Continuous evolution of Omicron has led to a rapid and simultaneous emergence of numerous variants that display growth advantages over BA.5. Despite their divergent evolutionary courses, mutations on their receptor-binding domain (RBD) converge on several hotspots.
The driving force and destination of such 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, BA.4.6.3, XBB, and CH.1.1 are the most antibody-evasive strain tested, even exceeding SARS-CoV-1 level.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.09.15.507787v4
In this work, we showed that convergent RBD evolution can cause severe immune evasion and could be rationalized by integrating DMS profiles. Given the existence of immune imprinting, the humoral immune repertoire is not effectively diversified by infection with new Omicron variants, while the immune pressure on the RBD becomes increasingly concentrated and promotes convergent evolution, posing a great challenge to current vaccines and antibody drugs.
Although this study only examines inactivated vaccines, immune imprinting is also observed in those receiving mRNA vaccines 44,45. In fact, mRNA-vaccinated individuals displayed an even higher proportion of cross-reactive memory B cells, probably because the overall humoral immune response induced by mRNA vaccines is stronger than that induced by inactivated vaccines 45.
Also, recent studies on mRNA vaccinees who receive a BA.5 booster or BA.5 breakthrough infection displayed similar neutralization reduction trend against BA.2.75.2, BQ.1 and BQ.1.1, suggesting high consistency of neutralization data among vaccine types 46,47.
As the antibodies undergo affinity maturation, their SHM rate would increase 45. This may lead to a higher proportion of variant-specific antibodies, enhanced binding affinity, and increased neutralization breadth, which could potentially resist the convergent mutations carried by variants like XBB and BQ.1.1 48. However, the effect of affinity maturation may be counteracted by waning immunity 45,49. The affinity-matured memory B cells would require a second booster or reinfection to be effectively deployed.
We also observed that plasma from convalescents with BA.5 breakthrough infection exhibited higher neutralization against BA.5-derived variants like BQ.1 and BQ.1.1, suggesting that BA.5-based boosters are beneficial to protection against convergent variants of BA.5 sublineages.
However, this may be mainly driven by the enrichment of NTD-targeting antibodies after BA.5 breakthrough infection, which was also reported in BA.2 convalescents Significant mutations on NTD, such as Y144del in XBB and BQ.1.18, and mutations of many BA.2.75 sublineages, would cause severe reduction in BA.5 breakthrough infection plasma neutralization titers. Therefore, the effectiveness of BA.5-based boosters against the convergent mutants carrying critical NTD mutations should be closely monitored.
Notably, the antibody evasion capability of many variants, such as BQ.1.1, CA.1, BQ.1.18, XBB, and CH.1.1, have already reached or even exceeded SARS-CoV-1, indicating extensive antigenic drift (Fig. 5d-g). Indeed, by constructing an antigenic map of the tested SARS-CoV-2/ SARS-CoV-1 variants using the plasma NT50 data, we found that the antigenicity distances of SARS-CoV-2 ancestral strain to CA.1, CH.1.1, XBB and BQ.1.1 are already comparable to that of SARS-CoV-1 (Extended Data Fig. 10a-b).
Given that there are ~50 different amino acids between SARS-CoV-1 and SARS-CoV-2 RBD, but only 21 mutations on BQ.1.1 RBD compared to the ancestral strain, these results indicate that the global pandemic indeed has greatly promoted the efficiency of the virus to evolve immune escape mutations.
Finally, our prediction demonstrated a remarkable consistency with real-world observations. Some variants close to the predicted and constructed variants have already emerged while we performed the experiments, validating our prediction model. For example, BQ.1.1 is highly similar to BA.5-S3, and CH.1.1 to BA.2.75-S4/S6 (Fig. 4c).
The whole pipeline for constructing pseudoviruses carrying predicted mutations could be safely conducted in biosafety level 2 (BSL-2) laboratories, and does not involve any infectious pandemic virus. If we had this prediction model at the beginning of the pandemic, the development of NAb drugs and vaccines might not be so frustrated against the continuously emerging SARS-CoV-2 variants. 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.