In a recently published article in The New England Journal of Medicine, scientists have described how multi-mutational variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may evolve in patients with immunosuppression.
Background
The risk of prolonged SARS-CoV-2 infection is considerably high in patients with immunosuppression, including cancer patients, organ transplant patients, and HIV-positive patients. Due to the suppressed functioning of the immune system, these patients have only partial immune control over SARS-CoV-2 infection, which can induce sudden and large mutational changes in the pathogen (saltation evolution).
In recently emerged SARS-CoV-2 variants of concern (VOCs), including the B.1.1.7, B.1.351, P1, and B.1.617.2, multiple spike mutations have been identified. This suggests that the prolonged course of infection in immunosuppressed patients may facilitate viral evolution, leading to the emergence of multi-mutational variants with increased infectivity, pathogenicity, and immune evasion ability.
As a proof of concept, scientists have identified 31 substitution mutations and 3 deletion mutations in the genome of SARS-CoV-2 isolated from an immunosuppressed patient with persistent SARS-CoV-2 infection for 152 days. A total of 12 spike mutations have been identified, including 7 in the receptor-binding domain (RBD). Importantly, some of these mutations have been found to associate with immune evasion.
Similarities in viral sequences derived from patients and variants of concern
Several major similarities have been identified in viral mutational patterns observed in immunosuppressed patients and SARS-CoV-2 VOCs. Whole-genome sequencing studies have revealed that in a given geographical location, the most recently emerged VOC contains significantly higher numbers of mutations compared to the previously dominant variant. Moreover, more than 40% of these mutations have been identified in the spike protein, which constitutes only 13% of the viral proteome. Because the spike protein is the main mediator of viral entry and the primary target of therapeutic and vaccine antibodies, a high mutational prevalence in this protein further supports the notion of adaptive viral evolution, especially in immunosuppressed patients.
Furthermore, convergent mutations, including deletions/substitutions in the N-terminal domain (NTD), NTD supersites, and RBD, have been observed in VOCs and in sequences isolated from immunosuppressed patients. Mutations appearing in these domains play crucial roles in increasing viral infectivity and immune escape. A very rapid evolution of VOCs and a high efficiency of VOCs to gain global predominance clearly highlight the selective advantage of convergent mutations.
The emergence of sub-lineages in these VOCs further indicates a shifting evolutional landscape wherein new sub-lineages can soon become dominant. One classic example, in this context, is the rapid transmission dynamics of the B.1.617.2 variant, which was first identified in India and soon became dominant worldwide. This variant contains a group of mutations that are also present in previously circulating VOCs.
Taken together, these observations indicate that in immunosuppressed patients, inadequate immune control can act as a positive selection pressure to trigger immune-escape mutations and subsequently facilitate the emergence of novel viral variants.
Thus, it is important to identify the association between types of immunosuppression therapies and the risk of immune-escape mutations.
How may escape variants impact public health?
As a potential reservoir of escape mutants, immunosuppressed patients with prolonged SARS-CoV-2 infection could potentially increase the risk of community transmission of novel immune-escape variants. As a precautionary measure, these patients and their family members/close contacts should be prioritized for the COVID-19 vaccination. Moreover, they should be properly informed about the importance of self-isolation until having a SARS-CoV-2-negative test result.
Regarding anti-SARS-CoV-2 immunity, studies have shown that cancer patients and the recipients of organ transplants have reduced ability to induce anti-spike antibody responses. Given these observations, more studies are needed to evaluate whether COVID-19 vaccines are effective in preventing SARS-CoV-2 infection and controlling prolonged viral replication in immunosuppressed patients. Similarly, it is important to develop next-generation vaccines against novel variants that can inhibit immune escape pathways.
Recurrence of SARS-CoV-2 infection with high viral load and reactivation of symptomatic COVID-19 has been reported in immunosuppressed patients. Viral isolates derived from such patients should be sequenced to identify potential immune-escape mutants.
What are the potential therapies for immunosuppressed patients?
One of the potential approaches to treat immunosuppressed COVID-19 patients is the use of combination monoclonal antibodies that have mutations in the Fc portion to increase the biological half-life and/or to improve SARS-CoV-2 neutralizing efficacy. Some monoclonal antibodies, including bamlanivimab, casirivimab, and imdevimab, have already received emergency use approval and have shown high potency in reducing disease progression, viral load, and viral shedding duration.
Another promising approach is the use of antiviral small molecules that target viral replication. One such agent is molnupiravir, which has shown promising results in two ongoing clinical trials.
Proper implementation of these therapies in immunosuppressed patients could offer an opportunity to mitigate the emergence of immune-escape variants. Moreover, continuous monitoring of viral sequence for rapid identification of resistance to these therapies is simultaneously required.
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