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Effects of human anti-spike protein receptor binding domain antibodies on severe acute respiratory syndrome coronavirus neutralization escape and fitness.
J Virol. 2014 Dec; 88(23):13769-80.JV

Abstract

The receptor binding domain (RBD) of the spike (S) glycoprotein of severe acute respiratory syndrome coronavirus (SARS-CoV) is a major target of protective immunity in vivo. Although a large number of neutralizing antibodies (nAbs) have been developed, it remains unclear if a single RBD-targeting nAb or two in combination can prevent neutralization escape and, if not, attenuate viral virulence in vivo. In this study, we used a large panel of human nAbs against an epitope that overlaps the interface between the RBD and its receptor, angiotensin-converting enzyme 2 (ACE2), to assess their cross-neutralization activities against a panel of human and zoonotic SARS-CoVs and neutralization escape mutants. We also investigated the neutralization escape profiles of these nAbs and evaluated their effects on receptor binding and virus fitness in vitro and in mice. We found that some nAbs had great potency and breadth in neutralizing multiple viral strains, including neutralization escape viruses derived from other nAbs; however, no single nAb or combination of two blocked neutralization escape. Interestingly, in mice the neutralization escape mutant viruses showed either attenuation (Urbani background) or increased virulence (GD03 background) consistent with the different binding affinities between their RBDs and the mouse ACE2. We conclude that using either single nAbs or dual nAb combinations to target a SARS-CoV RBD epitope that shows plasticity may have limitations for preventing neutralization escape during in vivo immunotherapy. However, RBD-directed nAbs may be useful for providing broad neutralization and prevention of escape variants when combined with other nAbs that target a second conserved epitope with less plasticity and more structural constraint.

IMPORTANCE

The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 has resulted in severe human respiratory disease with high death rates. Their zoonotic origins highlight the likelihood of reemergence or further evolution into novel human coronavirus pathogens. Broadly neutralizing antibodies (nAbs) that prevent infection of related viruses represent an important immunostrategy for combating coronavirus infections; however, for this strategy to succeed, it is essential to uncover nAb-mediated escape pathways and to pioneer strategies that prevent escape. Here, we used SARS-CoV as a research model and examined the escape pathways of broad nAbs that target the receptor binding domain (RBD) of the virus. We found that neither single nAbs nor two nAbs in combination blocked escape. Our results suggest that targeting conserved regions with less plasticity and more structural constraint rather than the SARS-CoV RBD-like region(s) should have broader utility for antibody-based immunotherapy.

Authors+Show Affiliations

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, Boston Massachusetts, USA.Departments of Epidemiology and Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA.Departments of Epidemiology and Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA.Infectious and Inflammatory Disease Center, Stanford-Burnham Medical Research Institute, La Jolla, California, USA.Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, Boston Massachusetts, USA.Departments of Epidemiology and Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA rbaric@email.unc.edu wayne_marasco@dfci.harvard.edu.Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, Boston Massachusetts, USA rbaric@email.unc.edu wayne_marasco@dfci.harvard.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

25231316

Citation

Sui, Jianhua, et al. "Effects of Human Anti-spike Protein Receptor Binding Domain Antibodies On Severe Acute Respiratory Syndrome Coronavirus Neutralization Escape and Fitness." Journal of Virology, vol. 88, no. 23, 2014, pp. 13769-80.
Sui J, Deming M, Rockx B, et al. Effects of human anti-spike protein receptor binding domain antibodies on severe acute respiratory syndrome coronavirus neutralization escape and fitness. J Virol. 2014;88(23):13769-80.
Sui, J., Deming, M., Rockx, B., Liddington, R. C., Zhu, Q. K., Baric, R. S., & Marasco, W. A. (2014). Effects of human anti-spike protein receptor binding domain antibodies on severe acute respiratory syndrome coronavirus neutralization escape and fitness. Journal of Virology, 88(23), 13769-80. https://doi.org/10.1128/JVI.02232-14
Sui J, et al. Effects of Human Anti-spike Protein Receptor Binding Domain Antibodies On Severe Acute Respiratory Syndrome Coronavirus Neutralization Escape and Fitness. J Virol. 2014;88(23):13769-80. PubMed PMID: 25231316.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of human anti-spike protein receptor binding domain antibodies on severe acute respiratory syndrome coronavirus neutralization escape and fitness. AU - Sui,Jianhua, AU - Deming,Meagan, AU - Rockx,Barry, AU - Liddington,Robert C, AU - Zhu,Quan Karen, AU - Baric,Ralph S, AU - Marasco,Wayne A, Y1 - 2014/09/17/ PY - 2014/9/19/entrez PY - 2014/9/19/pubmed PY - 2015/2/19/medline SP - 13769 EP - 80 JF - Journal of virology JO - J Virol VL - 88 IS - 23 N2 - UNLABELLED: The receptor binding domain (RBD) of the spike (S) glycoprotein of severe acute respiratory syndrome coronavirus (SARS-CoV) is a major target of protective immunity in vivo. Although a large number of neutralizing antibodies (nAbs) have been developed, it remains unclear if a single RBD-targeting nAb or two in combination can prevent neutralization escape and, if not, attenuate viral virulence in vivo. In this study, we used a large panel of human nAbs against an epitope that overlaps the interface between the RBD and its receptor, angiotensin-converting enzyme 2 (ACE2), to assess their cross-neutralization activities against a panel of human and zoonotic SARS-CoVs and neutralization escape mutants. We also investigated the neutralization escape profiles of these nAbs and evaluated their effects on receptor binding and virus fitness in vitro and in mice. We found that some nAbs had great potency and breadth in neutralizing multiple viral strains, including neutralization escape viruses derived from other nAbs; however, no single nAb or combination of two blocked neutralization escape. Interestingly, in mice the neutralization escape mutant viruses showed either attenuation (Urbani background) or increased virulence (GD03 background) consistent with the different binding affinities between their RBDs and the mouse ACE2. We conclude that using either single nAbs or dual nAb combinations to target a SARS-CoV RBD epitope that shows plasticity may have limitations for preventing neutralization escape during in vivo immunotherapy. However, RBD-directed nAbs may be useful for providing broad neutralization and prevention of escape variants when combined with other nAbs that target a second conserved epitope with less plasticity and more structural constraint. IMPORTANCE: The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 has resulted in severe human respiratory disease with high death rates. Their zoonotic origins highlight the likelihood of reemergence or further evolution into novel human coronavirus pathogens. Broadly neutralizing antibodies (nAbs) that prevent infection of related viruses represent an important immunostrategy for combating coronavirus infections; however, for this strategy to succeed, it is essential to uncover nAb-mediated escape pathways and to pioneer strategies that prevent escape. Here, we used SARS-CoV as a research model and examined the escape pathways of broad nAbs that target the receptor binding domain (RBD) of the virus. We found that neither single nAbs nor two nAbs in combination blocked escape. Our results suggest that targeting conserved regions with less plasticity and more structural constraint rather than the SARS-CoV RBD-like region(s) should have broader utility for antibody-based immunotherapy. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/25231316/Effects_of_human_anti_spike_protein_receptor_binding_domain_antibodies_on_severe_acute_respiratory_syndrome_coronavirus_neutralization_escape_and_fitness_ L2 - https://journals.asm.org/doi/10.1128/JVI.02232-14?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -