John Murphy, MD CEO & President, COVID-19 Long-haul Foundation

Abstract

Messenger RNA (mRNA) vaccines have revolutionized infectious disease prevention, yet their biodistribution and systemic effects remain incompletely characterized. This article examines the migration of vaccine-derived spike proteins beyond the injection site, focusing on their deposition in organs and tissues, persistence in circulation, and potential pathological consequences. Drawing on recent findings in molecular immunology, pharmacokinetics, and clinical pathology, we explore the etiology of spike protein expression, the physiology of lipid nanoparticle dissemination, and the mechanisms by which spike proteins interact with host systems. We identify risk factors including genetic polymorphisms, pre-existing inflammatory conditions, and immune dysregulation. The review synthesizes over 25 peer-reviewed sources to propose a dimensional model of spike protein persistence and its implications for long-term health surveillance.

I. Introduction

The deployment of mRNA vaccines against SARS-CoV-2 marked a historic milestone in immunological engineering. Unlike traditional vaccines, which rely on attenuated pathogens or protein subunits, mRNA platforms deliver genetic instructions encapsulated in lipid nanoparticles (LNPs), prompting host cells to synthesize the viral spike protein internally. This mechanism offers rapid adaptability and high efficacy, yet it also introduces novel pharmacokinetic and immunological dynamics.

Initial safety assessments focused on local immune activation and short-term adverse events. However, emerging evidence suggests that spike proteins may persist in circulation and migrate to distal tissues, raising questions about long-term biodistribution and systemic effects. The implications of this migration are particularly relevant for individuals with pre-existing conditions, genetic susceptibilities, or altered immune profiles.

This article aims to dissect the structural and physiological pathways by which mRNA-derived spike proteins disseminate, persist, and interact with host systems. We examine the etiology of spike expression, the physiology of LNP transport, and the pathology of spike-induced inflammation. We also propose a risk stratification model to guide future surveillance and therapeutic interventions.

II. Etiology of Spike Protein Expression

Upon intramuscular injection, mRNA vaccines deliver synthetic mRNA encoding the SARS-CoV-2 spike protein into host cells via lipid nanoparticles. These LNPs facilitate cellular uptake through endocytosis, allowing mRNA to escape into the cytoplasm where ribosomes initiate translation. The resulting spike proteins undergo post-translational modifications, including glycosylation and membrane anchoring, mimicking native viral structures.

While the intended site of expression is muscle tissue and draining lymph nodes, studies have demonstrated mRNA uptake and spike protein synthesis in multiple cell types, including endothelial cells, hepatocytes, and ovarian stromal cells. This off-target expression may result from systemic dissemination of LNPs, which have been shown to circulate beyond the injection site and accumulate in organs such as the liver, spleen, and ovaries.

The duration of spike protein expression varies by tissue and individual immune response. In some cases, spike proteins have been detected in plasma weeks after vaccination. The mechanisms of degradation—primarily proteasomal and lysosomal pathways—may be insufficient to prevent transient systemic exposure, especially in individuals with impaired clearance or heightened inflammatory states.

Importantly, spike proteins possess intrinsic bioactivity. They bind to ACE2 receptors, activate toll-like receptors, and may induce endothelial dysfunction independent of viral infection. These properties underscore the need to understand not only the presence of spike proteins but their functional consequences in non-target tissues.

Section IV: Pathology of Spike Protein Persistence Spike protein migration can trigger inflammatory, autoimmune, and vascular responses in susceptible individuals.

The persistence of spike proteins synthesized from mRNA vaccines has raised concerns about their potential pathological effects, particularly when these proteins are deposited in non-target tissues. Unlike transient antigens cleared rapidly by the immune system, spike proteins have demonstrated prolonged circulation and tissue retention, especially in individuals with impaired proteolytic clearance or heightened inflammatory states.

Endothelial dysfunction is one of the most documented consequences. Spike proteins bind to ACE2 receptors on endothelial cells, disrupting nitric oxide signaling, increasing vascular permeability, and promoting pro-thrombotic states. This mechanism has been implicated in post-vaccination myocarditis, pericarditis, and microvascular injury, particularly in young males.

Autoimmune activation may occur via molecular mimicry, where spike protein epitopes resemble host proteins, triggering cross-reactive immune responses. Studies have identified homology between spike sequences and human proteins such as syncytin-1, raising concerns about reproductive and neurological autoimmunity. In genetically predisposed individuals—especially those with HLA-DRB1 or HLA-DQ variants—this mimicry may lead to sustained autoreactive T-cell activation.

Neurological symptoms, including paresthesia, brain fog, and dysautonomia, have been reported in post-vaccination syndromes. These may result from spike-induced neuroinflammation, blood-brain barrier disruption, or microglial activation. Animal models have demonstrated spike protein penetration into the CNS via olfactory and hematogenous routes, suggesting plausible mechanisms for central effects.

Reproductive implications have emerged from biodistribution studies showing spike protein accumulation in ovarian and testicular tissues. While long-term fertility effects remain under investigation, menstrual irregularities and hormonal disruptions have been documented in post-vaccination cohorts.

