Nature publishes: It is extremely difficult to achieve herd immunity through Omicron infection!

It has been more than two years since the outbreak of the Sars-Cov-2, and the raging situation of the virus around the world has not subsided, which has a serious impact on human life and health. 4. The successive emergence of BA.5 poses a serious challenge to the preventive effect of vaccination and the therapeutic effect of antibody drugs. The receptor binding ability and immune escape ability of the new variant strains need to be studied in detail.

On June 17, 2022, Peking University Biomedical Frontier Innovation Center (BIOPIC), Changping Laboratory Xie Xiaoliang/Cao Yunlong research group, Peking University School of Life Sciences Xiao Junyu research group, Chinese Academy of Sciences Institute of Biophysics Wang Xiangxi research group, China Food and Drug Control Wang Youchun's research group from the Institute and Shen Zhongyang's research group from Nankai University published a research paper online in the journal Nature entitled BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection, and found that Omicron mutant BA The new subtypes of .2.12.1, BA.4 and BA.5 showed stronger immune escape ability, and showed significant neutralization escape phenomenon in the plasma of Omicron BA.1 infected patients after recovery.

After high-throughput single-cell sequencing, isolation and characterization of thousands of new crown monoclonal neutralizing antibodies, researchers found that the new mutations evolved by Omicron BA.2.12.1, BA.4, BA.5 can be specific Neutralizing antibodies induced by escape from BA.1 infection. In addition, Omicron BA.1 infection has the phenomenon of "immunogenic sin", that is, BA.1 infection mainly evokes memory B cells induced by the original vaccine, and it is difficult to produce neutralizing antibodies specific to BA.1. These findings suggest that the BA.1-based Omicron vaccine may no longer be suitable as a booster in the current immune context, and the antibodies induced will not have broad-spectrum protective efficacy against the new variant. Moreover, due to the phenomenon of "immunogenic sin" in the new coronavirus and the rapid evolution of immune escape mutation sites, it is extremely difficult to achieve herd immunity through Omicron infection.

This study was first published online on the bioRxiv preprint platform on May 2, 2022. It is the world's first systematic study of the structure and humoral immune escape properties of the BA.2.12.1 and BA.4/5 spike proteins, revealing that Omic The research paper on the molecular mechanism of the "immunogenic sin" of the Rong mutant strain has attracted widespread attention in the international academic community, and has been reported by many well-known overseas media such as Science, New York Times, and ABC News.

At present, the main Omicron mutants all have high transmission ability. In order to study the relationship between their transmission ability and the conformation of Spike glycoprotein and receptor binding ability, the cooperative team analyzed the Omicron mutant BA. .2, BA.3, BA.2.12.1, BA.2.13, and BA.4/5 Cryo-EM structures of spike protein trimers, and assayed for each mutant spike protein or receptor binding domain (RBD), respectively Affinity to hACE2. Structural analysis indicated that the F486V mutation carried by BA.4/5 may lead to a decrease in hACE2 affinity, but the L452R and 493Q backmutations reduced this effect. The results showed that the affinity of BA.2.12.1, BA.2.13 and BA.4/5 for hACE2 was comparable to that of BA.2.

The study found that the neutralization ability of BA.2.12.1 and BA.4/5 by the plasma of the three-injection vaccine group was significantly lower than that of BA.2, and the plasma of the recovered patients who had broken through the infection with BA.1 was significantly lower than that of BA.2.12. The neutralization ability of 1 and BA.4/5 also decreased significantly. The results of flow cytometry and single-cell VDJ sequencing showed that the breakthrough infection of BA.1 mainly evokes the humoral immune memory of the original strain after vaccination in the human body, and the antibodies induced thereby can neutralize the original strain and BA.1 at the same time, However, the broad-spectrum neutralizing activity of the new variant is poor, which is in line with the "immunogenic sin" theory, suggesting that the BA.1-based Omicron vaccine is difficult to provide broad-spectrum and effective preventive ability against the new variant, which may not It is suitable as a booster needle under the background of existing population immunization.

The study of antibody drugs also confirmed the high neutralizing antibody evasion ability of the new subtype of the Omicron strain, and the neutralizing activity of most of the existing antibody drugs was greatly reduced. The S371F, D405N and R408S site mutations carried by BA.2, BA.4 and BA.5 resulted in inactivation of most betacoronavirus broad-spectrum antibodies (such as S309), while LY-CoV1404 (Bebtelovimab) and COV2-2130 ( Cilgavimab) remained neutralizing activity against BA.2.12.1 and BA.4/BA.5. In addition, the team screened a pair of broad-spectrum beta-coronavirus neutralizing antibody combinations SA58 and SA55 that do not conflict with epitopes. strains, as well as SARS virus, RaTG13, Pangolin-GD and other Sarbecovirus viruses, are expected to become drugs with both potent preventive and therapeutic effects.

