Structural basis for broad coronavirus neutralization

Sauer, M.M.; Tortorici, Marcello; Park, Young-Jun; Walls, Alexandra C.; Homad, Leah J.; Acton, Oliver; Bowen, John E.; Wang, Chunyan; Xiong, Xiaoli; Schueren, Willem de van der; Quispe, Joel; Hoffstrom, Benjamin G.; Bosch, Berend-Jan; McGuire, Andrew T.; Veesler, David

doi:10.1101/2020.12.29.424482

Cited by 76 publications

(123 citation statements)

References 151 publications

Supporting

Mentioning

117

Contrasting

Order By: Relevance

“…However, the ACE2-binding region of the RBD also tends to accumulate amino acid changes, as evidenced by substitutions identified in the current SARS-CoV-2 variants of concern (Annavajhala et al, 2021;Faria et al, 2021;Rambaut et al, 2020;Tegally et al, 2020;Voloch et al, 2020;West et al, 2021;Zhang et al, 2021), thus reducing the potential efficacies of vaccines and monoclonal antibody therapies. Recent studies suggest that antibodies against the S2 subunit offer the potential of greater cross-reactivity across coronaviruses, but these antibodies generally lack strong neutralization potency (Sauer et al, 2021;Shah et al, 2021;Wang et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies

Jette

Cohen

Gnanapragasam

et al. 2021

Preprint

View full text Add to dashboard Cite

SummaryMany anti-SARS-CoV-2 neutralizing antibodies target the ACE2-binding site on viral spike receptor-binding domains (RBDs). The most potent antibodies recognize exposed variable epitopes, often rendering them ineffective against other sarbecoviruses and SARS-CoV-2 variants. Class 4 anti-RBD antibodies against a less-exposed, but more-conserved, cryptic epitope could recognize newly-emergent zoonotic sarbecoviruses and variants, but usually show only weak neutralization potencies. We characterized two class 4 anti-RBD antibodies derived from COVID-19 donors that exhibited broad recognition and potent neutralization of zoonotic coronavirus and SARS-CoV-2 variants. C118-RBD and C022-RBD structures revealed CDRH3 mainchain H-bond interactions that extended an RBD β-sheet, thus reducing sensitivity to RBD sidechain changes, and epitopes that extended from the cryptic epitope to occlude ACE2 binding. A C118-spike trimer structure revealed rotated RBDs to allow cryptic epitope access and the potential for intra-spike crosslinking to increase avidity. These studies facilitate vaccine design and illustrate potential advantages of class 4 RBD-binding antibody therapeutics.

show abstract

Section: Discussionmentioning

confidence: 99%

Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies

Jette

Cohen

Gnanapragasam

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…D614G SARS-CoV-2 S (YP 009724390.1), RaTG13 S (QHR63300.2), Pangolin-Guangdong S (QLR06867.1), SARS-CoV S (YP 009825051.1), WIV1 S (AGZ48831.1), B.1.351 S and B1.1.7 S pseudotypes VSV viruses were prepared as described previously 54,86 . Briefly, 293T cells in DMEM supplemented with 10% FBS, 1% PenStrep seeded in 10-cm dishes were transfected with the plasmid encoding for the corresponding S glycoprotein using lipofectamine 2000 (Life Technologies) following manufacturer’s indications.…”

Section: Methods Detailsmentioning

confidence: 99%

Elicitation of broadly protective sarbecovirus immunity by receptor-binding domain nanoparticle vaccines