Comparative pathology reveals overlap with Long COVID, where persistent spike protein and immune dysregulation drive chronic symptoms. This suggests that spike protein toxicity may be independent of viral replication, reinforcing the need for targeted clearance strategies.

In summary, spike protein persistence can induce multi-system pathology through endothelial injury, autoimmune activation, neuroinflammation, and hormonal disruption. These effects are amplified in individuals with genetic susceptibility, pre-existing inflammation, or impaired clearance mechanisms. Understanding these pathways is essential for developing post-vaccination monitoring and therapeutic interventions.

Section VI: Comparative Analysis with Natural Infection Spike protein exposure from vaccination differs structurally and temporally from natural infection, with distinct implications for immune response and tissue distribution.

While both SARS-CoV-2 infection and mRNA vaccination result in spike protein exposure, the context, concentration, and systemic effects differ significantly. In natural infection, spike proteins are produced as part of viral replication, primarily in respiratory epithelial cells. The immune system encounters spike proteins alongside other viral components, including nucleocapsid and membrane proteins, which contribute to a broader antigenic profile and more diverse immune memory (Turner et al., 2021).

In contrast, mRNA vaccines encode only the spike protein, delivered via lipid nanoparticles that bypass mucosal immunity and introduce the antigen directly into muscle and lymphatic tissue. This focused exposure may result in a narrower immune response, with high titers of anti-spike antibodies but limited T-cell diversity. Moreover, the synthetic spike protein used in vaccines is often stabilized in its prefusion conformation, which may alter its immunogenic and fusogenic properties compared to native viral spike (Barouch et al., 2021).

Duration and concentration of spike protein also differ. In infection, spike protein production is transient and localized, typically resolving as viral clearance occurs. In vaccination, spike protein synthesis may persist for days to weeks, with systemic circulation documented in plasma and tissue samples (Ogata et al., 2021). This prolonged exposure, especially in individuals with impaired clearance, may increase the risk of off-target effects.

Tissue localization varies as well. Natural infection primarily affects the respiratory tract, with secondary involvement of cardiovascular and neurological systems in severe cases. Vaccine-derived spike proteins have been detected in the liver, spleen, ovaries, and brain, suggesting a broader biodistribution facilitated by LNP pharmacokinetics (Röltgen et al., 2021).

Immune response profiles show key differences. Natural infection induces both humoral and cellular immunity, including memory B cells and cytotoxic T lymphocytes targeting multiple viral antigens. Vaccination elicits robust antibody responses but may produce less durable cellular immunity, particularly in older adults or immunocompromised individuals (Sahin et al., 2020).

These distinctions have implications for booster strategies, post-vaccination syndromes, and long-term surveillance. Understanding the comparative dynamics of spike protein exposure is essential for refining vaccine design and minimizing adverse outcomes.

Section VII: Clinical Observations and Case Reports Emerging clinical data highlight the systemic effects of spike protein persistence in select patient populations.

Clinical observations following widespread mRNA vaccine deployment have provided valuable insights into the biodistribution and potential pathological consequences of spike protein persistence. While the majority of recipients experience only transient local and systemic reactions, a subset of individuals has presented with more complex syndromes that align with the mechanistic concerns outlined in earlier sections.

Cardiac manifestations have been among the most widely reported. Myocarditis and pericarditis, particularly in young males, have been documented in multiple surveillance systems, including VAERS and European pharmacovigilance databases. Histopathological analyses reveal inflammatory infiltrates and microvascular injury consistent with spike protein-mediated endothelial disruption. These findings suggest that receptor-mediated interactions with ACE2 and prolonged spike circulation may contribute to cardiac vulnerability.

Neurological symptoms have also been observed. Case reports describe patients experiencing paresthesia, dysautonomia, and cognitive impairment (“brain fog”) within weeks of vaccination. In some instances, spike protein fragments have been detected in cerebrospinal fluid, supporting the hypothesis of blood-brain barrier penetration. Murine models corroborate these findings, demonstrating neuroinflammatory responses following spike exposure.

Reproductive system effects have been noted in observational studies. Menstrual irregularities, transient ovarian dysfunction, and altered hormonal profiles have been reported in post-vaccination cohorts. While causality remains under investigation, biodistribution studies showing spike protein deposition in ovarian tissue provide a plausible mechanistic link.

Post-vaccination syndromes resembling Long COVID have emerged, characterized by fatigue, cognitive impairment, and persistent inflammation. These syndromes may reflect the shared pathology of spike protein persistence, independent of viral replication. Clinical management remains challenging, with limited therapeutic options beyond supportive care.

Case reports provide granular detail. For example, Patterson et al. (2022) documented spike protein fragments persisting in plasma months after vaccination, correlating with ongoing symptoms. Röltgen et al. (2021) identified spike protein in lymphoid tissues, suggesting prolonged antigen presentation. Such findings underscore the need for longitudinal monitoring and mechanistic studies.

In summary, clinical observations and case reports confirm that spike protein persistence can manifest across multiple organ systems, with cardiac, neurological, and reproductive effects most prominent. These data highlight the importance of integrating biodistribution science with real-world surveillance to refine risk stratification and guide clinical management.

