Efficacy of Licensed Monoclonal Antibodies and Antiviral Agents against the SARS-CoV-2 Omicron Sublineages BA.1 and BA.2

Abstract

Newly emerging SARS-CoV-2 variants may escape monoclonal antibodies (mAbs) and antiviral drugs. By using live virus assays, we assessed the ex vivo inhibition of the B.1 wild-type (WT), delta and omicron BA.1 and BA.2 lineages by post-infusion sera from 40 individuals treated with bamlanivimab/etesevimab (BAM/ETE), casirivimab/imdevimab (CAS/IMD), and sotrovimab (SOT) as well as the activity of remdesivir, nirmatrelvir and molnupiravir. mAbs and drug activity were defined as the serum dilution (ID₅₀) and drug concentration (IC₅₀), respectively, showing 50% protection of virus-induced cytopathic effect. All pre-infusion sera were negative for SARS-CoV-2 neutralizing activity. BAM/ETE, CAS/IMD, and SOT showed activity against the WT (ID₅₀ 6295 (4355-8075) for BAM/ETE; 18,214 (16,248-21,365) for CAS/IMD; and 456 (265-592) for SOT) and the delta (14,780 (ID₅₀ 10,905-21,020) for BAM/ETE; 63,937 (47,211-79,971) for CAS/IMD; and 1103 (843-1334) for SOT). Notably, only SOT was active against BA.1 (ID₅₀ 200 (37-233)), whereas BA.2 was neutralized by CAS/IMD (ID₅₀ 174 (134-209) ID₅₀) and SOT (ID₅₀ 20 (9-31) ID₅₀), but not by BAM/ETE. No significant inter-variant IC₅₀ differences were observed for molnupiravir (1.5 ± 0.1/1.5 ± 0.7/1.0 ± 0.5/0.8 ± 0.01 μM for WT/delta/BA.1/BA.2, respectively), nirmatrelvir (0.05 ± 0.02/0.06 ± 0.01/0.04 ± 0.02/0.04 ± 0.01 μM) or remdesivir (0.08 ± 0.04/0.11 ± 0.08/0.05 ± 0.04/0.08 ± 0.01 μM). Continued evolution of SARS-CoV-2 requires updating the mAbs arsenal, although antivirals have so far remained unaffected.

Keywords: SARS-CoV-2; cell-based assay; mAbs; microneutralization assay; molnupiravir; nirmatrelvir; omicron sublineages; remdesivir.

Figure 1

Ex vivo anti-SARS-CoV-2 wild type, delta, omicron (BA.1 and BA.2) neutralizing antibody titers measured in sera from 40 patients following infusion of bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab monoclonal antibodies. Blue dots, red squares and green triangles represents patients treated with bamlanivimab + etesevimab, casirivimab + indevimab and sotrovimab, respectively. Paired data were analyzed by the non-parametric Wilcoxon Signed Rank Sum test. NtAb titers before infusion were negative against each variant tested (not shown in figure). NtAb: neutralizing antibody; ID₅₀: the reciprocal value of the sera dilution showing the 50% protection of virus-induced cytopathic effect; WT: wild type.

Figure 2

Comparison between antiviral activity of EIDD-1931, Nirmatrelvir and Remdesivir against wild-type SARS-CoV-2 virus with (0.5 µM) or without the addition of P-gp inhibitor. On the x-axis is indicated the micromolar drug concentration in logarithmic scale. The horizontal dashed line indicates the drug IC₅₀ corresponding to 50% cell viability whereas the dashed curves indicate the dose response fitting curve generated by GraphPad PRISM software version 6.01 (La Jolla, CA, USA).