作者: Chan, Kwok-Hung ; Hung, Ivan Fan-Ngai ; Lam, Hoi-Yan ; Zhao, Xiaofeng ; Zhang, Wanying ; Chen, Yuxin ; Pan, Kai ; Wang, Wei ; Jiang, Lei ; Zhao, Liwei ; Liu, Lian ; Zhou, Minyun ; Wang, Mengyu ; Zhou, Kangping ; Yu, Jie ; Wang, Feng ; Li, Chuang

ABSTRACT Simnotrelvir is an oral small-molecule antiviral agent targeting the 3C-like protease (3CL pro ) of SARS-CoV-2, proven effective against the Delta variant with favorable pharmacokinetics and safety in preclinical study. In this study, we further evaluated the antiviral efficacy of simnotrelvir against a range of emerging Omicron variants, including BA.1, BA.4, BA.5, CH.1.1, XBB.1.5, XBB.1.16, EG.5, and JN.1. In vitro assays with Vero E6 cells confirmed that simnotrelvir exhibited robust antiviral activity across these variants, comparable to the Food and Drug Administration (FDA)-approved drug nirmatrelvir. Additionally, simnotrelvir demonstrated effective inhibition against several nirmatrelvir-resistant SARS-CoV-2 3CL pro mutants, including A260V, Y54A, (T21I + S144A), F140A, H172Y, and E166V. Importantly, simnotrelvir showed better potency against the E166V mutation compared to nirmatrelvir. Resistance selection studies revealed that BA.5 developed reduced sensitivity after 5 and 10 passages, increasing the IC 50 values by 3.2 and 4.5-fold, respectively, while HCoV-OC43 showed an 8.3-fold increase after 12 passages. Despite this, simnotrelvir’s overall efficacy remains strong. Furthermore, clinical trials demonstrated that combining simnotrelvir with ritonavir significantly shortened symptom resolution in COVID-19 patients. Genomic analysis of treated patients found random nucleotide substitutions but no significant mutations linked to 3CL pro resistance. In conclusion, simnotrelvir shows strong antiviral activity against SARS-CoV-2 variants and maintains a high barrier to resistance, reinforcing its potential as an effective therapeutic option for current and future SARS-CoV-2 variants.

2025-03-13·Eurosurveillance

Impact of SARS-CoV-2 variant mutations on susceptibility to monoclonal antibodies and antiviral drugs: a non-systematic review, April 2022 to October 2024

Review

作者: Vukovikj, Maja ; Melidou, Angeliki ; Kraus, Annette ; Nannapaneni, Priyanka ; Normark, Tanja ; Broberg, Eeva K

BackgroundMonoclonal antibodies (mAbs) and antiviral drugs have emerged as additional tools for treatment of COVID-19.AimWe aimed to review data on susceptibility of 14 SARS-CoV-2 variants to mAbs and antiviral drugs authorised in the European Union/European Economic Area (EU/EEA) countries.MethodsWe constructed a literature review compiling 298 publications from four databases: PubMed, Science Direct, LitCovid and BioRxiv/MedRxiv preprint servers. We included publications on nirmatrelvir and ritonavir, remdesivir and tixagevimab and cilgavimab, regdanvimab, casirivimab and imdevimab, and sotrovimab approved by the European Medicines Agency (EMA) by 1 October 2024.ResultsThe mutations identified in the open reading frame (ORF)1ab, specifically nsp5:H172Y, nsp5:H172Y and Q189E, nsp5:L50F and E166V and nsp5:L50F, E166A and L167V, led to a decrease in susceptibility to nirmatrelvir and ritonavir, ranging from moderate (25-99) to high reductions (> 100). Casirivimab and imdevimab exhibited highly reduced neutralisation capacity across all Omicron sub-lineages. Sub-lineages BA.1, BA.2 and BA.5 had decreased susceptibility to regdanvimab, while sotrovimab showed decreased efficacy for BA.2, BA.4, BQ.1.1 and BA.2.86. Tixagevimab and cilgavimab exhibited highly reduced neutralisation activity against BQ.1, BQ.1.1, XBB, XBB.1.5 and BA.2.86 sub-lineages.ConclusionsThe emergence of new variants, some with altered antigenic characteristics, may lead to resistance against mAbs and/or antiviral drugs and evasion of immunity induced naturally or by vaccination. This summary of mutations, combination of mutations and SARS-CoV-2 variants linked to reduced susceptibility to mAbs and antiviral drugs, should aid the selection of appropriate treatment strategies and/or phasing out therapies that have lost their effectiveness.

