Alessandro M Carabelli, David L Robertson and Sharon Peacock
In recent work from COG-UK consortium investigators, released as a pre-print, Professor Ravindra Gupta and colleagues investigated SARS-CoV-2 evolution in a single immunosuppressed individual treated with convalescent plasma. Here, we explain the results of the study and what they could mean for the COVID-19 pandemic.
Administration of blood plasma collected from people who have recovered from SARS-CoV-2 (also known as convalescent plasma) transfers anti-SARS-CoV-2 antibodies to those with active infection in an attempt to neutralise the virus and treat disease (Ref 1). Convalescent plasma has been used for over 100 years in the treatment of other infectious diseases. Following early studies during the COVID-19 pandemic, this therapy has been shown to improve the clinical outcomes in people with severe COVID-19 disease, but not in the people with moderate disease (Ref 2, Ref 3 and Ref 4).
All viruses, including SARS-CoV-2, accumulate mutations as they evolve over time. Most mutations have no detectable effect on the biology of the virus. But a few have the potential to change the virus in minor ways and be spread to other hosts. But what are the drivers of viral evolution, and could antibody treatment have any influence on this process?
In recent work from COG-UK consortium investigators, released as a pre-print, Professor Ravindra Gupta and colleagues investigated SARS-CoV-2 evolution in a single immunosuppressed individual treated with convalescent plasma (Ref 5). The vast majority of SARS-CoV-2 infections are usually acute and the virus is cleared in a few weeks. Here, the virus was detected in 23 samples from the same patient over a period of 101 days from the first positive test to the day that the patient regrettably died.
The virus population identified from this patient did not mutate detectably over the first 65 days, possibly due to two courses of the antiviral drug remdesevir, the action of which is through the inhibition of virus replication. The patient did not improve and was given three treatments with convalescent plasma, two on day 65 and one on day 95, that failed to clear the virus infection. Following each convalescent plasma treatment important changes in the virus genome were observed, with the emergence of a viral variant bearing two mutations in the Spike protein: a two amino acid deletion (at positions 69-70) and one amino acid replacement in position 796 (D796H). These may be important changes because the Spike protein is used by the virus to bind host cells and is targeted by most of the antibodies from COVID-19 recovered plasma and vaccines. The Spike 69-70 deletion has been observed many times in circulating viruses.
Laboratory experiments with viruses carrying these mutations confirmed that the variant has a decreased sensitivity to convalescent plasma administered to the patient and sera from different recovered patients compared with the non-mutated virus. Importantly, in laboratory experiments the virus carrying the combination of mutations was as infectious as other SARS-CoV-2 variants in general circulation.
This study of a chronic SARS-CoV-2 infection represents a rare insight into virus evolution likely driven under the pressure of convalescent plasma. Given that therapeutics (vaccines and antibody-based) mainly target the SARS-CoV-2 Spike protein, this provides evidence for an increased chance of escape mutants being generated in persistent infections, and the need for careful monitoring of their transmission and potential to evade vaccines-mediated immunity.
References
- https://www.thelancet.com/article/S1473-3099(20)30141-9/fulltext
- https://www.pnas.org/content/117/17/9490
- https://www.nature.com/articles/s41591-020-1088-9
- https://www.bmj.com/content/371/bmj.m4072
- https://www.medrxiv.org/content/10.1101/2020.12.05.20241927v1
COVID-19 Genomics UK (COG-UK)
The current COVID-19 pandemic, caused by the SARS-CoV-2, represents a major threat to health. The COVID-19 Genomics UK (COG-UK) consortium has been created to deliver large-scale and rapid whole-genome virus sequencing to local NHS centres and the UK government.
Led by Professor Sharon Peacock of the University of Cambridge, COG-UK is made up of an innovative partnership of NHS organisations, the four Public Health Agencies of the UK, the Wellcome Sanger Institute and twelve academic partners providing sequencing and analysis capacity. A full list of collaborators can be found here: https://www.cogconsortium.uk/about/. Professor Peacock is also on a part-time secondment to PHE as Director of Science, where she focuses on the development of pathogen sequencing through COG-UK.
COG-UK was established in March 2020 supported by £20 million funding from the UK Department of Health and Social Care (DHSC), UK Research and Innovation (UKRI) and the Wellcome Sanger Institute, administered by UK Research and Innovation. For more information, visit: https://www.cogconsortium.uk
