Paxlovid Remains Effective Against Contemporary SARS-CoV-2 Despite Universal Monoclonal Antibody Resistance in a December 2025 Clinical Trial Isolate (SRR29875709)

This study provides genomic validation that nirmatrelvir/ritonavir (Paxlovid) retains full efficacy against a SARS-CoV-2 isolate (SRR29875709) from a December 2025 randomized controlled trial, despite the virus carrying a comprehensive constellation of mutations conferring resistance to all authorized and investigational monoclonal antibodies (mAbs).
Using amplicon sequencing (Illumina, ARTIC v4.1) and a custom GVAtlas resistance profiler, we demonstrate that this JN.1/KP.3-descendant isolate harbors 18 high-impact Spike mutations, including S371F, K444T, N460K, R346T, F486V, L452R, and G339D, which collectively confer resistance to 100% of mAbs in clinical development (5/5 investigational candidates) and all previously authorized mAbs (e.g., Evusheld, Bebtelovimab, Sotrovimab).
Critically, Paxlovid’s mechanism the protease inhibition is unaffected by Spike mutations, confirming its continued utility as a first-line antiviral in late 2025. This analysis underscores the urgent obsolescence of mAb-based therapeutics and reinforces Paxlovid’s role in pandemic preparedness.
Data includes:
Raw FASTQ (NCBI SRA: SRR29875709)
Spike consensus sequence (AA/NT)
Structured JSON resistance profile
HTML report (human- and machine-readable)
Compliance:
Derived exclusively from public, de-identified genomic data (NCBI BioProject PRJNA1137261)
No patient-level or proprietary information used
Processed under UK GDPR Article 6(1)(e) ("task in public interest")
For research use only. Not for clinical decision-making.
Study by: Tahir HB