SARS-CoV-2 evolution during treatment of chronic infection

Abstract

Summary SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2 1 , and is a major antibody target. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences over 23 time points spanning 101 days. Little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days. However, following convalescent plasma therapy we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and ΔH69/ΔV70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro , the Spike escape double mutant bearing ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility but incurred an infectivity defect. The ΔH69/ΔV70 single mutant had two-fold higher infectivity compared to wild type, possibly compensating for the reduced infectivity of D796H. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with evidence of reduced susceptibility to neutralising antibodies.

Mutation hotspots, geographical and temporal distribution of SARS-CoV-2 lineages in Brazil, February 2020-2021: insights and limitations from uneven sequencing efforts

“…Under specific circumstances, the combination of prolonged viral shedding with high selective pressure could lead to major evolutionary leaps. Critically ill and immunosuppressed patients chronically infected with SARS-CoV-2 and treated with convalescent plasma have been linked to viral breakthroughs caused by mutant viruses (Kemp et al 2021) . Whichever phenomena allow for rapid viral evolution, they probably have to permit multiple substitutions to occur almost simultaneously, since our phylodynamics analysis shows constant and relatively slow rates of mutation accumulation, except for VOC viruses.…”

The emergence and ongoing convergent evolution of the N501Y lineages coincides with a major global shift in the SARS-CoV-2 selective landscape

“…Such long-term infections are relatively common but mostly involve dead-end viral shedding into the digestive tract 49 . Occasionally, particularly in the context of immune-compromised patients 50,51 , these long-term infections also involve chronic upper respiratory tract infections with transmissible virus shedding. The local SARS-CoV-2 fitness landscapes within chronically-infected patients may be either softened, or shifted: perhaps because the main selective pressures within these patients are immunity evasion instead of transmission.…”

“…The apparent absence of substantial SARS-CoV-2 adaptations during the early pandemic would simply be a consequence of the durations of the chronic infections within which the progenitors of these lineages evolved. Chronic infections lasting between three and five months have been well documented [50][51][52][53] . Chronic infections that occurred in April 2020 when the first global peak of infections occurred might be expected to only yield substantially adapted variants by July or August 2020 which is approximately concordant with estimates of the times when the most recent common ancestors of viruses in the V2 lineage arose 7 .…”

Increased transmission of SARS-CoV-2 lineage B.1.1.7 (VOC 2020212/01) is not accounted for by a replicative advantage in primary airway cells or antibody escape

“…Deletions around position 144 have been observed during extended replication in vitro and withinhost evolution in immunocompromised patients, and have also been linked to escape from NTDtargeting antibodies (Andreano et al, 2020;Choi et al, 2020;Kemp et al, 2021;McCallum et al, 2021; preprint (which was not certified by peer review) is the author/funder. All rights reserved.…”