Long COVID linked to persistence of SARS-CoV-2 spike protein in blood

The coronavirus disease 2019 (COVID-19), which is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can lead to a wide spectrum of clinical features, ranging from asymptomatic infection to life-threatening or fatal disease. In fact, some patients continue to be symptomatic for weeks or months following their clinical recovery.

This syndrome is called post-acute sequelae of COVID-19 (PASC) or long COVID. A new Clinical Infectious Diseases study reports SARS-CoV-2 spike antigen and cytokine levels in a sample of infected individuals, of which a subset had long COVID.

Study: Persistent Circulating SARS-Cov-2 Spike Is Associated with Post-Acute COVID-19 Sequelae. Image Credit: Donaldb / Shutterstock.com

Study: Persistent Circulating SARS-Cov-2 Spike Is Associated with Post-Acute COVID-19 Sequelae. Image Credit: Donaldb / Shutterstock.com


While most SARS-CoV-2-infected individuals recover, a considerable proportion continues to experience persistent symptoms that can affect various organ systems for different periods of time after convalescence. Long COVID may affect as many as 25% of infected people, about 10% of whom still report persistent symptoms four months after recovery.

The cause of long COVID remains unknown; thus, scientists are exploring potential biomarkers that could help categorize which patients are at higher risk for PASC. The current study aimed to assess the levels of SARS-CoV-2 antigens and cytokines to identify marker molecules for each type of patient presentation.

The current study included 63 samples obtained from 37 patients with PASC and 26 patients with a history of acute COVID-19. Most of the PASC patients were female. Only two patients had been hospitalized with PASC, thus indicating that few suffered severe illness.

Samples were collected for up to one year and five months, respectively, after the initial COVID-19 diagnosis. The researchers measured viral antigen levels and a 10-cytokine panel from each plasma sample. The viral antigens included the S1 spike subunit, full-length spike, and nucleocapsid (N) antigens.

Study findings

About 67% of PASC patients had one of the viral antigens present within their plasma at any time point following recovery from acute infection. The spike antigen was detected most frequently in 60% of PASC patients; however, it was not detected in the plasma of any acute COVID-19 patient. Conversely, the S1 subunit was observed in about 20% of PASC patients, with the N protein reported in only one patient.

Both S1 and N antigens were present in acute COVID-19 samples, often in the first week of illness, as well as among those who required hospitalization for severe illness.

In follow-up samples taken from 12 PASC patients and six COVID-19 patients, the S1 antigen was also observed. Earlier, the researchers had shown that the presence of S1 is associated only with the first dose of vaccination, with the spike protein rarely identified in patient samples following vaccination.

In contrast, the spike antigen was identified for several months in many of the PASC patients, while others exhibited fluctuating levels of this antigen. This observation emphasizes the importance of correlating results with the time of sampling.

SARS-CoV-2 antigens were found in almost 75% of patients with current cardiovascular, systemic, or musculoskeletal symptoms, as well as those with head, eye, ear, nose, or throat (HEENT) symptoms. Acute gastrointestinal (GI) or neuropsychiatric symptoms were also associated with a high chance of antigen detection. When a greater number of organs were affected, antigen detection was much more likely.

Spike antigen levels in acute COVID-19 patients were high immediately after diagnosis, with the levels waning rapidly thereafter to undetectable levels. The cytokine panel failed to show any significant change from the normal range.

The small size of the study is a major limitation; however, detection of the spike antigen in the blood several months following the initial infection and fluctuating antigen levels over time are significant findings from the study. These effects are likely due to the infection itself, rather than the weakness and debility of severe illness.

The study cohorts were not well-matched for sampling time, with most COVID-19 patients sampled in the first month after diagnosis and many having been hospitalized prior to sample collection. Thus, further research will be needed to validate the study findings.


The finding that the spike antigen is circulating in the blood strengthens the possibility of persistent SARS-CoV-2 infection in the body from a viral reservoir. Autopsy results have shown SARS-CoV-2 to be present in multiple body tissues up to seven months from diagnosis. Children with a diagnosis of multisystem inflammatory syndrome (MIS-C) several weeks following infection also exhibited higher levels of the spike protein in the blood, presumably from a leaky gut.

This has also been observed in the feces of recovered patients, who have been shown to shed SARS-CoV-2 through this route for at least seven months following their initial infection. This phenomenon, along with an explanation for the absence of the N antigen, must be explored further and validated.

Some researchers believe that the persistent circulation of the SARS-CoV-2 spike protein is due to the increased efficiency of spike transport into the blood, while the N antigen is broken down more rapidly. The spike has been shown to be transported within vesicles in the blood, thus preventing its degradation.

Conversely, antibody-mediated clearance of the N antigen may occur at a higher rate than that of the spike. However, this is unlikely, as high neutralizing titers do not preclude spike detection.

A final hypothesis is that since PASC involves several organ systems, the site of viral replication may determine which antigen is detectable.

PASC symptoms may be due to spike-induced hyperinflammation resulting from altered activation of the T-cell receptor repertoire by superantigen-like spike motifs. Without causing a cytokine storm, this may lead to malfunction of the vascular lining cells and blood-brain barrier (BBB).

Another explanation is cellular exhaustion or prolonged inflammation that produces localized dysfunction of specific tissues. Such focal inflammatory processes may account for the largely normal cytokine profile in circulating blood. For this reason, larger studies should employ longitudinal blood sampling to confirm the persistence of the viral spike in PASC patients.

Even if this is not due to an active viral reservoir, detection of the spike protein could be used to predict the occurrence of PASC following COVID-19, thus enabling preventive and treatment strategies to be adopted in a timely manner.

Journal reference:
  • Swank, Z., Senussi, Y., Manickas-Hill, Z., et al. (2022). Persistent Circulating SARS-Cov-2 Spike Is Associated with Post-Acute COVID-19 Sequelae. Clinical Infectious Diseases. doi:10.1093/cid/ciac722.
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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