Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein

Suryadevara, Naveenchandra; Shrihari, Swathi; Gilchuk, Pavlo; VanBlargan, Laura A.; Binshtein, Elad; Zost, Seth J.; Nargi, Rachel S.; Sutton, Rachel E.; Winkler, Emma S.; Chen, Elaine C.; Fouch, Mallorie E.; Davidson, Edgar; Doranz, Benjamin J.; Chen, Rita E.; Shi, Pei Yong; Carnahan, Robert H.; Thackray, Larissa B.; Diamond, Michael S.

doi:10.1016/j.cell.2021.03.029

Cited by 377 publications

(418 citation statements)

References 90 publications

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“…Whereas RBD neutralizing mAbs target various antigenic sites, all known NTD-specific neutralizing mAbs recognize the same antigenic supersite( 12 , 16 – 18 ). Both types of mAbs represent a key aspect of immunity to SARS-CoV-2 influencing viral evolution( 12 ).…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 immune evasion by variant B.1.427/B.1.429

McCallum

Bassi

Marco

et al. 2021

Preprint

153

186

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SARS-CoV-2 entry is mediated by the spike (S) glycoprotein which contains the receptor-binding domain (RBD) and the N-terminal domain (NTD) as the two main targets of neutralizing antibodies (Abs). A novel variant of concern (VOC) named CAL.20C (B.1.427/B.1.429) was originally detected in California and is currently spreading throughout the US and 29 additional countries. It is unclear whether antibody responses to SARS-CoV-2 infection or to the prototypic Wuhan-1 isolate-based vaccines will be impacted by the three B.1.427/B.1.429 S mutations: S13I, W152C and L452R. Here, we assessed neutralizing Ab responses following natural infection or mRNA vaccination using pseudoviruses expressing the wildtype or the B.1.427/B.1.429 S protein. Plasma from vaccinated or convalescent individuals exhibited neutralizing titers, which were reduced 3-6 fold against the B.1.427/B.1.429 variant relative to wildtype pseudoviruses. The RBD L452R mutation reduced or abolished neutralizing activity of 14 out of 35 RBD-specific monoclonal antibodies (mAbs), including three clinical-stage mAbs. Furthermore, we observed a complete loss of B.1.427/B.1.429 neutralization for a panel of mAbs targeting the N-terminal domain due to a large structural rearrangement of the NTD antigenic supersite involving an S13I-mediated shift of the signal peptide cleavage site. These data warrant closer monitoring of signal peptide variants and their involvement in immune evasion and show that Abs directed to the NTD impose a selection pressure driving SARS-CoV-2 viral evolution through conventional and unconventional escape mechanisms.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 immune evasion by variant B.1.427/B.1.429

McCallum

Bassi

Marco

et al. 2021

Preprint

153

186

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“…Assessment of antibody responses to different betacoronaviruses has recently underlined that the SARS-CoV-2 RBD is the prime target for COVID-19 vaccination. While SARS-CoV-1 and MERS-CoV S proteins encode a number of VNA epitopes located outside of the RBD, the SARS-CoV-2 RBD seems to account for almost all human antibodies with potent neutralization capacity [22,[32][33][34]77], with rare exceptions [78,79]. Furthermore, presentation of the antigen is key for the success of immunization.…”

Section: Plos Pathogensmentioning

confidence: 99%

Safe and effective two-in-one replicon-and-VLP minispike vaccine for COVID-19: Protection of mice after a single immunization