2025-03-01·eBioMedicine

A humanised ACE2, TMPRSS2, and FCGRT mouse model reveals the protective efficacy of anti-receptor binding domain antibodies elicited by SARS-CoV-2 hybrid immunity

Article

作者: Verma, Shailendra Kumar ; Varghese, Krithik ; Timis, Julia ; Street, Audrey Elizabeth ; Hastie, Kathryn M ; Shresta, Sujan ; Maule, Erin ; Shafee, Norazizah ; Webb, David R ; Zandonatti, Michelle ; Madany, Henry ; Saphire, Erica Ollmann ; Conner, Chris ; Ana-Sosa-Batiz, Fernanda ; Tran, Linda ; Nguyen, Michael N ; Kim, Kenneth ; Miller, Robyn ; Jarnagin, Kurt ; Moi, Meng Ling

BACKGROUNDDespite the importance of vaccination- and infection-elicited antibodies (Abs) to SARS-CoV-2 immunity, current mouse models do not fully capture the dynamics of Ab-mediated immunity in vivo, including potential contributions of the neonatal Fc receptor, encoded by FCGRT.METHODSWe generated triple knock-in (TKI) mice expressing human ACE2, TMPRSS2, and FCGRT; and evaluated the protective efficacy of anti-SARS-CoV-2 monoclonal Abs (mAbs) and plasma from individuals with immunity elicited by vaccination alone plus SARS-CoV-2 infection-induced (hybrid) immunity.FINDINGSA human anti-SARS-CoV-2 mAb harbouring a half-life-extending mutation, but not the wild-type mAb, exhibited prolonged half-life in TKI mice and protected against lung infection with Omicron BA.2, validating the utility of these mice for evaluating therapeutic Abs. Pooled plasma from individuals with hybrid immunity to Delta, but not from vaccinated-only individuals, cleared infectious Delta from the lungs of TKI mice (P < 0.01), even though the two plasma pools had similar Delta-binding and -neutralising Ab titres in vitro. Similarly, plasma from individuals with hybrid Omicron BA.1/2 immunity, but not hybrid Delta immunity, decreased lung infection (P < 0.05) with BA.5 in TKI mice, despite the plasma pools having comparable BA.5-binding and -neutralising titres in vitro. Depletion of receptor-binding domain-targeting Abs from hybrid immune plasma abrogated their protection against infection.INTERPRETATIONThese results demonstrate the utility of TKI mice as a tool for the development of anti-SARS-CoV-2 mAb therapeutics, show that in vitro neutralisation assays do not accurately predict in vivo protection, and highlight the importance of hybrid immunity for eliciting protective anti-receptor-binding domain Abs.FUNDINGThis work was funded by grants from the e-Asia Joint Research Program (N10A650706 and N10A660577 to MLM, in collaboration with SS); the NIH (U19 AI142790-02S1 to EOS and SS and R44 AI157900 to KJ); the GHR Foundation (to SS and EOS); the Overton family (to SS and EOS); the Arvin Gottlieb Foundation (to SS and EOS), the Prebys Foundation (to SS); and the American Association of Immunologists Fellowship Program for Career Reentry (to FASB).

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适应症	最高研发状态	国家/地区	公司	日期
肝细胞癌	临床前	中国台湾	台北医学大学	2020-06-20
肝纤维化	临床前	中国台湾	国立阳明大学	2020-03-31
肝纤维化	临床前	中国台湾	台北医学大学	2020-03-31