The neutralizing breadth of antibodies targeting diverse conserved epitopes between SARS-CoV and SARS-CoV-2

Xiong, Hualong; Sun, Hui; Wang, Siling; Yuan, Lunzhi; Liu, Liqin; Zhu, Yuhe; Zhang, Jinlei; Huang, Yang; Qi, Ruoyao; Jiang, Yao; Ma, Jian; Zhou, Ming; Ma, Yue; Fu, Rao; Yan, Siping; Yue, Mingxi; Wu, Yangtao; Wei, Min; Wang, Yizhen; Li, Tingting; Wang, Yingbin; Zheng, Zizheng; Yu, Hai; Cheng, Tong; Li, Shaowei; Yuan, Quan; Zhang, Jun; Guan, Yi; Zheng, Qingbing; Zhang, Tianying; Xia, Ningshao

doi:10.1073/pnas.2204256119

Cited by 19 publications

(8 citation statements)

References 71 publications

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“…1F ). It is an established fact that the combination of two or more antibodies targeting distinct epitopes can enhance therapeutic efficacy and resist viral escape ( Copin et al 2021 , Wang et al 2022d , Xiong et al 2022 , Zhang et al 2021 ). Thus, we next sought to evaluate the synergetic neutralization of two nAbs by the LV-based pseudoviruses.…”

Section: Resultsmentioning

confidence: 99%

Two antibodies show broad, synergistic neutralization against SARS-CoV-2 variants by inducing conformational change within the RBD

et al. 2023

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Continual evolution of the SARS-CoV-2 virus has allowed for its gradual evasion of neutralizing antibodies (nAbs) produced in response to natural infection or vaccination. The rapid nature of these changes has incited a need for the development of superior broad nAbs and/or the rational design of an antibody cocktail that can protect against the mutated virus strain. Here, we report two ACE2 competing nAbs—8H12 and 3E2—with synergistic neutralization but evaded by some Omicron subvariants. Cryo-EM reveals the two nAbs synergistic neutralizing virus through a rigorous pairing permitted by rearrangement of the 472-489 loop in the RBD to avoid steric clashing. Bispecific antibodies based on these two nAbs tremendously extend the neutralizing breadth and restore neutralization against recent variants including currently dominant XBB.1.5. Together, these findings expand our understanding of the potential strategies for the neutralization of SARS-CoV-2 variants toward the design of broad-acting antibody therapeutics and vaccines.

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Section: Resultsmentioning

confidence: 99%

Two antibodies show broad, synergistic neutralization against SARS-CoV-2 variants by inducing conformational change within the RBD

et al. 2023

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“…(A) IC 50 values of a series of reported anti‐SARS‐CoV‐2 bNAbs with cross‐neutralizing activity against SARS‐CoV‐1. Most of these IC 50 values were collected from previous literatures: ADG20, S309, and DH1047 36 ; X mAbs 37 ; CC mAbs 38 ; GW01 39 ; and SW186 40 . The IC 50 values for 47D11 41 and BG10‐19 42 were evaluated in this study.…”

Section: Resultsmentioning

confidence: 99%

Characterization of cross‐reactive monoclonal antibodies against SARS‐CoV‐1 and SARS‐CoV‐2: Implication for rational design and development of pan‐sarbecovirus vaccines and neutralizing antibodies

Jiang

et al. 2023

Journal of Medical Virology

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Emergence of various circulating SARS‐CoV‐2 variants of concern (VOCs) promotes the identification of pan‐sarbecovirus vaccines and broadly neutralizing antibodies (bNAbs). Here, to characterize monoclonal antibodies cross‐reactive against both SARS‐CoV‐1 and SARS‐CoV‐2 and to search the criterion for bNAbs against all emerging SARS‐CoV‐2, we isolated several SARS‐CoV‐1‐cross‐reactive monoclonal antibodies (mAbs) from a wildtype SARS‐CoV‐2 convalescent donor. These antibodies showed broad binding capacity and cross‐neutralizing potency against various SARS‐CoV‐2 VOCs, including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta), but failed to efficiently neutralize Omicron variant and its sublineages. Structural analysis revealed how Omicron sublineages, but not other VOCs, efficiently evade an antibody family cross‐reactive against SARS‐CoV‐1 through their escape mutations. Further evaluation of a series of SARS‐CoV‐1/2‐cross‐reactive bNAbs showed a negative correlation between the neutralizing activities against SARS‐CoV‐1 and SARS‐CoV‐2 Omicron variant. Together, these results suggest the necessity of using cross‐neutralization against SARS‐CoV‐1 and SARS‐CoV‐2 Omicron as criteria for rational design and development of potent pan‐sarbecovirus vaccines and bNAbs.

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“…Immune evasion of variants of concern is driven by mutations in the spike protein that threaten natural and vaccine-induced immunity. However, the presence of conserved pan-variant epitopes that conferred broad neutralization has great potential for therapy and vaccine design [20][21][22][23].…”

Section: Discussionmentioning

confidence: 99%

Humoral Response to Dengue Virus Infections Potentiates Antibody-Dependent Enhancement of SARS-CoV-2

Lechuga¹,

Temerozo²,

Napoleão-Pêgo³

et al. 2023

Preprint

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Despite successful vaccination efforts, the emergence of new SARS-CoV-2 variants poses ongoing challenges to control COVID-19. Understanding humoral responses concerning SARS-CoV-2 infections and their impact is crucial for developing future vaccines that are effective worldwide. Here, we identified 41 immunodominant linear IgG B-cell epitopes in its Spike glycoprotein with a SPOT synthesis peptide array probed with a pool of serum from hospitalized COVID-19 patients. Bioinformatics showed a restricted set of epitopes unique to SARS-CoV-2 compared to other coronavirus family members. Potential crosstalk was also detected with Dengue virus (DENV), confirmed by screening individuals infected with DENV before the COVID-19 pandemic in a commercial ELISA assay for anti-SARS-CoV-2 antibodies. Higher reactivity indices were often measured in individuals with a pre-pandemic dengue infection than those with COVID-19. A high-resolution evaluation of antibody reactivity against peptides representing epitopes in the spike protein identified ten sequences in the NTD, RBD, and S2 domains. Functionally, antibody-dependent enhancement (ADE) in SARS-CoV-2 infection of monocytes was observed with pre-pandemic dengue-positive sera. A significant increase in viral load was measured compared to controls, with no detectable neutralization or considerable cell death, suggesting its role in viral entry. This study highlights the importance of identifying the epitopes generated during the humoral response to a pathogenic infection to understand the potential interplay of previous and future conditions on disease. Vaccine development and optimization strategies should be mindful of the potential for A.D.E. that could differ geographically due to endemic biological risks.

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The neutralizing breadth of antibodies targeting diverse conserved epitopes between SARS-CoV and SARS-CoV-2

Cited by 19 publications

References 71 publications

Two antibodies show broad, synergistic neutralization against SARS-CoV-2 variants by inducing conformational change within the RBD

Two antibodies show broad, synergistic neutralization against SARS-CoV-2 variants by inducing conformational change within the RBD

Characterization of cross‐reactive monoclonal antibodies against SARS‐CoV‐1 and SARS‐CoV‐2: Implication for rational design and development of pan‐sarbecovirus vaccines and neutralizing antibodies

Humoral Response to Dengue Virus Infections Potentiates Antibody-Dependent Enhancement of SARS-CoV-2

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