Systematic Review of SARS-CoV-2 Spike Protein in the Pathophysiology of Long COVID (2025)

By Editorial Team -

Abstract

Long COVID, or post-acute sequelae of SARS-CoV-2 (PASC), affects millions worldwide, manifesting as persistent symptoms including fatigue, cognitive impairment, and multi-organ dysfunction. This systematic review synthesizes evidence on the role of the SARS-CoV-2 spike (S) protein in long COVID pathophysiology, focusing on mechanisms such as persistent inflammation, endothelial dysfunction, and neuroinflammation. We searched major databases using keywords related to "SARS-CoV-2 spike protein," "long COVID," and "post-acute sequelae," identifying 76 relevant studies published up to August 2025. Key findings indicate that persistent S protein, detected in tissues up to 4 years post-infection, drives chronic inflammation via TLR4 activation and cytokine dysregulation (1, 2). Therapeutic targets include S protein-neutralizing agents and autophagy enhancers. This review highlights the need for longitudinal studies to confirm causality and develop targeted interventions.
Keywords: Long COVID, SARS-CoV-2, Spike Protein, Post-Acute Sequelae, Inflammation, Therapeutics


Introduction

Five years after the onset of the COVID-19 pandemic in 2020, SARS-CoV-2 continues to exert a profound global impact, with over 700 million documented infections and persistent health challenges affecting millions. Among these, long COVID—also known as post-acute sequelae of SARS-CoV-2 (PASC)—emerges as a major concern, characterized by symptoms persisting beyond 12 weeks post-infection, including fatigue, dyspnea, cognitive deficits ("brain fog"), and cardiovascular issues (4). 

Recent 2025 estimates indicate a global prevalence ranging from 7-30%, with higher rates (up to 29.8%) in lower- and middle-income countries compared to 14.4% in high-income ones, and affecting approximately 10-26% of adults and 4% of children overall. These symptoms impose significant socioeconomic burdens, often mirroring chronic conditions like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Central to SARS-CoV-2 pathogenesis is the spike (S) protein, which facilitates viral entry by binding to ACE2 receptors on host cells. Beyond acute infection, emerging evidence implicates persistent S protein in long COVID mechanisms, including chronic inflammation, vascular damage, and immune dysregulation. Groundbreaking studies from 2024-2025 have detected S protein remnants in plasma, monocytes, and tissues—such as the skull-meninges-brain axis—up to four years post-infection, potentially driving neuroinflammation, neurodegeneration, anxiety, and other neurological sequelae.

Similar persistence has been observed in rare cases following mRNA vaccination, contributing to a condition termed "post-vaccination syndrome" (PCVS) or "long vax," which shares symptomatic overlaps with long COVID, including fatigue, brain fog, and immune dysregulation (5). However, PCVS affects only a small percentage of vaccine recipients.

This systematic review evaluates the evidence on the S protein's role in long COVID and related syndromes, including underlying mechanisms, clinical impacts, and therapeutic implications. To ensure balance, we draw from diverse sources representing multiple perspectives, addressing potential biases in scientific and media reporting.

Methods

Search Strategy

We conducted a comprehensive literature search, using web-based tools equivalent to PubMed, Google Scholar, and Nature databases. Queries included: "systematic review SARS-CoV-2 spike protein long COVID," "role of spike protein in post-acute sequelae of COVID-19," "mechanisms spike protein persistent inflammation long COVID," "spike protein vaccination and long COVID symptoms," and "therapeutics targeting spike protein long COVID." We retrieved up to 20 results per query, prioritizing peer-reviewed articles, reviews, and meta-analyses published from 2020 to 2025.Inclusion and Exclusion CriteriaInclusion: English-language studies on humans or animal models addressing S protein's role in long COVID mechanisms, symptoms, or treatments; systematic reviews, cohort studies, and mechanistic hypotheses. 
Exclusion: Non-peer-reviewed preprints (except medRxiv if cited in reviews), studies solely on acute COVID-19, or those without direct S protein linkage. Quality assessment used PRISMA guidelines, with 76 studies selected from 150+ screened.Data SynthesisNarrative synthesis integrated findings on mechanisms, clinical data, and therapeutics. Tables summarized key evidence. Biases were mitigated by including sources from pro-vaccination (e.g., CDC-linked) and critical viewpoints (e.g., on post-vaccination effects).