Walls

Miranda

Pham

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Understanding the ability of SARS-CoV-2 vaccine-elicited antibodies to neutralize and protect against emerging variants of concern and other sarbecoviruses is key for guiding vaccine development decisions and public health policies. We show that a clinical stage multivalent SARS-CoV-2 receptor-binding domain nanoparticle vaccine (SARS-CoV-2 RBD-NP) protects mice from SARS-CoV-2-induced disease after a single shot, indicating that the vaccine could allow dose-sparing. SARS-CoV-2 RBD-NP elicits high antibody titers in two non-human primate (NHP) models against multiple distinct RBD antigenic sites known to be recognized by neutralizing antibodies. We benchmarked NHP serum neutralizing activity elicited by RBD-NP against a lead prefusion-stabilized SARS-CoV-2 spike immunogen using a panel of single-residue spike mutants detected in clinical isolates as well as the B.1.1.7 and B.1.351 variants of concern. Polyclonal antibodies elicited by both vaccines are resilient to most RBD mutations tested, but the E484K substitution has similar negative consequences for neutralization, and exhibit modest but comparable neutralization breadth against distantly related sarbecoviruses. We demonstrate that mosaic and cocktail sarbecovirus RBD-NPs elicit broad sarbecovirus neutralizing activity, including against the SARS-CoV-2 B.1.351 variant, and protect mice against severe SARS-CoV challenge even in the absence of the SARS-CoV RBD in the vaccine. This study provides proof of principle that sarbecovirus RBD-NPs induce heterotypic protection and enables advancement of broadly protective sarbecovirus vaccines to the clinic.

show abstract

“…When it comes to MERS-CoV-specific NmAbs with cross-neutralizing activity against SARS-CoV-2, aside from Chouchane et al ( Chouchane et al, 2021 ) who recently identified MERS-CoV-specific pAbs from non-immunized camel, with SARS-CoV-2 cross neutralization, but without further characterization, only one SARS- and MERS-CoV specific antibody, namely B6 was able to cross-neutralize SARS-CoV-2 in nanomolar concentration range ( Sauer et al, 2021 ).…”

Section: Sars-cov-2 Nmab Molecular Neutralizing Activitiesmentioning

confidence: 99%

Potent Molecular Feature-based Neutralizing Monoclonal Antibodies as Promising Therapeutics Against SARS-CoV-2 Infection

Kombe

Zahid

Mohammed

et al. 2021

Front. Mol. Biosci.

View full text Add to dashboard Cite

The 2019–2020 winter was marked by the emergence of a new coronavirus (SARS-CoV-2) related disease (COVID-19), which started in Wuhan, China. Its high human-to-human transmission ability led to a worldwide spread within few weeks and has caused substantial human loss. Mechanical antiviral control approach, drug repositioning, and use of COVID-19 convalescent plasmas (CPs) were the first line strategies utilized to mitigate the viral spread, yet insufficient. The urgent need to contain this deadly pandemic has led searchers and pharmaceutical companies to develop vaccines. However, not all vaccines manufactured are safe. Besides, an alternative and effective treatment option for such an infectious disease would include pure anti-viral neutralizing monoclonal antibodies (NmAbs), which can block the virus at specific molecular targets from entering cells by inhibiting virus-cell structural complex formation, with more safety and efficiency than the CP. Indeed, there is a lot of molecular evidence about the protector effect and the use of molecular feature-based NmAbs as promising therapeutics to contain COVID-19. Thus, from the scientific publication database screening, we here retrieved antibody-related papers and summarized the repertory of characterized NmAbs against SARS-CoV-2, their molecular neutralization mechanisms, and their immunotherapeutic pros and cons. About 500 anti-SARS-CoV-2 NmAbs, characterized through competitive binding assays and neutralization efficacy, were reported at the writing time (January 2021). All NmAbs bind respectively to SARS-CoV-2 S and exhibit high molecular neutralizing effects against wild-type and/or pseudotyped virus. Overall, we defined six NmAb groups blocking SARS-CoV-2 through different molecular neutralization mechanisms, from which five potential neutralization sites on SARS-CoV-2 S protein are described. Therefore, more efforts are needed to develop NmAbs-based cocktails to mitigate COVID-19.

show abstract

Structural basis for broad coronavirus neutralization

Cited by 76 publications

References 151 publications

Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies

Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies

Elicitation of broadly protective sarbecovirus immunity by receptor-binding domain nanoparticle vaccines

Potent Molecular Feature-based Neutralizing Monoclonal Antibodies as Promising Therapeutics Against SARS-CoV-2 Infection

Contact Info

Product

Resources

About