Guangzhou Health Center has made progress in the research of antibody immune response in the new coronavirus escaping population

Recently, the Guangzhou Institute of Biomedicine and Health of the Chinese Academy of Sciences and other cooperation published a title in Nature Microbiology Research paper by SARS-CoV-2 Delta and Omicron variants evade population antibody response by mutations in a single spike epitope.

The study found a human neutralizing antibody R1-32 that targets the viral protein receptor binding domain (RBD) semi-hidden epitope and has a high affinity, mainly Prevents the virus from entering the cell by breaking open the spike protein and disintegrating it; Analysis of the antibody panel library showed that R1-32-like antibodies encoded by IGHV1-69 were widely induced
in people infected with the new crown.
This is another class of IGHV discovered after the previously discovered new crown-specific IGHV 3-53 and IGHV 1-58 people share antibody lineages 1-69 encodes a public antibody lineage
for the new crown-specific population.
The study provides evidence that specific targeting of the L452 locus by R1-32 antibody lineages may be a catalyst for Delta and O An important reason for micron BA.
4/BA.
5 mutations at this site.

Since its outbreak at the end of 2019, the novel coronavirus pneumonia epidemic has continued to spread around the world, seriously affecting human health and social economy
.
Under the pressure of herd immunity established by natural infection and vaccination, SARS-CoV-2 is constantly found to mutate to evade neutralization
of antibodies.
In particular, the spike protein of the Omicron mutant strain currently in the global pandemic carries mutations of more than 30 sites and continues to evolve.

The constant emergence of mutant strains poses a huge challenge
to the effectiveness of vaccines and antibody drugs.
Therefore, elucidating the mechanism of antibodies in evading populations with new mutant strains is of great significance for the design and development of next-generation vaccines and antibody drugs.

Focusing on the above problems, this study used a variety of technical means to study a strain of targeted RBD, non-angiotensin-converting enzyme 2 ( ACE2) competing high-affinity neutralizing antibodies R1-32
.
Experiments in mice showed thatR1-32 had a good protective effect
against infection with the original strain of the new coronavirus.
The research team obtained the high-resolution structure
of R1-32 Fa b,ACE2 and the spike protein trimer ternary complex by cryo-EM analysis.
The results showed that although R1-32 did not hinder ACE2 receptor binding, it destroyed the spike protein structure by targeting a semi-occult epitope, so that the spike protein could not mediate membrane fusion and inhibited virus invasion of cells
.
Further structural analysis showed that R1-32 mainly interacted with RBD using HCDR2 and HCDR3, especially the antibody IGHV1- The germline hydrophobic residues I52, I54, L55 and I57 encoded by the 69 gene HCDR2 and the hydrophobic residues L452, The hydrophobic effect formed by F490 and L492 plays an important role in antibody recognition of antigens (Figure 1).

The study noted that L452 and F490 are the mutation hotspots of the new coronavirus spike protein, and the point mutation experiment further confirmed that the mutation of L452 and F490 sites significantly affects R 1-32 binding
with RBD.
Virus neutralization experiments also proved thatR1-32 can be escaped by the Delta mutant strain carrying L452R, the first highly mutated OmicronBA 1 Although it did not escape R1-32, BA.
4 and B A.
5 variants with L452R mutations quickly emerged and became popular
today.

SinceR1-32 uses IGHV 1-69-encoded germline residues to identify RBD, and the key recognition site is a mutation hotspot, the research team used high-throughput antibody panel sequencing technology to identify R-like The distribution of 1-32 antibodies in the population was analyzed (Figure 2).

The results showed that such antibodies existed in the antibody panel library in healthy people and could be detected in the form of IgM, butR1-32 antibodies were significantly enriched after new coronavirus infection and mainly existed
in the form of class-switched IgG.
Through sequence alignment with the new crown spike protein-specific antibody database, it was found thatR1-32 antibodies were widely induced in both new crown virus infection and vaccination patients, suggesting IGHV 1-69 The encodedR1-32 antibody is an important component of antibody herd immunity and is likely to be the main immune stress for mutations in spike proteins 4 52,4 90
。

This study identified the lineage of a class of antibodies specific to the new crown spike protein encoded by IGHV 1-69, and revealed the unique epitope characteristics and neutralization mechanism of the representative antibody R 1-32.
It also explains the immune selection pressure on mutant strains, which is of great significance
for the design and evaluation of the next generation of new crown vaccines and antibody drugs.

The cooperation of this research is Bio Island Laboratory, Guangzhou Medical University, Wuhan Institute of Virology, Chinese Academy of Sciences, and Guangzhou National Laboratory
.
He Ping, Yan Qihong, doctoral students of Guangzhou Health Institute, Liu Banghui, postdoctoral fellow, Gao Xijie, research assistant of Bioisland Laboratory, and Wuhan Institute of Virology Associate Professor Pei Rongjuan is the co-first author
of this paper.
Researcher Xiaoli Xiong, Professor Ling Chen, Professor Jun He and Professor Xinwen Chen are the co-corresponding authors
of this paper.
Professor Zhao Jincun's team from Guangzhou Medical University provided strong support
for the animal experiments in this study.

This research has been awarded the National Natural Science Foundation of China, the Strategic Leading Science and Technology Project of the Chinese Academy of Sciences, the Key Project of Guangzhou Science Plan, the Natural Science Foundation of Guangdong Province, the Independent Project of the State Key Laboratory of Respiratory Diseases, the Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Diseases, Supporting Zhong Nanshan Medical Fund of Guangdong Province
.

Figure 1: Structure diagram of R1-32 and SARS-CoV-2 spike protein andR1-32 epitope

Figure 2: Widespread presence ofR1-32 antibodies in the population and rapid induction of production in patients with COVID-19

Paper link