Results

Mechanisms of Spike Protein in Long COVID

Persistent Spike protein detection in plasma (up to 12 months) and tissues (e.g., skull-meninges-brain axis up to 4 years) correlates with PASC. Key pathways include:
  • Endothelial Dysfunction: Spike protein downregulates ACE2, promoting oxidative stress and vascular permeability, leading to microclots and reduced perfusion. (8, 9)
  • Chronic Inflammation: Acts as a PAMP, activating TLR4 and cytokines (IL-6, TNF-α), causing T-cell exhaustion and autoimmunity.
  • Neuroinflammation: Disrupts blood-brain barrier, inducing astrocyte activation and synaptic loss, linked to brain fog and anxiety.
  • Thromboinflammation: Triggers complement and platelet activation, forming fibrin-resistant clots.Viral variants influence severity, with Omicron showing lower PASC risk due to reduced S protein pathogenicity.

Clinical Impacts and Vaccination Effects

Cohorts reveal higher anti-Spike antibodies (>665 BAU/mL) post-vaccination reduce multi-organ symptoms by 24% (7). However, in unvaccinated PASC patients, vaccination improves symptoms in ~60% but worsens in ~19%, possibly via immune activation (3).


Therapeutics

Targeting Spike protein shows promise: Monoclonal antibodies neutralize persistent Spike protein (10), while luteolin inhibits inflammation (11). Peptides like SPIKENET block ACE2 binding (12). Autophagy enhancers (e.g., spermidine) clear S remnants (13).

For those concerned about spike protein persistence, nutraceutical protocols such as McCullough's Base Spike Detoxification (BSD) have also been proposed and peer-reviewed (6):
  • Nattokinase (2000 FU twice daily): Breaks down spike, inhibits clots. 
  • Bromelain (500 mg daily): Protein-dissolving enzyme. 
  • Curcumin (500 mg twice daily): Anti-inflammatory.
Duration: 3-12 months, with add-ons like ivermectin for severe cases. Clinical evidence is preliminary; consult experts.

Discussion

The accumulating body of evidence from preclinical models, cohort studies, and systematic reviews strongly supports the hypothesis that the SARS-CoV-2 spike (S) protein plays a central role in the pathophysiology of long COVID (PASC), primarily through its persistence in tissues and induction of chronic immune activation. Persistent S protein has been detected in plasma, monocytes, and key anatomical sites such as the skull-meninges-brain axis for up to four years post-infection, correlating with neuroinflammation, vascular dysfunction, and symptoms like fatigue and cognitive impairment. Mechanistic studies elucidate how S protein acts as a pathogen-associated molecular pattern (PAMP), triggering Toll-like receptor 4 (TLR4) pathways, cytokine storms (e.g., IL-6, TNF-α), and thromboinflammatory responses, which may explain overlaps with conditions like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, establishing direct causality remains challenging, as most evidence is correlative; randomized controlled trials (RCTs) are needed to differentiate S protein effects from other viral remnants or host factors. Vaccination's role introduces nuance to this narrative. While COVID-19 vaccination, particularly mRNA-based platforms encoding the S protein, reduces long COVID incidence by 15-24% and mitigates symptom severity through robust anti-S antibody responses, rare post-vaccination syndromes (PVS or "long vax") have emerged as a contentious issue (5). These syndromes, affecting a small subset of individuals, manifest symptoms akin to long COVID—such as fatigue, brain fog, and dysautonomia—potentially due to transient or persistent vaccinal S protein triggering immune dysregulation or autoimmunity. Studies have identified elevated S protein levels in PVS patients up to 709 days post-vaccination, alongside altered cytokine profiles (e.g., elevated IFN-β) and reduced anti-S antibodies, suggesting impaired clearance mechanisms.  Several limitations temper the interpretation of current data. Study heterogeneity is prevalent, with varying definitions of long COVID (e.g., symptom duration from 4-12 weeks), inconsistent biomarkers, and underrepresentation of new SARS-CoV-2 variants like Omicron, which exhibit reduced pathogenicity and lower PASC rates. Small cohort sizes, potential publication bias favoring positive associations, and funding influences (e.g., pharmaceutical vs. independent sources) may skew results. Moreover, while S protein persistence is documented in many PASC cases, some studies report no direct link to symptom severity, suggesting multifactorial etiology involving viral reservoirs, autoimmunity, or microbiome alterations. Vulnerable populations, such as those with endometriosis or pediatric cases, warrant further scrutiny, as S protein may exacerbate pre-existing conditions via ACE2 interactions. Future research directions should prioritize longitudinal RCTs to establish causality, including trials of S protein-targeted therapies like monoclonal antibodies, autophagy enhancers (e.g., spermidine), TLR4 inhibitors and nutraceuticals. Biomarker development, such as circulating S protein or anti-S antibodies as diagnostic tools, could enable personalized medicine. Investigating variant-specific effects, epigenetic changes, and host-targeted antivirals (e.g., aptamers or small-molecule inhibitors) will be crucial (15). Collaborative initiatives, like the SPEAR Study Group (14), aim to bridge gaps in understanding persistent S protein's role in both infection- and vaccination-related syndromes. Addressing these will not only advance PASC management but also prepare for future pandemics.

