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BA.1)>10CCCTY40-385 (Omicron. insight into variant emergence’s impact on choosing optimal drug treatment. Keywords: SARS-CoV-2, Omicron, BA.2, BA.1, Casirivimab, Imdevimab, Sotrovimab, Molnupiravir, Nirmatrelvir, Antiviral The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (lineage B.1.1.529) has rapidly spread worldwide and become the most prevalent SARS-CoV-2 in many countries (Elliott et al., 2022; Viana et al., 2022). Of the recognized Omicron subvariants, the subvariant BA.1 was dominantly prevalent in the early days after Omicron emerged from November 2021. However, alternative with BA.1 with another subvariant, BA.2, has grown in prevalence in several countries, including Denmark, UK, and South Africa, alerting a higher transmission of this new subvariant worldwide that can prolong the current wave of COVID-19 (UK Health Security Agency, 2022). The BA.1 and BA.2 have more than 30 shared amino acid substitutions from your Wuhan strain, especially with approximately 20 shared mutations in the Spike protein. They also have some unique mutations (Fig. 1 ). For example, the S1 69C70 deletion as a hallmark of BA.1, associated with S-gene target failure in PCR assessments, is unconserved in BA.2 (Majumdar and Sarkar, 2021; WHO, 2021). BA.2 also has four unique substitutions (S371F, T376A, D405N, and R408S) compared with BA.1, with lacking three mutations (S371L, G446S, and G496S) in the receptor-binding domain name of the S1, which is involved in vaccine and antibody responses (Majumdar and Sarkar, 2021). Such unique mutation patterns in BA.1 and BA.2 possibly affect their sensitivities to approved drugs/antibodies against COVID-19. Therefore, we quantified such drug/antibody responses of BA.1 and BA.2 compared to other variants of concern (Alpha, Gamma, Delta) and a Wuhan strain in cell culture contamination assays. Furthermore, most reports have so far evaluated only 50% (or 90%) inhibitory concentrations to quantify the drug activity. Yet, these concentrations are pharmacologically not the sole factor that determines antiviral efficacy. Thus, we also estimated the slopes of dose-response sigmoid curves to quantitatively discuss their drug effects at clinical drug concentrations (Koizumi et al., 2017; Shen et al., 2008). Open in a separate windows Fig. 1 Schematic representations for amino acid substitutions within the B.1.1.7, P.1, B.1.617.2, BA.1, and BA.2 lineage in NSP5, NSP12, and Spike proteins. Upper boxes show coding regions for NSP5 (the target of nirmatrelvir), NSP12 (the target of EIDD-1931), and Spike (the target of imdevimab, casirivimab, and S309) in the SARS-CoV-2 genome Kv2.1 antibody RNA. Mutated amino acids from your Wuhan strain in B.1.1.7 (Alpha, orange), P.1 (Gamma, green), B.1.617.2 (Delta, yellow), BA.1 (Omicron), and BA.2 (Omicron) are shown. Shared BA.1 and BA.2 mutations are indicated in black, and those unique to BA.1 and BA.2 are shown in blue and red, respectively. We evaluated the intrinsic sensitivity of SARS-CoV-2 variants (Wuhan, Alpha, Gamma, Delta, Omicron-BA.1, and Omicron-BA.2) to the approved antibodies/drugs [casirivimab, imdevimab, S309 (the prototype antibody of sotrovimab), EIDD-1931 (the active form of molnupiravir), and nirmatrelvir]. Each SARS-CoV-2 strain was inoculated and cultivated in VeroE6/TMPRSS2 cells upon treatment with varying concentrations of antibodies/drugs (up to 4C10?M or g/mL) to measure viral RNA in the culture supernatant, as well as cell viability at 24?h postinoculation (Matsuyama et al., 2020). Fig. 2 shows the dose-response curve of each variant against tested antibodies/drugs (Fig. 2). No cytotoxicity induced by antibody/drug was observed in all tested concentrations (Fig. S1). Overall, inhibition potency of the three tested antibodies, casirivimab, imdevimab, and S309 to Omicron subvariants BA.1 and BA.2, were severely impaired, in contrast to their outstanding activities against the Wuhan strain and Alpha, Gamma, and Delta variants (Fig. 2ACC). Casirivimab did not show any antiviral activity to BA.1 and BA.2 up to 10?g/ml (Fig. 2A). Also, imdevimab lost its activity to BA.1, but retained a minor antiviral activity to reduce BA.2 infections (Fig. 2B). S309’s antiviral activity to BA.1 was more modest than that of other variants, and that to BA.2 was even weaker (Fig. 2C). These tendencies of the IC50 shifts between BA.1 and other variants (Table 1 ) are overall consistent with the previous reports Ciprofloxacin HCl (Cameroni et al., 2021; Cao et al., 2021; Liu et al., 2021; Planas et al., 2021). Additionally, our dose-response curves clearly show the impaired potency of all three Ciprofloxacin HCl antibodies against BA.2. As a Ciprofloxacin HCl possible mechanistic explanation, a class 2 antibody, casirivimab, completely lost its antiviral activity to both BA.1 and BA.2, probably because of the mutations at K417N, S477N, T478K, E484A, Q493R, Q498R, and N501Y (Fig. 1, black), contained in the reported epitope footprints of casirivimab (VanBlargan et al., 2022). The class 3 imdevimab showed the reduced activity to BA.2.