Abstract
Continuous evolution of Omicron has led to numerous subvariants that exhibit growth advantage over BA.5. Such rapid and simultaneous emergence of variants with enormous advantages is unprecedented. Despite their rapidly divergent evolutionary courses, mutations on their receptor-binding domain (RBD) converge on several hotspots, including R346, K356, K444, L452, N460K and F486. The driving force and destination of such convergent evolution and its impact on humoral immunity established by vaccination and infection remain unclear. Here, we demonstrate that these convergent mutations can cause striking evasion of convalescent plasma, including those from BA.5 breakthrough infection, and existing antibody drugs, including Evusheld and Bebtelovimab. BR.2, CA.1, BQ.1.1, BM.1.1.1, and especially XBB, are the most antibody-evasive strain tested, far exceeding BA.5 and approaching SARS-CoV-1 level. 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. Importantly, due to humoral immune imprinting, BA.2 and especially BA.5 breakthrough infection caused significant reductions in the epitope diversity of neutralizing antibodies and increased proportion of non-neutralizing mAbs, which in turn concentrated humoral immune pressure and promoted the convergent RBD evolution. Additionally, the precise convergent RBD mutations and evolution trends of BA.2.75/BA.5 subvariants could be inferred by integrating the neutralization-weighted DMS profiles of mAbs from various immune histories (3051 mAbs in total). Moreover, we demonstrated that as few as five additional convergent mutations based on BA.5 or BA.2.75 could completely evade most plasma samples, including those from BA.5 breakthrough infection, while retaining sufficient hACE2-binding affinity. These results suggest that current herd immunity and BA.5 vaccine boosters may not provide sufficiently broad protection against infection. Broad-spectrum SARS-CoV-2 vaccines and NAb drugs development should be of high priority, and the constructed convergent mutants could serve to examine their effectiveness in advance.
Competing Interest Statement
X.S.X and Y.C. are co-founders of Singlomics Biopharmaceuticals and listed as inventors on patents related to DXP-604, SA55, and SA58. The remaining authors declare no competing interests.
Footnotes
Update information on BU.1, BR.2, BM.1.1.1, CA.1, and XBB
