SARS-CoV-2 Delta and Omicron variants evade population antibody response by mutations in a single spike epitope

He, Ping; Liu, Banghui; Gao, Xijie; Yan, Qihong; Pei, Rongjuan; Sun, Jing; Chen, Qiuluan; Hou, Ruitian; Li, Zimu; Zhang, Yanjun; Zhao, Jincun; Sun, Hao; Feng, Bo; Wang, Qian; Yi, Haisu; Hu, Peiyu; Li, Pingchao; Zhang, Yudi; Chen, Zhilong; Niu, Xuefeng; Zhong, Xiaolin; Liang, Jin; Liu, Xiaofeng; Qu, Kun; Ciazynska, Katarzyna A.; Carter, Andrew P.; Briggs, John; Chen, Jizheng; Liu, Jinsong; Chen, Xinwen; He, Jun; Chen, Ling; Xiong, Xiaoli

doi:10.1038/s41564-022-01235-4

Cited by 29 publications

(43 citation statements)

References 62 publications

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“…For example, certain antibody responses are repeatedly shared among large number of individuals regardless of their genetic origins, as has been observed previously during different pathogen infections including influenza, dengue, HIV and Malaria (8–11). With SARS-CoV-2, these are encoded by IGHV3-53/66, IGHV1-58, IGHV3-30 and IGHV1-69 which are found both following natural infection and post-vaccination (5, 6, 12). Such information can be collectively used to fine tune the immune response focused on broad and potent neutralizing epitopes through antigen design for a universal vaccine (20, 22).…”

Section: Discussionmentioning

confidence: 99%

“…Among these, nAbs encoded by human antibody heavy chain variable germline genes such as IGHV3-53/3-66, IGHV1-58, IGHV3-30 and IGHV1-69 are commonly observed in many individuals across the globe (7). These related rearrangements, known as a public antibody response, suggest a shared immune response with a similar genetic makeup and modes of antigen recognition that has been found in large number of individuals infected with influenza, dengue, malaria, HIV and SARS-CoV-2 (5,6,(8)(9)(10)(11)(12)(13). Mapping the immunogenetic makeup, structure, and function of these public clonotypes allows us to better understand how certain mutations affect the binding of an antibody and thus potentially expedite antibody re-purposing for emerging variants.…”

Section: Introductionmentioning

confidence: 95%

“…Mutations acquired in the spike protein of SARS-CoV-2 variants, a target for neutralizing antibodies (nAbs), are primarily responsible for this immune escape (1, 4). Identifying nAbs / non-nAbs to these variants and determining their prevalence in human population allows us to understand the shared mechanisms of immune protection among diverse populations (5, 6). Since the emergence of COVID-19, >11,000 SARS-CoV-2 mAbs have been identified (7).…”

Section: Introductionmentioning

confidence: 99%

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Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response

Patel

Kumar

Lai

et al. 2022

Preprint

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A detailed understanding of the molecular features of the neutralizing epitopes developed by viral escape mutants is important for predicting and developing vaccines or therapeutic antibodies against continuously emerging SARS-CoV-2 variants. Here, we report three human monoclonal antibodies (mAbs) generated from COVID-19 recovered individuals during first wave of pandemic in India. These mAbs had publicly shared near germline gene usage and potently neutralized Alpha and Delta, but poorly neutralized Beta and completely failed to neutralize Omicron BA.1 SARS-CoV-2 variants. Structural analysis of these three mAbs in complex with trimeric spike protein showed that all three mAbs are involved in bivalent spike binding with two mAbs targeting class-1 and one targeting class-4 Receptor Binding Domain (RBD) epitope. Comparison of immunogenetic makeup, structure, and function of these three mAbs with our recently reported class-3 RBD binding mAb that potently neutralized all SARS-CoV-2 variants revealed precise antibody footprint, specific molecular interactions associated with the most potent multi-variant binding / neutralization efficacy. This knowledge has timely significance for understanding how a combination of certain mutations affect the binding or neutralization of an antibody and thus have implications for predicting structural features of emerging SARS-CoV-2 escape variants and to develop vaccines or therapeutic antibodies against these.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response

