The world is watching the evolution of SARS-CoV-2 as it moves around the globe, with new variants becoming important factors in the path of the pandemic. But how does the virus evolve over the course of one infection? A team of scientists sought to answer that question by analyzing the genomes of the virus over the course of the infection in one immunosuppressed patient.

The data suggest that treatment with convalescent plasma coincided with the emergence of different variants of SARS-CoV-2 in the immunosuppressed individual. After plasma therapy, the dominant variant included a deletion present in the B.1.1.7 SARS-CoV-2 variant discovered in the U.K. The findings raise the possibility that evolution of SARS-CoV-2 can occur in immunosuppressed individuals when prolonged viral replication can take place.

This work is published in Nature in the article, “SARS-CoV-2 evolution during treatment of chronic infection.

Ravindra Gupta, MD, PhD, of the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID) in Cambridge, U.K., and the Africa Health Research Institute in Durban, South Africa, and colleagues document a case study involving an immunocompromised male patient in their seventies with SARS-CoV-2, who had previously received chemotherapy for lymphoma.

The individual was admitted to the hospital in the summer of 2020 and was unsuccessfully treated with antibiotics, steroids, and courses of remdesivir and convalescent plasma therapy over the course of 101 days.

During treatment, the authors collected samples of the virus on 23 occasions. The infecting variant of SARS-CoV-2 was assigned to the lineage 20B, which bears the mutation that leads to the D614G substitution in the spike protein (a mutation that was first reported in China).

Little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days, the authors noted. However, they found that between days 66 and 82, after administration of the first two rounds of convalescent plasma, a shift in the virus population was observed.

They observed large, dynamic virus population shifts, with the emergence of a dominant viral strain variant with two alterations in the spike protein—a deletion at position 69/70 (ΔH69/ΔV70) which is present in the U.K. variant B.1.1.7, and the mutation that leads to the D796H substitution.

In vitro, the authors explained, the spike escape double mutant bearing ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility but incurred an infectivity defect. Moreover, the ΔH69/ΔV70 single mutant had two-fold higher infectivity compared to wild type, possibly compensating for the reduced infectivity of D796H.

This population re-emerged after a third course of remdesivir (day 93) and plasma (day 95).

The authors noted that, “as passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma.”

The authors suggested that the repeated increase in the frequency of this viral population after plasma therapy may mean that the mutations conferred a selective advantage. However, they concluded that the emergence of this variant was not the primary reason for the failure of the treatment.

The authors noted that this is a single case study and therefore limited conclusions can be drawn about the generalizability of the results. However, the findings might warrant caution in the use of convalescent plasma to treat SARS-CoV-2 infections in immunosuppressed patients.

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