Preprint Long-term serum spike protein persistence but no correlation with post-COVID syndrome, 2024, Fehrer, Scheibenbogen+

[SNT Gatchaman]

Long-term serum spike protein persistence but no correlation with post-COVID syndrome
Annick Fehrer; Franziska Sotzny; Friederike Hoheisel; Elisa Stein; Laura Kim; Claudia Kedor; Helma Freitag; Cornelia Heindrich; Sandra Bauer; Rebekka Rust; Martina Seifert; Patricia Grabowski; Nina Babel; Carmen Scheibenbogen; Kirsten Wittke

According to the World Health Organization (WHO) and the Centers for Diseases Control and Prevention (CDC), currently an estimated 3 -6 % of people suffer from post-COVID condition or syndrome (PCS). A subset meets diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Several studies have reported persistence of SARS-CoV-2 proteins or RNA in serum or tissues of both recovered individuals and PCS patients. In this exploratory study, we investigated whether serum spike protein is associated with PCS and whether it correlates with symptom severity and laboratory biomarkers.

We analyzed serum spike protein levels in 121 PCS patients following mild-to-moderate COVID 19, 72 of whom met diagnostic criteria for ME/CFS (post-COVID ME/CFS, pcMECFS). Pre-pandemic seronegative healthy controls (ppHC, n = 32) and post-COVID recovered healthy controls (pcHC, n = 37) after SARS-CoV-2 infection were also included in the study.

We found persistent serum SARS-CoV-2 spike protein in a subset of pcHC (11 %), PCS non-ME/CFS patients (2 %), and pcMECFS patients (14 %). There was no significant association with disease severity, symptoms, or laboratory markers. The spike protein concentration was independent of the time since last spike exposure (infection or vaccination). In five spike-positive out of a total of 22 patients who underwent immunoglobulin depletion via immunoadsorption (IA), spike protein was reduced or completely removed after treatment, indicating binding to immunoglobulins.

In summary, our study identified serum spike protein in a subset of patients after SARS-CoV-2 infection without evidence for a role in the pathogenesis of PCS.


Link | PDF (Preprint: MedRxiv) [Open Access]

 

[EndME]

Interesting that they mention no relationship between spike protein concentration to time since last exposure. Could of course be very difficult to quantify as the correct description is likely "time since last known exposure", but I do think it contradicts some other results previously seen.

 

[RedFox]

This paper might be important by making the viral persistence hypothesis more difficult to support. If the authors are right, then some people have remnants of the spike protein but it has little to no influence on the disease.

 

[rvallee]

This paper might be important by making the viral persistence hypothesis more difficult to support. If the authors are right, then some people have remnants of the spike protein but it has little to no influence on the disease.

Viral persistence is probably not very significant in circulating blood. Lots of other viruses are for life, can be found in organs and some cells, how many of them are found circulating in the blood? Even their proteins?

It limits the potential for easy identification, but I don't think it means much in terms of viral persistence.

 

[EndME]

Viral persistence is probably not very significant in circulating blood. Lots of other viruses are for life, can be found in organs and some cells, how many of them are found circulating in the blood? Even their proteins?

It limits the potential for easy identification, but I don't think it means much in terms of viral persistence.

I think the crucial point may be that it is precisely such circumstantial evidence that lead people down the viral persistence route in the first place and thus far none of this evidence has stood the test of time (Simoa, Paxlovid etc were all the initial motivators and subsequent studies have not yielded any meaningful results).

That doesn't mean it can't be viral persistence but perhaps instead of continuously going down the same path, initially motivated by evidence that has since been found to be noise, one ought to asks oneself is there any evidence left that makes following this path meaningful and especially what one can learn from all of the past mistakes where evidence for viral persistence was presumably based on qualitatively bad research.

 

[Mij]

2025
LINK

 

[Utsikt]

Original conclusion in abstract:

In summary, our study identified serum spike protein in a subset of patients after SARS-CoV-2 infection without evidence for a role in the pathogenesis of PCS.

New conclusion in abstract:

In summary, this study identified serum spike protein in a subset of patients but found no association with ME/CFS

They went from the broad ‘pathogensis of PCS’ to a more narrow ‘association with ME/CFS’.

Why?

 

[Jonathan Edwards]

The spike protein concentration was independent of the time since last spike exposure (infection or vaccination).

This is a very odd finding. If anything I think it casts doubt on the validity of the assays. It is hard to think of a theoretical model in which there is no decline in spike protein after exposure.

