By John Murphy, The COVID 19 Long-haul Foundation
When the SARS-CoV-2 virus first emerged, the world’s attention quickly turned to its crown-like protrusions—the spike proteins that give coronaviruses their name. These molecular grappling hooks, designed to latch onto human cells, became the focal point of vaccine development, diagnostic testing, and therapeutic targeting. But five years into the pandemic, scientists are uncovering a deeper truth: the spike protein is not just a viral entry tool—it’s a lingering agent of disease.
Recent clinical trials and molecular studies suggest that the spike protein may persist in the body long after the virus has cleared, contributing to vascular inflammation, neurological symptoms, and the enigmatic condition known as long COVID. Understanding how this protein behaves, where it hides, and how the body clears—or fails to clear—it is now central to the next phase of COVID-19 research.
A Molecular Trojan Horse
The spike protein is a trimeric glycoprotein composed of two subunits: S1, which binds to the ACE2 receptor on human cells, and S2, which facilitates membrane fusion. This elegant mechanism allows the virus to slip inside cells and hijack their machinery. But the spike’s impact doesn’t end at the cellular membrane.
Endothelial cells lining blood vessels express ACE2 abundantly, making them prime targets. Once the spike protein binds, it triggers a cascade of inflammatory signals—upregulating adhesion molecules, recruiting immune cells, and disrupting the vascular barrier. This endothelial activation has been linked to microclot formation, myocarditis, and even stroke.
Tissue Tropism and Hidden Reservoirs
While the lungs were the initial battlefield, the spike protein’s reach extends far beyond. Studies have detected spike fragments in the brain, heart, kidneys, and gastrointestinal tract. In some cases, spike protein has been found in the meninges and skull bone marrow years after infection, suggesting immune-privileged reservoirs where viral antigens evade clearance.
This persistence is not merely academic. Patients with long COVID often report cognitive dysfunction, fatigue, and cardiovascular symptoms—conditions that correlate with the tissues where spike protein lingers. The hypothesis gaining traction is that residual spike protein may act as a chronic irritant, sustaining low-grade inflammation and disrupting normal function.
The Clearance Conundrum
In healthy individuals, the immune system mounts a robust response to the spike protein. Neutralizing antibodies bind to the receptor-binding domain (RBD), blocking ACE2 interaction. Cytotoxic T cells recognize spike-derived peptides presented on MHC-I molecules and eliminate infected cells. Vaccines, particularly mRNA-based ones, prime this response by encoding the spike protein and inducing transient expression.
Yet clearance is not always complete. A retrospective cohort study published in Frontiers in Public Health analyzed over 190,000 individuals and found that detectable spike-protein antibodies correlated with reduced hospitalization and death, but not necessarily with complete antigen clearance. In some cases, spike protein fragments persisted despite robust antibody titers.
Clinical Trials Illuminate the Path Forward
Several recent trials are probing the spike protein’s role in long COVID and testing therapies aimed at its elimination.
One such effort is the SPEAR Study Group, a consortium of researchers proposing a clinical trial using monoclonal antibodies (mAbs) like VYD2311 to neutralize circulating spike protein in long COVID patients. These mAbs are engineered for broad neutralization and may offer symptom relief by targeting residual spike antigens. The trial design includes standardized symptom tracking and correlation with antigen levels, aiming to establish causality between spike persistence and clinical outcomes.
Another promising avenue is Tevogen Bio’s TVGN 489, an allogeneic cytotoxic T lymphocyte (CTL) therapy targeting the entire SARS-CoV-2 genome—not just the spike protein. In a dose-finding trial, high-risk patients receiving TVGN 489 showed >99% viral elimination by day 14, with no progression to long COVID. The CTLs persisted for six months, suggesting durable immune support.
Meanwhile, researchers at La Trobe University and Kumamoto University have identified internal viral proteins that mutate less frequently than the spike, offering new vaccine targets that may reduce the need for frequent boosters5. These proteins activate killer T cells via HLA-C presentation, potentially providing cross-variant protection and mitigating long COVID risk.
Implications for Public Health and Policy
The evolving understanding of spike protein biology has profound implications. If persistent spike protein contributes to long COVID, then therapies targeting it could transform treatment. Moreover, vaccine design may shift toward internal viral proteins that offer broader and longer-lasting immunity.
For clinicians, measuring spike protein antibody levels may become a tool for assessing risk and guiding booster decisions. For patients, especially those with lingering symptoms, the promise of targeted therapies offers hope.
But challenges remain. The CDC currently does not recommend routine spike antibody testing due to limited evidence of clinical utility. And while monoclonal antibodies show promise, their cost and scalability must be addressed.
Conclusion: The Spike’s Second Act
The spike protein, once seen as a mere entry mechanism, is now recognized as a persistent actor in COVID-19’s long tail. Its ability to inflame, linger, and evade clearance makes it a central figure in post-viral syndromes. As clinical trials advance and molecular insights deepen, the scientific community is poised to rewrite the narrative—from acute infection to chronic impact, and from viral entry to therapeutic exit.
The spike may have launched the pandemic, but understanding how to silence it could be the key to ending its legacy.