The research highlights the emergence of immune-evasive SARS-CoV-2 variants in immunocompromised patients

The research highlights the emergence of immune-evasive SARS-CoV-2 variants in immunocompromised patients

New research to be presented next week at the ESCMID Global Congress (formerly ECCMID) in Barcelona, ​​Spain (April 27-30) highlights the risk of new immune-evasive SARS-CoV-2 variants emerging in immunocompromised patients. The report is by PhD student Magda Vergouwe, Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Center (Amsterdam UMC), University of Amsterdam, Netherlands, and colleagues.

They describe the prolonged viral development in a patient infected with SARS-CoV-2 over 613 days, which led to a heavily mutated new variant. To the authors' knowledge, this is the longest duration of SARS-CoV-2 infection to date, although several cases lasting hundreds of days have already been recorded.

While healthy SARS-CoV-2 infected patients can clear the virus within days to weeks, an immunocompromised person can develop a persistent infection with prolonged viral replication and evolution. For example, the initial emergence of the Omicron variant is thought to have originated in an immunocompromised individual, highlighting the importance of close genomic monitoring in this patient population. Furthermore, the use of targeted immune pressure, including monoclonal antibody therapies and/or novel antiviral drugs, may further promote the emergence of viral escape variants.

In their report, Vergouwe and colleagues describe a 72-year-old immunocompromised male patient admitted to the University Hospital Amsterdam in February 2022 with a SARS-CoV-2 infection. He was considered immunocompromised due to a history of allogeneic stem cell transplantation for treatment of myelodysplastic and myeloproliferative overlap syndrome. This was complicated by the development of lymphoma after the transplant, for which he received rituximab, which depletes all available B cells, including those that normally produce the antibodies directed against SARS-CoV-2.

He had previously received several SARS-CoV-2 vaccinations without there being a measurable SARS-CoV-2 IgG antibody reaction upon hospital admission. Routine genomic surveillance revealed infection with the Omicron SARS-CoV-2 variant BA.1.17. He received treatment with the anti-SARS-CoV-2 antibody sotrovimab, the anti-IL6 antibody sarilumab, and dexamethasone without clinical response.

Subsequent SARS-CoV-2 sequencing showed the development of the known sotrovimab resistance mutation S:E340K as early as 21 days after receiving the sotrovimab infusion. SARS-CoV-2-specific T cell activity and anti-spike antibody development were minimal in the first month, suggesting that the patient's immune system was unable to clear the virus. The ongoing infection has led to the emergence of a new immune-evasive variant due to extensive evolution within the host. Ultimately, the patient died due to a relapse of his hematological disease after remaining SARS-CoV-2 positive with high viral load for a total of 613 days. Fortunately, there has been no documented transmission of the highly mutated variant to secondary cases in the community.

More specifically, the 613 days after the first detection of SARS-CoV-2 were characterized by multiple SARS-CoV-2-related and unrelated symptomatic episodes requiring hospitalization. The persistent SARS-CoV-2 infection caused the patient to have longer periods of isolation and increased use of personal protective materials during hospitalization, which significantly impaired his self-reported quality of life. Whole genome sequencing of SARS-CoV-2 was performed on 27 nasopharyngeal samples collected from February 2022 to September 2023. This identified over 50 nucleotide mutations compared to BA.1 variants currently circulating worldwide with multiple amino acid substitutions, including the ACE-2 receptor binding site substitutions S:L452M/K and S:Y453F. Furthermore, multiple deletions developed in the N-terminal domain of Spike, suggesting immune escape.

The authors say: “This case highlights the risk of persistent SARS-CoV-2 infections in immunocompromised individuals, as unique SARS-CoV-2 virus variants can emerge due to extensive evolution within the host. We emphasize the importance of continued genomic monitoring of SARS-CoV-2 evolution in immunocompromised individuals with persistent infections, given the potential public health threat posed by the introduction of viral escape variants into the community.“

Although close surveillance is needed, the authors emphasize that there must be a balance between protecting the public from potential new variants and humane supportive care at home for critically ill patients at the end of life. Possible solutions may include increased awareness of potential risks combined with the provision of early accessible diagnostic testing to known (family) contacts as soon as they develop relevant symptoms. This should be combined with genomic surveillance to assess the threat to public health together with public health experts. The authors emphasize that while there may be an increased risk of new variants developing in immunocompromised patients, not every new variant in these patients will develop into a novel variant of concern (VOC) for the community. The underlying mechanisms involved in the development of a VOC are much more complex as they also depend on factors in the population surrounding the patient, including the prevalence of B- and T-cell-related immunity.

The authors conclude: “The duration of a SARS-CoV-2 infection in this case described is extreme, but longer infections occur much more frequently in immunocompromised patients than in the general population. Our team's further work includes describing a cohort of long-lasting infections in immunocompromised patients from our hospital with infection durations between 1 month and 2 years. However, from the perspective of the general public, persistent infections remain rare because the immunocompromised population represents a very small percentage of the total population.“

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