What the Evidence Says About Spike Protein in Long COVID & Post‑Vaccination (2026)

By Editorial Team -

Abstract

Persistent symptoms following SARS‑CoV‑2 infection, collectively termed Long COVID or post‑acute sequelae of COVID‑19 (PASC), remain a significant clinical challenge. One proposed biological mechanism involves prolonged presence of SARS‑CoV‑2 spike protein or viral RNA fragments post‑infection. Additional questions concern spike protein dynamics after COVID‑19 vaccination. This review synthesizes current peer‑reviewed evidence on spike protein detection after natural infection and vaccination, clarifying clinical context, limitations, and implications. Data indicate that SARS‑CoV‑2 spike protein and/or fragments can be detected in circulation or tissues up to a year or longer post‑infection, especially in PASC cohorts, whereas vaccine‑derived spike is typically transient and associated with rapid immune clearance. Mechanistic and clinical significance remains an area of ongoing research.

Keywords: SARS‑CoV‑2, spike protein, long COVID, PASC, post‑vaccination, antigen persistence, extracellular vesicles

Introduction

SARS‑CoV‑2 infection causes a range of acute symptoms and, in a substantial subset of individuals, persistent post‑acute sequelae that may last months or years, commonly called Long COVID or PASC. The biological underpinnings of PASC are complex and multifactorial and include immune dysregulation, viral persistence, microvascular dysfunction, and latent viral reactivation. Among these, the persistence of viral antigens — notably the spike protein — in circulation or tissues long after acute infection has attracted attention as a possible contributor to ongoing inflammation and symptomatology.

In contrast to infection, SARS‑CoV‑2 vaccines induce transient expression of spike protein to stimulate immunity. While early safety data indicated rapid clearance post‑vaccination, some studies have explored how long spike protein or its fragments might be detectable in circulation after vaccination and what that might mean clinically.

This review compiles existing peer‑reviewed evidence on spike protein persistence after natural infection and COVID‑19 vaccination.

Evidence of Spike Protein Persistence after SARS‑CoV‑2 Infection

Multiple lines of peer‑reviewed evidence support the presence of SARS‑CoV‑2 spike protein or its fragments in biological samples long after acute infection:

1. Circulating Spike Protein in PASC Patients

A clinical study published in Clinical Infectious Diseases detected circulating SARS‑CoV‑2 spike protein in the plasma of individuals diagnosed with PASC up to 12 months following acute COVID‑19 infection. In this study, spike protein was found predominantly in PASC patients, with persistence beyond the acute phase. Persistent circulating SARS‑CoV‑2 spike is associated with post‑acute COVID‑19 sequelae (PubMed)

Key finding: Spike protein detectable up to 12 months post‑infection in PASC cohorts, not just in acute infection. (PubMed)

2. Persistence with Extracellular Vesicle Association

A related report found that parts of the circulating spike protein can be linked to extracellular vesicles (EVs), independent of viral RNA, suggesting a mechanism by which spike antigens may persist in circulation without active viral replication. (PMC)

Implication: EV‑linked spike protein fragments may remain present longer than expected after viral clearance. (PMC)

3. Tissue Reservoirs and Antigen Persistence

Comprehensive reviews of post‑acute SARS‑CoV‑2 reservoirs show evidence of residual viral proteins, including spike protein, in tissues such as gut, lymphoid tissues, and possibly brain border regions even months after infection, suggesting that these reservoirs could produce viral antigens long after acute infection. (MDPI)

Example: Persistent SARS‑CoV‑2 antigens, including spike, have been detected in gut mucosa months after initial infection resolution. (MDPI)

Mechanistic Insights: What Detection Methods Tell Us

Most of the studies reporting spike protein persistence rely on sensitive detection methods, including ultrasensitive immunoassays (e.g., Simoa) for spike protein and droplet digital PCR for viral RNA fragments. These methods can detect very low antigen levels but do not necessarily establish ongoing viral replication. (PubMed)

Limitations:

  • Detection of spike fragments does not equate to intact infectious virus.

  • Correlation between antigen persistence and degree of PASC symptoms is not fully established.

  • Longitudinal data are still limited and variable across cohorts.

Spike Protein After COVID‑19 Vaccination

Peer‑reviewed literature on post‑vaccination spike persistence predominantly focuses on antibody responses to spike protein rather than detection of the antigen itself:

1. Antibody Dynamics Post‑Vaccination

Studies show that spike‑specific antibodies remain detectable many months after vaccination, reflecting durable immune responses. For example, anti‑spike IgG levels remain present and measurable at 6 months and even up to a year post‑vaccination in many individuals. (PubMed)

Important distinction: These studies assess antibodies to spike protein, not direct detection of spike protein itself.

2. Detection of Vaccine‑Related Spike or Vaccine mRNA

To date, high‑quality peer‑reviewed evidence describing persistent detection of vaccine‑derived spike protein itself in circulation beyond weeks after immunization remains limited. Initial expectations were that mRNA and spike antigen derived from vaccines are rapidly cleared within days to weeks. Rigorous long‑term antigen persistence studies specifically post‑vaccination are uncommon in the peer‑reviewed literature and not a well‑established finding. Large clinical data and vaccine safety studies have not identified chronic spike protein presence as a common pathogenic mechanism. (Wikipedia)

Discussion

1. Long COVID and Persistent Spike Protein

Evidence shows that SARS‑CoV‑2 spike protein and related viral fragments can be detectable in blood plasma and possibly tissues months after infection in subsets of PASC patients. Findings suggest potential roles in persistent antigenic stimulation and chronic inflammation, but causality with symptoms is not definitively proven. (MDPI)

2. Post‑Vaccination Spike Protein

Current peer‑reviewed evidence supports that antibody responses to spike remain long after vaccination. However, direct evidence of prolonged spike protein presence post‑vaccination in circulation or tissues is sparse and not well‑established in high‑quality clinical studies. Clinically, vaccines demonstrate strong safety profiles and no established mechanism of chronic spike persistence causing common disease. (Wikipedia)

3. Limitations in the Literature

  • Many reported observations are from small cohorts or specialized assays.

  • Lack of longitudinal, large‑cohort studies confirming causative links between spike persistence and clinical outcomes.

  • Differing methodologies complicate comparison across studies.

Conclusion

Current peer‑reviewed evidence indicates that SARS‑CoV‑2 spike protein and its fragments may persist in certain individuals after natural infection, particularly in those with Long COVID, for months or more. However, evidence of persistent spike protein post‑vaccination is limited in high‑quality studies. The clinical significance of antigen persistence remains an area of active research, and causation between persistent spike protein and long COVID symptoms has not been definitively established. Continued longitudinal and mechanistic studies are essential to fully understand these phenomena.

References

  1. Persistent circulating SARS‑CoV‑2 spike is associated with post‑acute COVID‑19 sequelae. Clin Infect Dis. 2023;76(3):e487‑e490. doi:10.1093/cid/ciac722 Persistent circulating SARS‑CoV‑2 spike is associated with post‑acute COVID‑19 sequelae (PubMed)

  2. Persistent circulation of soluble and extracellular vesicle‑linked spike protein and viral RNA in individuals with PASC. J Med Virol. 2023 (Open Access). (PMC)

  3. Insights into persistent SARS‑CoV‑2 reservoirs in chronic long COVID. Viruses. 2025;17(10):1310. (MDPI)

  4. SARS‑CoV‑2 antibody dynamics after infection and vaccination. J Med Virol. (various long‑term SARS‑CoV‑2 antibody studies). (PubMed)

  5. COVID‑19 vaccine misinformation and hesitancy — spike protein claims context. Wikipedia. (Wikipedia)


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