Yale Study Links Persistent Spike Protein to Post-Vaccination Syndrome, Immune Dysregulation

Findings Suggest Immune Imbalances and Viral Reactivation May Contribute to Chronic Symptoms After COVID-19 Vaccination

A new study from Yale University has identified distinct immunological patterns in individuals experiencing persistent health issues after COVID-19 vaccination, a condition called Post-Vaccination Syndrome (PVS). The findings, published on medRxiv, highlight immune dysregulation, increased markers of inflammation, and the unexpected persistence of spike protein in circulation months to years after vaccination.

The study, led by Akiko Iwasaki, PhD, and colleagues, examined 42 individuals with PVS alongside 22 healthy vaccinated controls through the Yale LISTEN study. Researchers found that a subset of PVS participants had detectable SARS-CoV-2 spike protein in their bloodstream, with some cases showing antigen persistence up to 709 days post-vaccination. This aligns with previous reports of long COVID, where prolonged spike protein exposure has been linked to chronic immune activation.

Beyond spike persistence, the study uncovered other immunological anomalies. Patients with PVS exhibited an increase in TNFα-expressing CD8+ T cells, a marker of heightened inflammation often associated with autoimmune-like activity. At the same time, they had significantly reduced levels of IL-4+ and IL-6+ CD4+ T cells, which are typically involved in immune regulation and anti-inflammatory responses. This imbalance may contribute to the widespread symptoms seen in PVS patients, including fatigue, neuropathy, cognitive dysfunction, and pain.

Another striking finding was the presence of Epstein-Barr virus (EBV) reactivation among PVS participants. Serological testing showed elevated anti-EBV gp42 IgG titers, suggesting that latent EBV infections may be reactivated in individuals experiencing post-vaccine symptoms. EBV reactivation has been implicated in a variety of post-viral syndromes, including long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and certain autoimmune conditions.

The study also reported significant reductions in key neuromodulatory factors, including fetuin A, neurotensin, and β-endorphins. These molecules play essential roles in regulating inflammation, pain perception, and neuroprotection, raising concerns that their depletion may exacerbate symptoms of chronic pain, brain fog, and fatigue observed in PVS patients.

Interestingly, lower anti-spike IgG antibody titers were observed in PVS participants, primarily due to fewer vaccine doses. This raises the question of whether this reflects an immune exhaustion phenomenon, a distinct immunological response, or a reluctance to receive further doses due to adverse reactions.

Although the study does not establish causation, the findings suggest that persistent antigen exposure and immune dysregulation may contribute to the prolonged symptoms seen in PVS. While most individuals tolerate COVID-19 vaccines well, a small subset appears to experience persistent immune activation, warranting further investigation.

These findings raise important questions about patient management for clinicians. There are currently no standardized treatment protocols for PVS but approaches targeting inflammation, viral reactivation, and immune modulation could be explored. The study’s authors emphasize the need for further longitudinal research to validate these findings and develop targeted therapeutic strategies.

As the scientific community continues to investigate post-viral syndromes, this research adds to a growing body of evidence suggesting that persistent spike protein, immune imbalances, and viral reactivation may play roles in chronic symptoms following SARS-CoV-2 infection and vaccination. More studies are needed to determine whether similar mechanisms underlie long COVID, PVS, and other post-viral conditions.

The full study is available on medRxiv

Bornali Bhattacharjee, Peiwen Lu, Valter Silva Monteiro, Alexandra Tabachnikova, Kexin Wang, William B. Hooper, Victoria Bastos, Kerrie Greene, Mitsuaki Sawano, Christian Guirgis, Tiffany J. Tzeng, Frederick Warner, Pavlina Baevova, Kathy Kamath, Jack Reifert, Danice Hertz, Brianne Dressen, Laura Tabacof, Jamie Wood, Lily Cooke, Mackenzie Doerstling, Shadan Nolasco, Amer Ahmed, Amy Proal, David Putrino, Leying Guan, Harlan M. Krumholz, Akiko Iwasaki

medRxiv 2025.02.18.25322379; doi: https://doi.org/10.1101/2025.02.18.25322379