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Continuous evolution of Omicron has led to a rapid and simultaneous emergence of numerous variants that display growth advantages over BA.5 1. Despite their divergent evolutionary courses, mutations on their receptor-binding domain (RBD) converge on several hotspots. The driving force and destination of such sudden convergent evolution and its impact on humoral immunity remain unclear. Here, we demonstrate that these convergent mutations can cause striking evasion of neutralizing antibody (NAb) drugs and convalescent plasma, including those from BA.5 breakthrough infection, while maintaining sufficient ACE2 binding capability. BQ.1.1.10 (BQ.1.1+Y144del), BA.4.6.3, XBB, and CH.1.1 are the most antibody-evasive strains tested. To delineate the origin of the convergent evolution, we determined the escape mutation profiles and neutralization activity of monoclonal antibodies (mAbs) isolated from BA.2 and BA.5 breakthrough-infection convalescents 2,3. Due to humoral immune imprinting, BA.2 and especially BA.5 breakthrough infection reduced the diversity of the NAb binding sites and increased proportions of non-neutralizing antibody clones, which in turn focused humoral immune pressure and promoted convergent evolution in the RBD. Moreover, we showed that the convergent RBD mutations could be accurately inferred by deep mutational scanning (DMS) profiles 4,5, and the evolution trends of BA.2.75/BA.5 subvariants could be well-foreseen through constructed convergent pseudovirus mutants. These results suggest current herd immunity and BA.5 vaccine boosters may not efficiently prevent the infection of Omicron convergent variants.

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