Lancet Psychiatry Increased risk of neurological disorders post-vaccination. DOI: 10.1016/S2215-0366(21)00380-5
20. Ota et al. (2025) – Journal of Clinical Neuroscience Spike protein expression in cerebral arteries post-vaccination. DOI: 10.1016/j.jocn.2025.111223
21. Posa et al. (2025) – Annals of Anatomy Neurological proteinopathies linked to spike persistence. DOI: 10.1016/j.aanat.2025.152662

📊 Pharmacovigilance & Mortality Signals

22. Rose (2021) – Science, Public Health Policy & the Law VAERS signal analysis for myocarditis and death. Link
23. Walach et al. (2021) – Vaccines Mortality estimates from European pharmacovigilance data. DOI: 10.3390/vaccines9070773
24. Platschek et al. (2024) – Vaccines PACVS in light of pharmacovigilance data. DOI: 10.3390/vaccines12121378
25. National Academies (2024) – Comprehensive Review Identified 19 harms with sufficient evidence for causality. Review Summary

🧪 Lack of Long-Term Safety Data

26. Penn Medicine CEP Report (2020) – Evidence Review Noted absence of long-term safety trials. PDF
27. Classen (2021) – Trends in Immunology Critique of trial design and long-term safety gaps. [DOI: 10.1016/j.it.2021.05.001](https://doi.org/10.101