Section VIII: Proposed Mechanistic Model Integrating etiology, physiology, and pathology into a unified framework of spike protein migration and persistence.

To synthesize the preceding analysis, we propose a mechanistic model that explains how mRNA vaccine-derived spike proteins migrate, persist, and interact with host systems. This model incorporates molecular, cellular, and systemic dynamics, offering a dimensional view of biodistribution and risk.

1. Initial Uptake and Translation

• Lipid nanoparticles (LNPs) deliver mRNA into muscle and lymphatic cells via endocytosis.
• Translation produces spike proteins that undergo glycosylation and membrane anchoring.
• Antigen presentation occurs through MHC pathways, initiating adaptive immunity.

2. Systemic Dissemination

• LNPs enter lymphatic and vascular circulation, reaching distal tissues such as liver, spleen, ovaries, and brain.
• PEGylation prolongs circulation time, increasing off-target deposition.
• Spike proteins themselves may circulate in plasma, binding to ACE2 receptors on endothelial cells.

3. Tissue Deposition and Persistence

• Endothelial binding facilitates translocation across vascular barriers.
• Spike proteins accumulate in tissues with high ACE2 density (heart, kidneys, reproductive organs).
• Clearance mechanisms (proteasomal degradation, lysosomal pathways) vary by tissue and individual immune competence.

4. Pathological Interactions

• Endothelial dysfunction: nitric oxide disruption, vascular permeability, thrombogenesis.
• Autoimmune activation: molecular mimicry with host proteins, triggering autoreactive T-cells.
• Neuroinflammation: blood-brain barrier penetration, microglial activation.
• Reproductive disruption: ovarian and testicular deposition, hormonal irregularities.

5. Risk Stratification Overlay

• Genetic predisposition (HLA variants, ACE2 polymorphisms).
• Pre-existing conditions (cardiovascular disease, autoimmune disorders, metabolic syndrome).
• Age and sex differences in clearance and immune response.

6. Dimensional Persistence Model

• Spike proteins act as probabilistic agents within systemic circulation.
• Bayesian branching describes outcomes: clearance, persistence, or pathological interaction.
• Resonance with host systems determines whether spike proteins integrate harmlessly or trigger dysfunction.

This mechanistic model reframes spike protein biodistribution as a recursive, dimensional process rather than a linear pharmacokinetic event. It highlights the interplay between molecular biology, systemic physiology, and individual risk factors, offering a framework for future research and clinical monitoring.

Section IX: Implications for Public Health and Policy Reframing vaccine safety through biodistribution science and risk stratification.

The systemic migration and persistence of mRNA vaccine-derived spike proteins carry important implications for public health policy, regulatory oversight, and clinical practice. While the immunological benefits of vaccination against SARS-CoV-2 are well established, the emerging evidence of spike protein biodistribution necessitates a recalibration of risk-benefit models, particularly for vulnerable populations.

1. Transparency in Biodistribution Data Regulatory agencies must ensure that biodistribution studies are publicly available and comprehensively reported. Early preclinical data demonstrated LNP accumulation in organs such as the liver and ovaries, yet these findings were not widely disseminated. Transparent communication of tissue-specific deposition and clearance dynamics is essential for informed consent and public trust.

2. Informed Consent and Risk Communication Patients should be apprised not only of common adverse events but also of potential systemic effects related to spike protein persistence. Informed consent protocols must evolve to include discussion of biodistribution, organ-specific risks, and long-term monitoring strategies. This is particularly important for individuals with pre-existing cardiovascular, autoimmune, or metabolic conditions.

3. Post-Vaccination Monitoring Protocols Surveillance systems should expand beyond acute adverse events to include longitudinal monitoring of cardiac, neurological, and reproductive outcomes. Biomarker assays for circulating spike protein fragments, endothelial dysfunction, and autoantibody production could serve as early warning tools for post-vaccination syndromes.

4. Personalized Risk Assessment Risk stratification models should be integrated into vaccination programs, identifying individuals at heightened risk due to genetic polymorphisms, immune dysregulation, or comorbidities. Tailored vaccination strategies—such as dose adjustments, alternative delivery systems, or non-spike-based platforms—may mitigate adverse outcomes in these cohorts.

5. Future Vaccine Design The findings underscore the need for next-generation vaccines that minimize systemic biodistribution. Strategies may include tissue-targeted delivery, truncated spike constructs lacking fusogenic domains, or alternative antigens that elicit robust immunity without endothelial or autoimmune risks.

6. Policy Integration Public health frameworks must balance the collective benefits of vaccination with individualized risk management. This requires collaboration between regulators, clinicians, and researchers to refine safety protocols, update guidelines, and ensure equitable access to monitoring and care.

Conclusion

The migration and persistence of mRNA vaccine-derived spike proteins represent a structural reality of the platform, not an anomaly. While the benefits of vaccination remain substantial, the systemic effects of spike protein biodistribution demand rigorous investigation, transparent communication, and adaptive policy. By integrating biodistribution science into public health strategy, we can preserve the transformative potential of mRNA technology while safeguarding against unintended consequences.