Patel

Kumar

Lai

et al. 2022

Preprint

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“…The HCDR3 amino acids similarity between structurally characterized IGHV1-69-encoded L452-contacting mAbs and IGHV1-69-encoded mAbs isolated from COVID-19 vaccinees, Delta breakthrough infected individuals, or Omicron BA.1 breakthrough infected individuals were calculated using R package stringdist v0.9.8 ( https://github.com/markvanderloo/stringdist ). Antibody with a GYSGYG/D-like motif or with >75% HCDR3 amino acid similarity to R1-32/FC08 was defined as a R1-32-like antibody [ 19 ]. The binding affinity data of R1-32-like antibodies to Delta RBD and WT RBD were compiled from published literatures [ 16 , 19–23 ], and foldchange of the binding affinities of R1-32-like mAbs to Delta RBD relative to WT RBD were calculated.…”

Section: Methodsmentioning

confidence: 99%

“…Antibody with a GYSGYG/D-like motif or with >75% HCDR3 amino acid similarity to R1-32/FC08 was defined as a R1-32-like antibody [ 19 ]. The binding affinity data of R1-32-like antibodies to Delta RBD and WT RBD were compiled from published literatures [ 16 , 19–23 ], and foldchange of the binding affinities of R1-32-like mAbs to Delta RBD relative to WT RBD were calculated.…”

Section: Methodsmentioning

confidence: 99%

Shared IGHV1-69-encoded neutralizing antibodies contribute to the emergence of L452R substitution in SARS-CoV-2 variants

Yan

Hou

Huang

et al. 2022

Emerging Microbes & Infections

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SARS-CoV-2 variants continue to emerge facing established herd immunity. L452R, previously featured in the Delta variant, quickly emerged in Omicron subvariants, including BA.4/BA.5, implying a continued selection pressure on this residue. The underlying links between spike mutations and their selective pressures remain incompletely understood. Here, by analyzing 221 structurally characterized antibodies, we found that IGHV1-69-encoded antibodies preferentially contact L452 using germline-encoded hydrophobic residues at the tip of HCDR2 loop. Whereas somatic hypermutations or VDJ rearrangements are required to acquire L452-contacting hydrophobic residues for non-IGHV1-69 encoded antibodies. Antibody repertoire analysis revealed that IGHV1-69 L452-contacting antibody lineages are commonly induced among COVID-19 convalescents but non-IGHV1-69 encoded antibodies exhibit limited prevalence. In addition, we experimentally demonstrated that L452R renders most published IGHV1-69 antibodies ineffective. Furthermore, we found that IGHV1-69 L452-contacting antibodies are enriched in convalescents experienced Omicron BA.1 (without L452R) breakthrough infections but rarely found in Delta (with L452R) breakthrough infections. Taken together, these findings support that IGHV1-69 population antibodies contribute to selection pressure for L452 substitution. This study thus provides a better understanding of SARS-CoV-2 variant genesis and immune evasion.

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Modulation of IRAK enzymes as a therapeutic strategy against SARS-CoV-2 induced cytokine storm

2023

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the current pandemic coronavirus disease 2019 (COVID-19). Dysregulated and excessive production of cytokines and chemokines, known as cytokine storm, is frequently seen in patients with severe COVID-19 disease and it can provoke a severe systematic inflammation in the patients. The IL-1R/TLRs/IRAKs signaling network is a key pathway in immune cells that plays a central role in regulating innate immunity and inflammatory responses via stimulating the expression and production of various proinflammatory molecules including cytokines. Modulation of IRAKs activity has been proposed to be a promising strategy in the treatment of inflammatory disorders. In this review, we highlight the biochemical properties of IRAKs and their role in regulating inflammatory molecular signaling pathways and discuss the potential targeting of IRAKs to suppress the SARS-CoV-2-induced cytokine storm in COVID-19 patients.

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SARS-CoV-2 Delta and Omicron variants evade population antibody response by mutations in a single spike epitope

Cited by 29 publications

References 62 publications

Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response

Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response

Shared IGHV1-69-encoded neutralizing antibodies contribute to the emergence of L452R substitution in SARS-CoV-2 variants

Modulation of IRAK enzymes as a therapeutic strategy against SARS-CoV-2 induced cytokine storm

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