et al. 2021

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Vaccines of outstanding efficiency, safety, and public acceptance are needed to halt the current SARS-CoV-2 pandemic. Concerns include potential side effects caused by the antigen itself and safety of viral DNA and RNA delivery vectors. The large SARS-CoV-2 spike (S) protein is the main target of current COVID-19 vaccine candidates but can induce non-neutralizing antibodies, which might cause vaccination-induced complications or enhancement of COVID-19 disease. Besides, encoding of a functional S in replication-competent virus vector vaccines may result in the emergence of viruses with altered or expanded tropism. Here, we have developed a safe single round rhabdovirus replicon vaccine platform for enhanced presentation of the S receptor-binding domain (RBD). Structure-guided design was employed to build a chimeric minispike comprising the globular RBD linked to a transmembrane stem-anchor sequence derived from rabies virus (RABV) glycoprotein (G). Vesicular stomatitis virus (VSV) and RABV replicons encoding the minispike not only allowed expression of the antigen at the cell surface but also incorporation into the envelope of secreted non-infectious particles, thus combining classic vector-driven antigen expression and particulate virus-like particle (VLP) presentation. A single dose of a prototype replicon vaccine complemented with VSV G, VSVΔG-minispike-eGFP (G), stimulated high titers of SARS-CoV-2 neutralizing antibodies in mice, equivalent to those found in COVID-19 patients, and protected transgenic K18-hACE2 mice from COVID-19-like disease. Homologous boost immunization further enhanced virus neutralizing activity. The results demonstrate that non-spreading rhabdovirus RNA replicons expressing minispike proteins represent effective and safe alternatives to vaccination approaches using replication-competent viruses and/or the entire S antigen.

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“…Indeed, FcγR engagement mediates pleiotropic antiviral immune functions, including the clearance of viral particles 9,10 , the cytotoxic elimination of virus-infected cells 11 , as well as the induction of protective T cell responses that contribute to antiviral immunity [12][13][14] . In the context of SARS-CoV-2 infection, a growing body of experimental evidence from various animal disease models supports that Fc-FcγR interactions are essential for the in vivo antiviral activity of anti-SARS-CoV-2 mAbs, as loss of the capacity of the Fc domain of these mAbs to engage FcγRs is associated with reduced antiviral activity in vivo [15][16][17][18] .…”

mentioning

confidence: 99%

“…This was due to presumptive safety concerns over the capacity of antibodies to exacerbate disease through ADE (antibodydependent enhancement) mechanisms 8 . However, numerous in vivo studies in animal disease models have failed to provide evidence for ADE [15][16][17][18][19] , and therapeutic administration of high doses of convalescent plasma or neutralizing anti-SARS-CoV-2 mAbs in COVID-19 patients has not been associated with worse disease outcomes [1][2][3]5,20 . Likewise, comparable safety profiles were evident in clinical trials of neutralizing mAbs with intact or diminished Fc effector function.…”

mentioning

confidence: 99%

Fc-engineered antibody therapeutics with improved efficacy against COVID-19

Ravetch

Yamin

Jones

et al. 2021

Preprint

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Monoclonal antibodies (mAbs) with neutralizing activity against SARS-CoV-2 have demonstrated clinical benefit in cases of mild to moderate SARS-CoV-2 infection, substantially reducing the risk for hospitalization and severe disease1-4. Treatment generally requires the administration of high doses of these mAbs with limited efficacy in preventing disease complications or mortality among hospitalized COVID-19 patients5. Here we report the development and evaluation of Fc-optimized anti-SARS-CoV-2 mAbs with superior potency to prevent or treat COVID-19 disease. In several animal models of COVID-19 disease6,7, we demonstrate that selective engagement of activating FcγRs results in improved efficacy in both preventing and treating disease-induced weight loss and mortality, significantly reducing the dose required to confer full protection upon SARS-CoV-2 challenge and treatment of pre-infected animals. Our results highlight the importance of FcγR pathways in driving antibody-mediated antiviral immunity, while excluding any pathogenic or disease-enhancing effects of FcγR engagement of anti-SARS-CoV-2 antibodies upon infection. These findings have important implications for the development of Fc-engineered mAbs with optimal Fc effector function and improved clinical efficacy against COVID-19 disease.

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Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein

Cited by 377 publications

References 90 publications

SARS-CoV-2 immune evasion by variant B.1.427/B.1.429

SARS-CoV-2 immune evasion by variant B.1.427/B.1.429

Safe and effective two-in-one replicon-and-VLP minispike vaccine for COVID-19: Protection of mice after a single immunization

Fc-engineered antibody therapeutics with improved efficacy against COVID-19

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