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. 2023 Mar:160:105382.
doi: 10.1016/j.jcv.2023.105382. Epub 2023 Jan 26.

Genotypic and predicted phenotypic analysis of SARS-COV-2 Omicron subvariants in immunocompromised patients with COVID-19 following tixagevimab-cilgavimab prophylaxis

Eloy E Ordaya  1 , Paschalis Vergidis  2 , Raymund R Razonable  2 , Joseph D Yao  3 , Elena Beam  2
Affiliations

Genotypic and predicted phenotypic analysis of SARS-COV-2 Omicron subvariants in immunocompromised patients with COVID-19 following tixagevimab-cilgavimab prophylaxis

Eloy E Ordaya et al. J Clin Virol. 2023 Mar.

Abstract

Background: Tixagevimab-cilgavimab is used for pre-exposure prophylaxis of COVID-19 in immunocompromised patients, though in vitro data has shown reduced neutralizing activity against SARS-CoV-2 Omicron subvariants.

Methods: We performed genomic sequencing of SARS-CoV-2 isolated from patients diagnosed with COVID-19 following tixagevimab-cilgavimab. Resistance-associated substitutions were used to generate a predicted phenotypic susceptibility analysis to tixagevimab-cilgavimab and bebtelovimab. Clinical data collected from these patients included SARS-CoV-2 immunization status, COVID-19-directed therapies, and outcomes.

Results: SARS-CoV-2 genome sequencing was performed in 25 patients. SARS-CoV-2 Omicron BA.2 was the most common identified subvariant. All patients had viral isolates with spike codon substitutions associated with reduced susceptibility to tixagevimab-cilgavimab; their predicted phenotypic analysis showed a >2-fold reduced susceptibility to tixagevimab-cilgavimab. Two patients had viral isolates with spike codon substitutions (K444N and G446D) associated with highly reduced susceptibility to bebtelovimab, although all the viral isolates had <2-fold reduced susceptibility based on predicted phenotypic analysis. Sixteen patients received rescue therapy with bebtelovimab, but one patient with BA.2 subvariant harboring K444N mutation died of COVID-19-related complications. Five patients received other COVID-19 therapies and survived. Four had mild or asymptomatic COVID-19 with an uncomplicated course despite not receiving any additional therapy.

Discussion: Multiple SARS-CoV-2 Omicron spike codon substitutions that correlated with reduced susceptibility to tixagevimab-cilgavimab were identified in patients with COVID-19 after receiving this monoclonal antibody. Most patients had an uncomplicated course. The identification of spike codon substitutions conferring resistance to bebtelovimab highlights the importance of performing genomic surveillance to identify new resistant SARS-CoV-2 variants.

Keywords: COVID-19; Immunocompromised hosts; Monoclonal antibodies; SARS-CoV-2 Omicron.

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Conflict of interest statement

Declaration of Competing Interest Raymund R. Razonable has received grants from Regeneron, Roche, and Gilead for research not directly related to this study. Paschalis Vergidis has received research grants from Ansun, Scynexis, and Cidara and has served on the data and safety monitoring board for AbbVie, Vanda, and Algernon Pharmaceuticals (all fees paid to Mayo Clinic). All other authors report no potential conflicts of interest.

Figures

Fig 1
Fig. 1
Spike protein mutation map (Stanford University Coronavirus Antiviral & Resistance Database, SARS-CoV-2 sequence analysis report, https://covdb.stanford.edu/sierra/sars2/by-patterns/) of the SARS-CoV-2 Omicron subvariants harboring the S codon substitutions G446D (BA.5.6, Fig. 1A) and K444N (BA.2, Fig. 1B).
See this image and copyright information in PMC

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