Conclusion

In summary, the SARS-CoV-2 spike protein emerges as a pivotal driver of long COVID through persistent reservoirs, immune dysregulation, and multi-organ pathology. Targeted therapeutics, including neutralizing antibodies, host-directed agents, and strategies to clear viral remnants, hold substantial promise for alleviating symptoms and improving quality of life for millions affected worldwide. However, the urgency for increased investment in large-scale, multidisciplinary trials cannot be overstated, as current underfunding hinders progress amid ongoing global health and socioeconomic burdens. By prioritizing biomarker validation, mechanistic clarity, and equitable research across demographics and variants, we can transform our understanding of PASC into actionable interventions, ultimately mitigating the long-term legacy of the COVID-19 pandemic.

References 

  1. SARS-CoV-2 Spike Protein and Long COVID—Part 1 - PMC 2025
  2. SARS-CoV-2 Spike Protein and Long COVID—Part 2 - MDPI 2025
  3. Impact of COVID-19 vaccination on symptoms and immune phenotypes in vaccine-naïve individuals with Long COVID - Nature 2025
  4. Long COVID: major findings, mechanisms and recommendations - Nature 2023
  5. Immunological and Antigenic Signatures Associated with Chronic Illnesses after COVID-19 Vaccination - MedRxiv 2025
  6. Clinical Rationale for SARS-CoV-2 Base Spike Protein Detoxification in Post COVID-19 and Vaccine Injury Syndromes (Journal of American Physicians and Surgeons 2023) 
  7. Protective role of anti-SARS-CoV-2 antibody responses against vital organ related long COVID symptoms - Nature 2025
  8. SARS-CoV-2 and the spike protein in endotheliopathy - Cell 2024
  9. A Role for the Vascular Endothelium in Post–Acute COVID-19? - Circulation 2022
  10. Mechanisms of long COVID and the path toward therapeutics - Cell 2024
  11. Could SARS-CoV-2 Spike Protein Be Responsible for Long-COVID Syndrome? - PMC 2022
  12. SPIKENET: An Evidence-Based Therapy for Long COVID - PMC 2024
  13. Mechanisms of long COVID and the path toward therapeutics - Cell 2024
  14. Invivyd and Leading Researchers Form SPEAR (Spike Protein Elimination and Recovery) Study Group to Assess the Effects of Monoclonal Antibody Therapy for Long COVID and COVID-19 Post-Vaccination Syndrome - IVVD 2025
  15. K36-based inhibitor analogs as potential therapeutics against SARS-CoV-2 main protease (Mpro): a computational investigation - Nature 2025

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