Evolution of a globally unique SARS-CoV-2 Spike E484T monoclonal antibody escape mutation in a persistently infected, immunocompromised individual

Abstract

Prolonged infections in immunocompromised individuals may be a source for novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants, particularly when both the immune system and antiviral therapy fail to clear the infection and enable within-host evolution. Here we describe a 486-day case of SARS-CoV-2 infection in an immunocompromised individual. Following monotherapy with the monoclonal antibody Bamlanivimab, the individual's virus acquired resistance, likely via the earliest known occurrence of Spike amino acid variant E484T. Recently, E484T has arisen again as a derivative of E484A in the Omicron Variant of Concern, supporting the hypothesis that prolonged infections can give rise to novel variants long before they become prevalent in the human population.

Keywords: SARS-CoV-2; Spike protein; antibody escape; immunocompromised host; novel mutation; prolonged infection.

Figure 1.

(A) RT-qPCR cycle threshold values for patient nasopharyngeal swab specimens collected over more than 400 days of follow-up. The vertical line marks Post-diagnosis Day 198, when the patient received the Bamlanivimab intravenous mAb treatment (700 mg). The dotted line on Post-diagnosis Day 432 indicates a positive PCR test but no available Ct value. Note that Ct values are inverted to correspond with the inverse relationship between PCR Ct threshold value and nasal RNA copy number. (B) Timeline of clinically relevant information for the patient’s chronic infection, including symptoms, therapeutics, and hospitalizations.

Figure 2.

(A) Consensus-level mutations (present in >50% of reads) across the SARS-CoV-2 genome throughout infection of the immunocompromised individual. Gray points represent consensus-level mutations that persisted throughout all sampled time points and may have been inherited from the infecting lineage. Black points represent consensus-level mutations that emerged or disappeared during the chronic infection. The vertical red line at Day 198 represents Bamlanivimab intravenous mAb treatment (700 mg). Amplicon dropouts are depicted as white horizontal bars. Consensus-level E484T mutations in Spike are shown as triangles. (B) Globally subsampled SARS-CoV-2 phylogeny with chronically infected patient’s twelve virus sequences. Patient sequences are indicated with enlarged dots toward the bottom of the tree. The patient’s virus descends from an ancestor in the lineage B.1.2. The phylogeny was constructed using UShER (https://genome.ucsc.edu/cgi-bin/hgPhyloPlace), a tool that allows rapid placement of sequences on the SARS-CoV-2 phylogeny. (C) The concentration of four commercially available antibody treatments required to neutralize 99% of the chronically infected patient’s SARS-CoV-2. While Etesevimab (Eli Lilly), Casirivimab (Regeneron), and Imdevimab (Regeneron) were able to neutralize virus near or below 1 μg/ml, Bamlanivimab was unable to neutralize the virus at concentrations as high as 10 μg/ml, indicating antibody escape after the previous Bamlanivimab treatment.