Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody

Rappazzo, C. Garrett; Tse, Longping V.; Kaku, Chengzi I.; Wrapp, Daniel; Sakharkar, Mrunal; Huang, Deli; Deveau, Laura M.; Yockachonis, Thomas J.; Herbert, Andrew S.; Battles, Michael B.; O’Brien, Cecilia M.; Brown, Michael E.; Geoghegan, James C.; Belk, Jonathan Philip; Peng, Linghang; Yang, Linlin; Hou, Yixuan J.; Scobey, Trevor; Burton, Dennis R.; Nemazee, David; Dye, John M.; Voss, James E.; Gunn, Bronwyn M.; McLellan, Jason S.; Baric, Ralph S.; Gralinski, Lisa E.; Walker, Laura M.

doi:10.1126/science.abf4830

Cited by 307 publications

(324 citation statements)

References 52 publications

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“…We tested our panel of viruses for antibody-mediated neutralization in Vero-hACE2-TMPRSS2 cells and then repeated some experiments with Vero-TMPRSS2 cells to evaluate for effects of hACE2 over-expression on neutralization 17 . We performed high-throughput focus reduction neutralization tests (FRNTs) 18 using a panel of neutralizing mAbs recognizing distinct and overlapping epitopes in the RBD, including some having potential use in humans.…”

Section: Resultsmentioning

confidence: 99%

Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies

Chen

Zhang

Case

et al. 2021

Nat Med

902

962

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evere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic infecting more than 111 million people and causing 2.4 million deaths. Clinical disease in humans ranges from asymptomatic infection to pneumonia, severe respiratory compromise, multi-organ failure and systemic inflammatory syndromes. The rapid expansion and prolonged nature of the COVID-19 pandemic and its accompanying morbidity, mortality and destabilizing socioeconomic effects have made the development of SARS-CoV-2 therapeutics and vaccines an urgent global health priority 1. Indeed, the emergency use authorization and rapid deployment of antibody-based countermeasures, including mAbs, immune plasma therapy and messenger RNA, and inactivated and viral-vectored vaccines has provided hope for curtailing disease and ending the pandemic. The spike protein of the SARS-CoV-2 virion binds the cell-surface receptor angiotensin-converting enzyme 2 (ACE2) to promote entry into human cells 2. Because the spike protein is critical for viral entry, it has been targeted for vaccine development and therapeutic antibody interventions. SARS-CoV-2 S proteins are cleaved to yield S1 and S2 fragments. The S1 protein includes the N-terminal (NTD) and receptor-binding (RBD) domains, whereas the S2 protein promotes membrane fusion. The RBD is recognized by many potently neutralizing monoclonal antibodies 3-7 , protein-based inhibitors 8 and serum antibodies 9. The current suite of antibody therapeutics and vaccines was designed with a spike protein based on strains circulating during the early phases of the pandemic in 2020. More recently, variants with enhanced transmissibility have emerged in the United Kingdom (B.1.1.7), South Africa (B.1.351), Brazil (B.1.1.248) and elsewhere with multiple substitutions in the spike protein, including in the NTD and the receptor-binding motif (RBM) of the RBD. Preliminary studies with pseudoviruses suggest that neutralization by some antibodies and immune sera may be diminished against variants expressing mutations in the spike gene 10-13. Given these

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Section: Resultsmentioning

confidence: 99%

Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies

Chen

Zhang

Case

et al. 2021

Nat Med

902

962

View full text Add to dashboard Cite

show abstract

“…We tested our panel of viruses for antibody-mediated neutralization in Vero-hACE2-TMPRSS2 cells and then repeated some experiments with Vero-TMPRSS2 cells to evaluate for effects of hACE2 over-expression on neutralization 8 . We performed high-throughput focus reduction neutralization tests (FRNTs) 9 using a panel of neutralizing mAbs recognizing distinct and overlapping epitopes in the RBD including some having potential use in humans.…”

Section: Full Textmentioning

confidence: 99%

SARS-CoV-2 variants show resistance to neutralization by many monoclonal and serum-derived polyclonal antibodies

