ECDC: SARS-CoV-2 Variant Mutations Conferring Reduced Susceptibility to Antiviral Drugs and Monoclonal Antibodies

[Michael Coston]

ECDC: SARS-CoV-2 Variant Mutations Conferring Reduced Susceptibility to Antiviral Drugs and Monoclonal Antibodies

#17,542

Two summers ago the UK's SAGE (Scientific Advisory Group for Emergencies) on COVID released a series of detailed reports on the SARS-CoV-2 pandemic, and where they thought things might go from there. Their concerns boiled down to three main areas:

1. The emergence of a much more severe variant
2. Decreasing vaccine effectiveness
3. The emergence of drug resistant variants

While their first `worst case' scenario has thankfully not occurred, the other two have.

A year ago a new Bivalent COVID Booster Shot was approved (which is now being updated again for XBB), and eight months ago the FDA Withdrew EUA (Emergency Use Authorization) For Last COVID Monoclonal Antibody: Bebtelovimab.​

Leaving antivirals like Paxlovid and Veklury and Lagevrio as the preferred treatment options for acute COVID. But as COVID continues to evolve, these treatments are not guaranteed to remain effective.

Today the ECDC has released an 11-page technical report reviewing the currently available data on SARS-CoV-2 therapeutic monoclonal antibodies and antiviral drugs authorized for use in the EU/EEA.

As the following excerpt indicates, there are already mutations showing up in some variants that greatly reduce the effectiveness of our remaining armamentarium:

The mutations found in ORF1ab, namely nsp5:S144A, nsp5:Q189K, nsp5:H172Y, nsp5:E166A, and nsp5:F140A conferred moderate to high reduction in susceptibility to Paxlovid (nirmatrelvir/ritonavir), while nsp12:S861G conferred 25–99-fold reduction in susceptibility to Veklury (remdesivir) (Table 3).​

This report will be primarily of interest to clinicians in the EU, but it is a reminder that COVID continues to evolve, and research on new therapeutics is essential.

SARS-CoV-2 variant mutations conferring reduced susceptibility to antiviral drugs and monoclonal antibodies: a non-systematic literature review for surveillance purposes
Literature review
12 Jul 2023

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Antiviral drugs and monoclonal antibodies (mAbs), administered either separately or as combination therapy 'cocktails’, have provided a valuable tool for fighting COVID-19. Surveillance data, coupled with data on antiviral treatment susceptibility, can guide clinical decisions on selecting the best therapy for the patient.

Executive summary

The aim of this report is to provide a non-systematic literature review on the currently available data on SARS-CoV-2 therapeutic mAbs and antiviral drugs authorised for use in the European Union/European Economic Area (EU/EEA). In total, 258 publications on the four approved mAbs and 23 publications on antiviral drugs were analysed.​

• According to these studies, the ORF1ab mutations nsp5:S144A, nsp5:Q189K, nsp5:H172Y, nsp5:E166A, and nsp5:F140A conferred moderate to high reduction in susceptibility to Paxlovid (nirmatrelvir/ritonavir).

• The data indicated a highly reduced neutralisation capacity of Ronapreve (casirivimab/imdevimab) for all Omicron sub-lineages included in this report.

• The sub-lineages BA.1, BA.2, and BA.5 showed high reduction in susceptibility to Regkirona (regdanvimab).

• Xevudy (sotrovimab) showed high neutralisation efficacy against most SARS-CoV-2 variants, but moderate reduction in neutralisation activity for BA.2, BA.4, and BQ.1.1.

• Highly reduced neutralisation activity against the BQ.1 and BQ.1.1 sub-lineages was observed for Evusheld (tixagevimab/cilgavimab).

Monitoring the resistance of circulating new variants to mAb-based antiviral treatments is important for making decisions on whether some of the developed mAbs should be discontinued or different combinations of mAbs should be used. Neutralising susceptibility data are quite variable, leading to discordant findings among investigations. Therefore, adopting a global external standard for calibration would improve concordance across various tests and results could be provided in global units.

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SARS-CoV-2 variant mutations conferring reduced susceptibility to antiviral drugs and monoclonal antibodies - EN - [PDF-498.78 KB]​

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https://afludiary.blogspot.com/2023/07/ecdc-sars-cov-2-variant-mutations.html