Emergence of neutralizing RBD antibodies following Omicron infection with limited activity against ancestral SARS-CoV-2.

Publication date: Aug 21, 2026

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution reduces the efficacy of prophylactic vaccines and monoclonal antibody (mAb) therapies. To evaluate potency and breadth, receptor binding domain (RBD)-targeting neutralizing mAbs were identified from patient B cells using an Omicron KP3. 1.1 Spike (S) protein bait. MAbs exhibiting the greatest neutralization potency (1332D4 and 1332E5) and binding breadth (1324A10 and 1316C10) were evaluated in greater detail. Cryo-electron microscopy (Cryo-EM) studies revealed 1332D4 and 1332E5 target RBD residue segments 439-446 and 498-506 of KP3. 1.1 S, respectively. 1332E5 is a knob-targeting class-1/4 mAb that exhibits pan-Omicron specificity but does not bind or neutralize ancestral Wuhan-1. Further analysis suggests mAbs generically defined as class 1/4 mAbs may be separated into two classes. Class 1/4 mAbs, like 1332E5, and class 4/1 mAbs that make extensive interactions with the class-4 epitope and limited contacts with the class-1 knob. Despite these differences, the specificity of both mAb classes can be altered by mutations in knob.

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Semantics

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