The removal of spike protein with immunoadsorption is also peculiar.

 

[forestglip]

This is a very odd finding. If anything I think it casts doubt on the validity of the assays. It is hard to think of a theoretical model in which there is no decline in spike protein after exposure.

Next, a potential relationship between serum SARS-CoV-2 spike protein and time since last infection or vaccination in all three post-COVID study groups (pcHC, PCS, and ME/CFS) was investigated. Neither the time since the last SARS-CoV-2 infection (Figure 2A), time since last SARS-CoV-2 vaccination (Figure 2B), nor time since last spike protein contact by either infection or vaccination (Figure 2C) correlated with the serum spike protein presence or concentration. Furthermore, there was no correlation between the time since the illness-triggering SARS-CoV-2 infection and serum spike protein concentration in PCS or ME/CFS patients (Figure 2D).

We found spike protein in serum to be independent of the time since the last SARS-CoV-2 infection or vaccination. This suggests that spike protein presence is independent of a recent exposure, but rather depends on individual differences in viral clearance, or persisting viral reservoirs, which needs to be clarified by further investigation.

 

[Utsikt]

Whole blood samples from participants were allowed to clot at room temperature for at least 30 min and then centrifuged at 2000× g for 10 min at room temperature.

@Jonathan Edwards could different clotting durations lead to different measurements?

Room temp is also not very specific, could that affect things if the samples are processed over multiple days or periods?

 

[Utsikt]

They went from the broad ‘pathogensis of PCS’ to a more narrow ‘association with ME/CFS’.

Why?

Answer: they did not assess the non-ME/CFS-PCS. The pre-print seemingly went beyond the evidence.

The 49 PCS patients not fulfilling ME/CFS criteria were not analyzed as there was only 1 spike-positive patient in this study group.

 

[Jonathan Edwards]

The results look very peculiar. There seem to be two grades of positivity.
I have no idea how to interpret but it doesn't seem to be the secret to Long Covid.

 

[Andy]

2025
LINK

New title for published version is "Serum Spike Protein Persistence Post COVID Is Not Associated with ME/CFS".

 

[SNT Gatchaman]

The spike protein concentration was independent of the time since last spike exposure (infection or vaccination).

This is a very odd finding. If anything I think it casts doubt on the validity of the assays. It is hard to think of a theoretical model in which there is no decline in spike protein after exposure.

Some other studies reporting persisting spike protein:

Immunological and Antigenic Signatures Associated with Chronic Illnesses after COVID-19 Vaccination (2025, Preprint: MedRxiv) —

Most notably, we found elevated levels of spike (S1 and full-length S) in circulation up to 709 days after vaccination among a subset with PVS, even in those with no evidence of detectable SARS-CoV-2 infection.

In our PVS-I group, anti-S antibody levels were lower in those with circulating S1. Why persistent spike antigen fails to elicit an antibody response, and what the source of persistent spike in circulation is, requires further investigation.

Circulating Spike Protein Detected in Post–COVID-19 mRNA Vaccine Myocarditis (2023, Circulation) —

In notable contrast, adolescents who developed myocarditis had markedly higher levels of free full-length spike protein in their plasma (33.9±22.4 pg/ mL), unbound by antibodies, whereas asymptomatic vaccinated control subjects had no detectable free spike protein (unpaired t test, P<0.0001). Although postvaccine myocarditis clinically occurs more commonly in males, elevated spike was seen equally in both affected females and males. […] Antibody-bound spike was detected in only ≈6% of the vaccinated control subjects. Similarly, we were not able to detect any free or antibody-bound spike in the healthy adult samples.

Measurement of circulating viral antigens post-SARS-CoV-2 infection in a multicohort study (2024, Clinical Microbiology and Infection) —

Of the 1569 samples analysed from 706 individuals infected with SARS-CoV-2, 21% (95% CI, 18–24%) were positive for either S1, spike, or nucleocapsid. Spike was predominantly detected, and the highest proportion of samples was spike positive (20%; 95% CI, 18–22%) between 4 and 7 months postinfection.

The findings of this multicohort study indicate that SARS-CoV-2 antigens can be detected in the blood of a substantial proportion of individuals up to 14 months after infection. While approximately one in five asymptomatic individuals was antigen-positive, roughly half of all individuals reporting ongoing cardiopulmonary, musculoskeletal, and neurologic symptoms were antigen-positive.