Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike

Huo, Jiandong; Zhao, Yumin; Ren, Ji Hua; Zhou, Dongbo; Hme., Duyvesteyn; Ginn, H.; Carrique, L.; Malinauskas, Tomas; Ruza, R.R.; Shah, Pranav N.M.; Tan, Tiong Kit; Rijal, Pramila; Coombes, Naomi; Bewley, Kevin R.; Tree, Julia A.; Radecke, Julika; Paterson, Neil G.; Supasa, Piyada; Mongkolsapaya, Juthathip; Screaton, Gavin; Carroll, Miles W.; Townsend, Alain; Fry, E.E.; Owens, Raymond J.; Stuart, D.

doi:10.1016/j.chom.2020.07.002

Cited by 63 publications

(42 citation statements)

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“…RBD antibody response in the convalescent plasma was tested on a cell-based RBD ELISA, since human plasma gives high background on NUNC plates in our hands. MDCK-RBD cells were generated as previously described 26 , 29 , 66 . Briefly, MDCK-SIAT1 cells (ECACC 05071502) 67 were stably transfected using lentiviral vector to express SARS-CoV-2 RBD (amino acid 331–529, NITN…GPKK 6 ) fused at the C-terminus to the transmembrane domain of HA H7 (A/HongKong/125/2017) (EPI977395) (KLSSGYKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI) for surface expression.…”

Section: Methodsmentioning

confidence: 99%

A COVID-19 vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain induces potent neutralising antibody responses

et al. 2021

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There is need for effective and affordable vaccines against SARS-CoV-2 to tackle the ongoing pandemic. In this study, we describe a protein nanoparticle vaccine against SARS-CoV-2. The vaccine is based on the display of coronavirus spike glycoprotein receptor-binding domain (RBD) on a synthetic virus-like particle (VLP) platform, SpyCatcher003-mi3, using SpyTag/SpyCatcher technology. Low doses of RBD-SpyVLP in a prime-boost regimen induce a strong neutralising antibody response in mice and pigs that is superior to convalescent human sera. We evaluate antibody quality using ACE2 blocking and neutralisation of cell infection by pseudovirus or wild-type SARS-CoV-2. Using competition assays with a monoclonal antibody panel, we show that RBD-SpyVLP induces a polyclonal antibody response that recognises key epitopes on the RBD, reducing the likelihood of selecting neutralisation-escape mutants. Moreover, RBD-SpyVLP is thermostable and can be lyophilised without losing immunogenicity, to facilitate global distribution and reduce cold-chain dependence. The data suggests that RBD-SpyVLP provides strong potential to address clinical and logistic challenges of the COVID-19 pandemic.

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Section: Methodsmentioning

confidence: 99%

A COVID-19 vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain induces potent neutralising antibody responses

et al. 2021

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“…Spike pseudotypes were generated and used in neutralization assays with HEK293T cells expressing ACE2 on the surface; the assays were performed using established vectors and protocols. 39 14,15,17,[40][41][42] Next, we tested the neutralization profile of the bispecific VH/Fab IgGs. To our surprise, we found that bispecifics that use the non-neutralizing Fab D01 neutralized significantly more potently than the parental mono-specific binders.…”

Section: Bispecific Kih Iggs Show Enhanced Neutralization Against Psementioning

confidence: 99%

Bispecific VH/Fab antibodies targeting neutralizing and non-neutralizing Spike epitopes demonstrate enhanced potency against SARS-CoV-2

Lim

Gramespacher

Pance

et al. 2021

mAbs

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Numerous neutralizing antibodies that target SARS-CoV-2 have been reported, and most directly block binding of the viral Spike receptor-binding domain (RBD) to angiotensin-converting enzyme II (ACE2). Here, we deliberately exploit non-neutralizing RBD antibodies, showing they can dramatically assist in neutralization when linked to neutralizing binders. We identified antigen-binding fragments (Fabs) by phage display that bind RBD, but do not block ACE2 or neutralize virus as IgGs. When these nonneutralizing Fabs were assembled into bispecific VH/Fab IgGs with a neutralizing VH domain, we observed a ~ 25-fold potency improvement in neutralizing SARS-CoV-2 compared to the mono-specific bi-valent VH-Fc alone or the cocktail of the VH-Fc and IgG. This effect was epitope-dependent, reflecting the unique geometry of the bispecific antibody toward Spike. Our results show that a bispecific antibody that combines both neutralizing and non-neutralizing epitopes on Spike-RBD is a promising and rapid engineering strategy to improve the potency of SARS-CoV-2 antibodies.

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“…Yuan et al. [ 46 ] have revealed the key motifs of the IGHV3–53 germline-derived NAbs for binding to RBD, which include the 32 NY 33 motif from heavy-chain complementarity-determining region 1 (HCDR1) and the 53 SGGS 56 motif from HCDR2. This information may help to investigate the specific binding mode of IGHV3-53 germline-derived antibodies and the corresponding epitopes.…”

Section: Nabs Targeting Sars-cov-2 Rbdmentioning

confidence: 99%

Neutralizing antibodies against SARS-CoV-2: current understanding, challenge and perspective

Huang

Sun

et al. 2020

Antibody Therapeutics

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The rapid emergence of Coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome 2 coronavirus (SARS-CoV-2) as a pandemic that presents an urgent human health crisis. Many SARS-CoV-2 neutralizing antibodies (NAbs) were developed with efficient therapeutic potential. NAbs-based therapeutics against SARS-CoV-2 are being expedited to preclinical and clinical studies with two antibody drugs, LY3819253 (LY-CoV555) and REGN-COV2 (REGN10933 and REGN10987), approved by the US Food and Drug Administration for emergency use authorization for treating COVID-19. In this review, we provide a systemic overview of SARS-CoV-2 specific or cross-reactive NAbs and discuss their structures, functions and neutralization mechanisms. We provide insight into how these NAbs specific recognize the spike protein of SARS-CoV-2 or cross-react to other CoVs. We also summarize the challenges of NAbs therapeutics such as antibody-dependent enhancement and viral escape mutations. Such evidence is urgently needed to the development of antibody therapeutic interventions that are likely required to reduce the global burden of COVID-19.

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Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike

Cited by 63 publications

References 0 publications

A COVID-19 vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain induces potent neutralising antibody responses

A COVID-19 vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain induces potent neutralising antibody responses

Bispecific VH/Fab antibodies targeting neutralizing and non-neutralizing Spike epitopes demonstrate enhanced potency against SARS-CoV-2

Neutralizing antibodies against SARS-CoV-2: current understanding, challenge and perspective

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