Emergence of a Predominant S371F-Driven Escape Architecture in SARS-CoV-2 Circulating in December 2025: Genomic Surveillance of Pemivibart (VYD2311) Vulnerability Across 8 Global BioSamples

We present a high-resolution genomic analysis of 8 SARS-CoV-2 BioSamples sequenced in December 2025, processed using the PEMI-ESC v2.0 pipeline to assess mutations associated with pemivibart (VYD2311) monoclonal antibody escape. All samples were retrieved from NCBI SRA and analyzed for codon-level substitutions at five canonical RBD positions: R346, S371, K444, F456, and F486 (Wuhan-Hu-1, NC_045512.2). Summary of Results (n=8) Escape Status Count Mutational Profile Partial Escape (2/5 canonical mutations) 3 S371F + F456L (all HIGH-confidence) No Escape (1/5) 5 S371F only (F456L absent; other sites show non-escape substitutions or stops) Key Observations: S371F is universal: Present in 100% (8/8) of December 2025 samples.F456L is recurrent: Detected in 3/8 (37.5%) samples, always co-occurring with S371F.F486P and K444T are absent: No sample carries F486P (all show F→S or F→F) or K444T (all show K→* or wild-type).No sample meets full resistance threshold (≥3 escape mutations). Interpretation & ConclusionThese data reveal a non-random, convergent evolutionary pattern in late-2025 SARS-CoV-2: S371F has become fixed globally, while F456L is emerging as a secondary mutation in a substantial minority of lineages. The complete absence of F486P and K444T suggests that pemivibart resistance, if evolving, is proceeding via a stepwise, S371F-initiated pathway and not the canonical triplet (K444T/F456L/F486P) observed in earlier mAb escape studies. Although no sample exhibits full pemivibart escape, the recurrent S371F+F456L constellation in 37.5% of samples indicates incipient resistance architecture. Given pemivibart’s mechanism of action, this mutational pair is biologically plausible for moderate neutralization reduction, warranting enhanced surveillance. This snapshot provides early genomic evidence that SARS-CoV-2 lineages circulating in December 2025 are navigating a constrained escape landscape centered on S371F, with potential implications for the durability of VYD2311-based therapeutics. Study by: [e-mail]