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Persistent spike protein may account for long COVID

8th July 2022

The presence of persistent spike protein has been detected in patients with long COVID and might account for continued symptoms

The continued presence of spike protein in patients with long COVID may be responsible for their persistent symptoms and serve as a biomarker for the condition according to a small scale study by researchers from Boston, US.

Although many millions of people who have been infected with COVID-19 make a full recovery, for some, symptoms may continue and they develop a wide range of persistent symptoms that fail to resolve over the course of many months. Such patients are diagnosed with long COVID or post-acute sequelae of COVID-19 (PASC). The World Health Organization have described what it terms ‘post COVID-19 condition’ defined as occurring in individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis. The cause of PASC remains to be determined although many theories have been proposed including tissue persistence of viral antigen, systemic and tissue localised inflammatory responses, reactivation of human herpesviruses (e.g., Epstein-Barr virus), alterations in the gut microbiome, issues related to clotting, and the interplay between SARS-CoV-2-specific and auto-reactive immunity. Nevertheless, untangling the complex biology involved may be assisted through the identification of biomarkers in those with PASC.

In the present study, the US team analysed plasma samples from patients with PASC and for comparative purposes those who had been infected with COVID-19 but made a full recovery. The researchers measured the levels of three antigens: the S1 subunit of spike, full length spike protein and nucleocapsid (N).

Spike protein levels in PASC

The study included a sample of 37 PASC patients with a median age of 46 years (81% female) and 26 (median age 63, 38% female) without PASC.

For the PASC patients, blood samples were collected two or more times up to 12 months after their initial PCR confirmed COVID-19 infection. Blood samples were collected from individuals who had COVID-19 but not PASC, up to five months post-diagnosis.

The team were able to detect either S1, full length spike protein or N in roughly 65% of PASC patients at any given point in time, several months post-COVID-19. For the 3 antigens however, spike protein was detected in 60% of PASC patients, whereas S1 was detected to a lesser extent and N only in a single patient at different time points. Spike protein was undetectable in those who had fully recovered from COVID-19 although both S1 and N were found.

In cases where PASC patients had blood samples collected a multiple time points, all three antigens could be detected several months after the acute infection, although spike protein was detected most often over time.

Commenting on these results, the authors noted how circulating levels of spike protein in the majority of PASC patients but none of those without PASC was compelling. Given that only two patients with PASC had been hospitalised, these results suggested the continued presence of spike protein was associated with COVID-19 infection per se rather than the severity of infection. The authors added that detection of spike protein was likely to indicate that PASC is associated with a reservoir of active virus and which persisted in the body.

The authors concluded that spike protein could potentially serve as a biomarker for PASC although further studies with larger patient cohorts were required to confirm these findings.

Citation
Swank Z et al. Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae MedRxiv 2022

RNA aptamer binds to COVID-19 spike protein preventing cellular entry

17th December 2021

An RNA aptamer has been developed which attaches to the spike protein and the receptor binding domain of COVID-19 preventing entry into cells

An RNA aptamer which specifically binds to the spike protein and the receptor binding domain (RBD) of COVID-19 has been found to block entry of the virus into cells and could serve as a promising treatment for the virus, according to researchers from the Interdisciplinary Nanoscience Center, Aarhus University, Denmark.

RNA aptamers (RNA AP) are RNA oligonucleotides (i.e., single strands of RNA) that bind to a specific target with high affinity and specificity in much the same way that an antibody binds to an antigen and RNA aptamers have been used previously both diagnostically and therapeutically in the management of viruses.

For the present study, the Danish researchers described the development of a serum-stable RNA AP, RDB-PB6, which binds with nanomolar affinity to the RBD of the COVID-19 spike protein and in doing so, neutralises infectivity of the virus. The aptamer contains 2-fluoropyrimidine modifications which increases its chemical stability and resistance to degradation by viral nucleases. The researchers developed the RNA AP to specifically target the spike protein which is used by COVID-19 to bind with the angiotensin converting enzyme 2 (ACE2) to gain entry into cells. Their analysis revealed how RBD-PB6 bound with high affinity to the virus RBD alone but also interacted with the spike protein. The binding with the spike protein was confirmed in a separate experiment and again demonstrated that once bound to the spike protein, this complex was unable to interact with the ACE2 receptor.

Using virus-like particles the researchers were able to show that RBD-PB6 did not bind with other viruses such as the Middle East Respiratory syndrome (MERS) or Severe Acute Respiratory Syndrome (SARS) suggesting that the agent was highly specific, for COVID-19 displaying no cross-reactivity despite the similarity in the RBD sequence of these two coronaviruses.

Finally, the Danish team examined whether RBD-PB6 could bind to COVID-19 variants and tested this with the alpha and beta variants. They demonstrated high affinity binding between RBD-PB6 and the two variants indicating that these mutated strains were still able to recognise RBD-BP6.

The authors described how RBD-PB6 was very easy to mass produce and in a fast and reproducible way using conventional synthetic methods, adding that it was a potentially less expensive treatment compared to monoclonal antibodies. They concluded that their RNA aptamer provided a promising lead for COVID-19 treatment and a cost-effective platform for the rapid diagnosis of the virus.

Citation

Valero J et al. A serum-stable RNA aptamer specific for SARS-CoV-2 neutralizes viral entry PNAS 2021