(A) Zou, Li, et al. (16) acquired and enriched Spike-specific (S-specific) B cells from subjects using FACS. Immunoglobulin heavy and light chains were cloned and expressed as mAbs. (B) Libraries of mutant S sequences were established for screening mAbs. (C) Potent mAbs bound with most mutants and neutralized pseudoviruses and variants of concern (VOCs) in vitro. mAb polymerization enhanced avidity to overcome some mutations that escaped neutralizing antibodies. (D) Similarly, potent mAbs reduced SARS-CoV-2 infection in vitro and in vivo. Escape mutants were identified by sequencing. (E) Ultrapotent mutation-resistant mAbs need to effectively neutralize emerging VOCs. Search strategies for screening and validation of escape-free mAbs could include the following: (i) Molecular dynamics to estimate binding free energy change, and AI to train and test mutation models, including replacement, insertion, and deletion mutations in the S receptor-binding domain (RBD) and N-terminal domain (NTD), and non-S proteins. These 2 strategies may identify potential escape mutants before they arise and serve as a reference for synthesis and validation of escape-free mAbs. (ii) Engineering of escape-free ACE2-Fc fusion proteins to directly neutralize VOCs while eliciting Fc effector functions. (iii) Sourcing mAbs from superimmune donors (those who had infection and later got vaccinated, or vice versa). Potential mAbs would require validation against complex RBD- and NTD-mutant libraries containing multiple mutations. The Spike protein structure shown was acquired from the Protein Data Bank (10.2210/pdb7LYO/pdb).