Global Genomic Surveillance Reveals Pre-EUA Fixation of Pemivibart (VYD2311) Escape Constellations in SARS-CoV-2

Pemivibart (VYD222) and its successor, VYD2311, target a shared, evolutionarily vulnerable epitope in the SARS-CoV-2 spike receptor-binding domain (RBD). Although VYD2311 an IND features an Fc-mediated half-life extension and demonstrates a reported 17-fold increase in in-vitro neutralization potency over pemivibart (marketed as Pemgarda™, VYD222), both antibodies engage identical contact residues such as R346, K444, F456, and F486, making them equally susceptible to the same escape pathways. Although Fc‑engineering strategies can enhance serum half‑life, they do not alter the vulnerable epitope specificity shared by these antibodies. To assess the real-world durability of this therapeutic axis, we conducted mass-scale genomic surveillance across 9,398,268 global SARS-CoV-2 spike sequences spanning January 2020 through September 2025 (Q3 2025), including 26,514 non-INSDC Chinese submissions. Using a reference-aligned, codon-resolved pipeline anchored to Wuhan-Hu-1 (YP_009724390.1), we systematically mapped the emergence, co-occurrence, and global fixation of 11 experimentally validated escape residues. Mutational constellations were stratified by haplotype tier (1/5 to 5/5), lineage, geography, and time to reconstruct the evolutionary trajectory of resistance. Our analysis reveals that pemivibart/VYD2311 resistance is now near-ubiquitous: 94.8% of 2025 isolates harbor ≥3 of the 5 core escape mutations (R346T, S371F, K444T, N460K, F486P), and over 95% of high-tier (≥3/5) escape genomes belong to KP.3-descendant lineages - embedding resistance as a baseline feature of the contemporary virome. Critically, we identified natural isolates carrying the complete 5/5 escape haplotype, including a clonal cluster in Puerto Rico as early as late 2023 - predating both the EUA for pemivibart (March 2024) and the IND clearance for VYD2311 (October 2025). In China, distinct but functionally convergent substitutions (S501T, S500T, S417T) dominate, illustrating regional pathways to the same outcome: the therapeutic failure. We cataloged 116 unique escape constellations, with up to eight co-occurring mutations, and confirmed that dominant 2024 - 2025 lineages - including LB.1, LB.1.81, and KP.3.1.1 - routinely carry 4 - 5 escape residues. Notably, Invivyd’s efficacy models rely on neutralization titers against JN.1, a variant already displaced by mid-2024; yet the targeted epitope was substantially eroded in circulating strains well before clinical deployment. The FDA’s August 2024 imposition of a 90% national susceptibility threshold for pemivibart use implicitly acknowledges this pre-existing vulnerability. We conclude that single-epitope monoclonal antibodies like VYD222 and VYD2311 are inherently fragile against the deterministic forces of SARS-CoV-2 evolution. Prolonged serum exposure enabled by Fc engineering cannot overcome pre-existing binding loss and may instead accelerate escape in immunocompromised hosts. Sustainable pandemic preparedness demands a strategic pivot: away from iterative, reactive optimization of single-target antibodies, and toward multi-epitope cocktails or therapeutics designed using co-evolving residue networks. This study provides a definitive, global evidence base for retiring lineage reactive mAbs in favor of evolutionarily resilient countermeasures.