Diamond¹,

Chen²,

Xie

et al. 2021

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic infecting more than 106 million people and causing 2.3 million deaths. The rapid deployment of antibody-based countermeasures has provided hope for curtailing disease and ending the pandemic1. However, the emergence of rapidly-spreading SARS-CoV-2 variants in the United Kingdom (B.1.1.7), South Africa (B.1.351), and elsewhere with mutations in the spike protein has raised concern for escape from neutralizing antibody responses and loss of vaccine efficacy based on preliminary data with pseudoviruses2-4. Here, using monoclonal antibodies (mAbs), animal immune sera, human convalescent sera, and human sera from recipients of the Pfizer-BioNTech (BNT162b2) mRNA vaccine, we report the impact on antibody neutralization of a panel of authentic SARS-CoV-2 variants including a B.1.1.7 isolate, a chimeric Washington strain with a South African spike gene (Wash SA-B.1.351), and isogenic recombinant variants with designed mutations or deletions at positions 69-70, 417, 484, 501, and/or 614 of the spike protein. Several highly neutralizing mAbs engaging the receptor binding domain (RBD) or N-terminal domain (NTD) lost inhibitory activity against Wash SA-B.1.351 or recombinant variants with an E484K spike mutation. Most convalescent sera and virtually all mRNA vaccine-induced immune sera tested showed markedly diminished neutralizing activity against the Wash SA-B.1.351 strain or recombinant viruses containing mutations at position 484 and 501. We also noted that cell line selection used for growth of virus stocks or neutralization assays can impact the potency of antibodies against different SARS-CoV-2 variants, which has implications for assay standardization and congruence of results across laboratories. As several antibodies binding specific regions of the RBD and NTD show loss-of-neutralization potency in vitro against emerging variants, updated mAb cocktails, targeting of highly conserved regions, enhancement of mAb potency, or adjustments to the spike sequences of vaccines may be needed to prevent loss of protection in vivo.

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“…We and others have demonstrated the SARS-CoV-2 RBD has an epitope to which broadly cross-reactive neutralizing antibodies can bind 13,24,32 , and the DH1047 RBD antibody cross-neutralizes SARS-CoV-1, CoV-2 and bat CoVs 24 .To focus the immune response on cross-reactive neutralizing epitopes on betaCoVs, we designed a 24-mer SARS-CoV-2 RBD-ferritin nanoparticle vaccine. The RBD nanoparticle was constructed by first expressing recombinant SARS-CoV-2 RBD with a C-terminal sortase A donor sequence.…”

Section: Mainmentioning

confidence: 99%

SARS-CoV-2 vaccination induces neutralizing antibodies against pandemic and pre-emergent SARS-related coronaviruses in monkeys

Saunders

Lee

Parks

et al. 2021

Preprint

Self Cite

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Betacoronaviruses (betaCoVs) caused the severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks, and now the SARS-CoV-2 pandemic. Vaccines that elicit protective immune responses against SARS-CoV-2 and betaCoVs circulating in animals have the potential to prevent future betaCoV pandemics. Here, we show that immunization of macaques with a multimeric SARS-CoV-2 receptor binding domain (RBD) nanoparticle adjuvanted with 3M-052-Alum elicited cross-neutralizing antibody responses against SARS-CoV-1, SARS-CoV-2, batCoVs and the UK B.1.1.7 SARS-CoV-2 mutant virus. Nanoparticle vaccination resulted in a SARS-CoV-2 reciprocal geometric mean neutralization titer of 47,216, and robust protection against SARS-CoV-2 in macaque upper and lower respiratory tracts. Importantly, nucleoside-modified mRNA encoding a stabilized transmembrane spike or monomeric RBD protein also induced SARS-CoV-1 and batCoV cross-neutralizing antibodies, albeit at lower titers. These results demonstrate current mRNA vaccines may provide some protection from future zoonotic betaCoV outbreaks, and provide a platform for further development of pan-betaCoV nanoparticle vaccines.

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Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody

Cited by 307 publications

References 52 publications

Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies

Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies

SARS-CoV-2 variants show resistance to neutralization by many monoclonal and serum-derived polyclonal antibodies

SARS-CoV-2 vaccination induces neutralizing antibodies against pandemic and pre-emergent SARS-related coronaviruses in monkeys

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