In order to further explore the neutralizing antibody evasion mechanism of Omicron mutants, the team used high-throughput deep mutation scanning technology to determine the escape map, epitope distribution and neutralization of 1640 RBD-binding antibodies. Efficacy, of which 614 and 411 were derived from BA.1 convalescent plasma and SARS convalescent plasma vaccinated with the new crown vaccine, respectively. Through unsupervised clustering of escape maps, the antibodies were divided into 12 classes A, B, C, D1, D2, E1, E2.1, E2.2, E3, F1, F2, F3, and the data indicated that they belonged to the same class. Antibodies have similar antigen binding and neutralizing characteristics, and the major escape sites of each type of antibody are consistent with the binding epitope of this type of representative antibody in the complex structure.

Among the 614 antibodies from the plasma of BA.1 survivors with breakthrough infection, 512 were cross-bound to the original strain/BA.1 RBD, and 102 were only bound to the BA.1 RBD. Cross-binding antibodies are mainly enriched in non-ACE2-competing epitopes such as E2.1, E2.2, E3, and F1. Among them, E3 and F1 antibodies generally have poor neutralizing activities, E2.2 antibodies have average neutralizing activities, and E2 antibodies have poor neutralizing activities. Although class 1 antibodies have good neutralizing activity, their neutralizing activity is reduced due to the influence of BA.2.12.1 carrying L452Q and BA.4/5 carrying L452R. The antibodies that only bind to BA.1 compete with ACE2, and the specific binding sites are very different from those that bind to the original strain RBD, which indicates that the antigenicity of the BA.1 RBD is greatly changed compared with the original strain RBD. At the same time, this part of the antibody was severely escaped by D405N of BA.2 and BA.2.12.1 and F486V/L452R of BA.4/5. These results at single antibody levels explain why plasma from survivors of BA.1 breakthrough infection is escaped by a new isoform of the Omicron strain.

Pseudovirus neutralization experiments and structural analysis showed that the epitopes (E1, F2, F3) of the SARS-CoV-1/2 RBD cross-binding broad-spectrum neutralizing antibody concentrated distribution were also affected by BA.2, BA.2.12.1 The effects of S371F, D405N, R408S mutations carried by BA.2.13 and BA.4/5. Among them, the affinity of E1 class antibodies decreased due to the local conformational change caused by S371F, and most of the F2/F3 class antibodies escaped by D405N and R408S mutations. This suggests that broad-spectrum neutralizing antibodies of betacoronavirus B (sarbecovirus) are also largely affected by the Omicron BA.2, BA.2.12.1, BA.2.13 and BA.4/5 variants escape.

This study demonstrates the strong application potential of combining high-throughput single-cell sequencing technology and high-throughput deep mutation scanning technology in antibody screening and characterization. Combined with escape map clustering and structural analysis of representative antibodies of each epitope, a single At the antibody level, the epitope distribution of antibodies in the plasma of the BA.1 strain of Omicron BA.1 strain of breakthrough infection was analyzed, as well as the physicochemical mechanism of the new subtype of Omicron strain escaping various neutralizing antibodies, and a new coronavirus was constructed. A comprehensive database of RBD antibody binding epitopes, escape maps, and neutralizing activities provides data support for the development of subsequent antibody drugs and broad-spectrum vaccines.

Changping Laboratory, Associate Researcher Cao Yunlong of Peking University Biomedical Frontier Innovation Center, Peking University Ph.D. students Ayijiang Ismayi, Jian Fanchong, Song Weiliang, Xiao Tianhe, Wang Jing, Ph.D. Du Shuo, School of Life Sciences, Peking University, Chinese Academy of Sciences Wang Lei from the Institute of Physics, Li Qianqian and Yu Yuanling from the China Institute for Food and Drug Control, and Chen Xiaosu from Nankai University are the co-first authors of this paper. Professor Xie Xiaoliang and Researcher Cao Yunlong of Changping Laboratory and Peking University Biomedical Frontier Innovation Center, Researcher Xiao Junyu of School of Life Sciences of Peking University and Changping Laboratory, Researcher Wang Xiangxi of Institute of Biophysics, Chinese Academy of Sciences, Researcher Wang Youchun of China Academy of Food and Drug Control, and Shen Zhongyang of Nankai University The professor is the co-corresponding author of this article. This research was supported by the Changping Laboratory Fund of the Ministry of Science and Technology.

Article source: Nanshan Breath

Finishing: IVD Practitioner Network

Original link:

https://www.nature.com/articles/s41586-022-04980-y

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