Author: John Murphy, President COVID 19 Long-haul Foundation
Abstract
Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), has emerged as a multifaceted syndrome affecting millions globally. While initial hypotheses focused on viral persistence, autoimmunity, and organ damage, recent evidence suggests that the spike protein itself may be the primary driver of chronic pathology. This article introduces and defines Post-Spike Syndrome (PSS) and Spikeopathy as umbrella terms for spike protein–mediated immune dysregulation, endothelial injury, and neurovascular compromise. Drawing from virology, immunology, and clinical trial data, we argue that spike persistence—whether from infection or mRNA exposure—induces a cascade of inflammatory, thrombotic, and metabolic dysfunctions. We propose diagnostic criteria, therapeutic targets, and a research framework for spike-centric investigation. This paradigm shift has implications for treatment, vaccine design, and public health policy.
1. Introduction
The COVID-19 pandemic has reshaped global health systems, economies, and scientific priorities. Yet as acute infections decline, a new crisis has emerged: Long COVID, a chronic, debilitating condition affecting an estimated 10–30% of those infected. Symptoms range from fatigue and brain fog to cardiovascular and neurological impairments. Despite extensive research, the underlying mechanisms remain poorly defined.
Recent studies suggest that spike protein persistence—either from viral reservoirs or repeated mRNA exposure—may be central to the pathogenesis of Long COVID. This article introduces the concept of Post-Spike Syndrome (PSS) and Spikeopathy, framing them as distinct clinical entities characterized by spike-induced immune and vascular dysfunction.
2. Virological Basis of Spike Persistence
The SARS-CoV-2 spike protein is a trimeric glycoprotein responsible for viral entry via ACE2 receptors. It is highly immunogenic and structurally stable, capable of persisting in tissues long after viral clearance. Studies have detected spike protein in monocytes, endothelial cells, and cerebrospinal fluid months post-infection.
Swank et al. (2022) demonstrated circulating spike protein in vaccinated individuals with Long COVID symptoms, suggesting that spike-only exposure may be sufficient to trigger chronic inflammation. Patterson et al. (2021) found spike protein in CD16+ monocytes up to 15 months post-infection.
3. Immunological Dysregulation
Spike protein interacts with toll-like receptors (TLRs), triggering NF-κB activation and cytokine release. IL-6, TNF-α, and interferon pathways are consistently elevated in Long COVID cohorts. T-cell exhaustion, clonal expansion, and autoantibody production further complicate immune recovery.
The RECOVER Initiative (2023) identified persistent IL-6 elevation in over 60% of Long COVID patients, correlating with fatigue and cognitive decline. Autoantibodies against ACE2, β2-glycoprotein, and phospholipids have been documented.
4. Endothelial and Microvascular Injury
Spike protein binds to ACE2-expressing endothelial cells, inducing apoptosis and vascular inflammation. Pretorius et al. (2022) identified microclots resistant to fibrinolysis in Long COVID patients. These clots impair oxygen delivery and contribute to multi-organ symptoms.
Kell & Pretorius (2023) proposed a model of spike-induced hypercoagulability, linking it to platelet activation and complement cascade dysregulation.
5. Neurological and Cognitive Sequelae
Spike protein has been detected in the brain and cerebrospinal fluid, suggesting neuroinvasion. Zubair et al. (2022) reported spike-induced blood-brain barrier disruption and microglial activation. Brain fog, memory loss, and executive dysfunction are common in Long COVID cohorts.
The NIH NeuroCOVID Consortium (2024) found elevated neurofilament light chain and glial fibrillary acidic protein in Long COVID patients, markers of neurodegeneration.
6. Mitochondrial Dysfunction and Metabolic Collapse
Spike protein interferes with mitochondrial respiration, leading to ATP depletion and oxidative stress. Davis et al. (2021) documented reduced NAD+ levels and increased lactate in Long COVID patients. Komaroff & Lipkin (2023) linked mitochondrial dysfunction to post-exertional malaise and chronic fatigue.
7. Comparative Pathology: Infection vs. Vaccination
While Long COVID is traditionally associated with infection, a subset of individuals report similar symptoms post-vaccination. Gessner et al. (2023) found distinct cytokine profiles in post-vaccine long-haulers, with elevated IL-6 and spike-specific IgG.
The Long COVID Research Network (2024) proposed phenotype mapping to distinguish between infection-induced and vaccine-induced spikeopathy.
8. Diagnostic Criteria and Biomarker Development
Current diagnostic tools are inadequate for detecting spike persistence. Novel assays targeting circulating spike, IL-6 receptor polymorphisms, and microclot imaging are under development.
The COVID-19 Long Haul Foundation (2025) proposed a biomarker panel including spike ELISA, D-dimer, and endothelial microparticles.
9. Therapeutic Targets and Clinical Trials
Therapies targeting spike-induced pathways include IL-6 inhibitors (e.g., tocilizumab), anticoagulants (e.g., rivaroxaban), and mitochondrial support agents (e.g., CoQ10, NAD+ precursors).
Plasmapheresis and apheresis protocols have shown promise in clearing circulating spike protein. Ultraviolet blood irradiation has been proposed as a rapid intervention for spike clearance.
10. Policy Implications and Research Gaps
Despite mounting evidence, spike-centric research remains underfunded. The Lancet Microbe (2025) reported a 40% decline in Long COVID research grants. Actuarial models from the Society of Actuaries (SOA) show increased all-cause mortality in Long COVID cohorts.
Ethical considerations include informed consent for spike exposure and equitable access to diagnostics and treatment.
11. Conclusion
Post-Spike Syndrome and Spikeopathy represent a paradigm shift in understanding Long COVID. By focusing on spike protein persistence and its systemic effects, we can develop targeted diagnostics and therapies. Future research must prioritize spike-centric models, genotype-specific interventions, and longitudinal cohort studies.
References
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- Helmholtz Zentrum München. Long COVID Breakthrough: Spike Proteins Persist in Brain for Years. SciTechDaily. Jan 2025. Link
- Pereira de Melo B et al. SARS-CoV-2 Spike Protein and Long COVID—Part 1: Impact of Spike Protein in Pathophysiological Mechanisms of Long COVID Syndrome. Viruses. 2025;17(5):617. DOI:10.3390/v17050617