Genome-first detection of emerging resistance to novel therapeutic agents for SARS-CoV-2

Abstract

Some COVID-19 patients are unable to clear their infection or are at risk of severe disease, requiring treatment with neutralising monoclonal antibodies (nmAb) and/or antivirals. The rapid roll-out of novel therapeutics means there is limited understanding of the likely genetic barrier to drug resistance. Unprecedented genomic surveillance of SARS-CoV-2 in the UK has enabled a genome-first approach to the detection of emerging drug resistance. Here we report the accrual of mutations in Delta and Omicron cases treated with casirivimab+imdevimab and sotrovimab respectively. Mutations occur within the epitopes of the respective nmAbs. For casirivimab+imdevimab these are present on contiguous raw reads, simultaneously affecting both components. Using surface plasmon resonance and pseudoviral neutralisation assays we demonstrate these mutations reduce or completely abrogate antibody affinity and neutralising activity, suggesting they are driven by immune evasion. In addition, we show that some mutations also reduce the neutralising activity of vaccine-induced serum.

Host immunological responses facilitate development of SARS-CoV-2 mutations in patients receiving monoclonal antibody treatments

“…Fifth, sotrovimab-receiving BA.1-infected patients had more robust SARS-CoV-2-specific Th cell immunity likely due to lack of SARS-CoV-2 neutralization. And, lastly, possible non-neutrality of some mutations described in the study are supported by prior reports on same or similar mutations [28][29][30][31][32][33][34][35] (see Supplementary Table 6). Amino acid residues typically observed in Omicron variants reverting back to those of the original Wuhan sequence (D339G, L371S, P373S, F375S, N417K, and K440N) are equally interesting, also observed previously 5 , supporting our seroneutralization data showing that sotrovimab is not active against Wuhan and some of the de-escalated variants.…”

“…Additionally, prolonged carriage in severely ill patients with high viral loads has been suggested to favor development and selection of mutants 27 . Several reports have highlighted an emergence of de novo mutations under mAb pressure, including E484Q/K and Q493K/R under bamlanivimab/etesevimab pressure [28][29][30] ; P337R/S, E340D/K/V, G446S/V under casirivimab/imdevimab and/or sotrovimab pressure [31][32][33][34] ; and substitutions of residues 346, 444, and 452 under tixagevimab/cilgavimab pressure 35 . However, the role of host immune pressure in selection of mAb-driven de novo SARS-CoV-2 mutations is not well studied.…”

Host immunological responses facilitate development of SARS-CoV-2 mutations in patients receiving monoclonal antibody treatments

“…Fifth, sotrovimab-receiving BA.1-infected patients had more robust SARS-CoV-2–specific Th cell immunity, likely due to lack of SARS-CoV-2 neutralization. And, lastly, possible non-neutrality of some mutations described in the study are supported by prior reports on identical or similar mutations (24-30) (see Supplementary Table 4). Amino acid residues typically observed in Omicron sub-variants reverting back to those of the original Wuhan sequence (D339G, L371S, P373S, F375S, N417K, and K440N) are equally interesting, some of which have also been observed previously (17), supporting our seroneutralization data showing that sotrovimab is not active against Wuhan and some of the other de-escalated variants.…”

“…These modifications target highly conserved epitopes on Spike causing conformational transitions necessary for association with the ACE2 receptor (15), resulting in reduced risk of disease progression and death (13,15). Several reports have also identified de novo mutations under therapeutic mAb pressure, including E484Q/K and Q493K/R under bamlanivimab/etesevimab pressure (24)(25)(26) and P337R/S, E340D/K/V, and G446S/V under casirivimab/imdevimab and/or sotrovimab pressure (27)(28)(29)(30). However, despite the widespread use of mAbs, these studies are rather few, and were conducted in limited number of patients.…”

“…Several reports have also identified de novo mutations under therapeutic mAb pressure, including E484Q/K and Q493K/R under bamlanivimab/etesevimab pressure (24-26) and P337R/S, E340D/K/V, and G446S/V under casirivimab/imdevimab and/or sotrovimab pressure (27-30). However, despite the widespread use of mAbs, these studies are rather few, and were conducted in limited number of patients.…”