PhD student University of Cambridge School of Clinical Medicine Cambridge, United Kingdom
Disclosure(s):
Kimia Kamelian, MSc: No financial relationships to disclose
Introduction/Rationale: Monoclonal antibodies have emerged as a prophylactic strategy to prevent symptomatic SARS-CoV-2 infection in immunocompromised individuals. However, the evolutionary and clinical implications of breakthrough infections remain unclear.
Methods: An 80-year-old male with a haematological/oncological diagnosis received a 2000 mg intravenous infusion of sotrovimab in March 2023 and was diagnosed with COVID-19 by RT-qPCR from a nasopharyngeal swab in August 2023. Weekly samples (n=24) were collected through February 2024 (171 days). All samples underwent whole-genome sequencing, with select mutations subjected to functional assessment.
Results: Sequencing identified the GE.1 lineage at all timepoints. An intra-host recombination event in ORF1ab (positions 8980-11203) was detected 100-107 days post-infection, followed by a 14-fold increase in viral load (7.42E+06 to 1.00E+08 RNA copies/mL) and a marked shift in the mutation landscape. E340D, a sotrovimab-resistance mutation, fluctuated over time and was selected 107 days post-infection. We assessed five spike mutations – V36M, S98F, and V213G in the N-terminal domain, Y505P in the receptor-binding domain, and P681Q near the S1/S2 cleavage site—and additionally evaluated the impact of E340D. V36M conferred the highest infectivity across all cell lines, with the most significant effect in low-TMPRSS2 cells. While all mutations showed enhanced infectivity with the addition of E340D, the effect was most pronounced in mutations with lower baseline infectivity. The addition of E340D significantly decreased relative neutralizing titres for V36M, S98F, and V213G, enabling escape from neutralizing antibodies in XBB-responsive individuals. Patient neutralizing activity was absent pre-sotrovimab, and sotrovimab-induced neutralization was further compromised by selection of E340D.
Conclusion: Fixation of E340D abolished the surrogate defence provided by sotrovimab, eliminating neutralizing activity and exerting a positive epistatic effect on emerging mutations.
