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A Combination of Receptor-Binding Domain and N-Terminal Domain Neutralizing Antibodies Limits the Generation of SARS-CoV-2 Spike Neutralization-Escape Mutants.
Haslwanter, Denise; Dieterle, M Eugenia; Wec, Anna Z; O'Brien, Cecilia M; Sakharkar, Mrunal; Florez, Catalina; Tong, Karen; Rappazzo, C Garrett; Lasso, Gorka; Vergnolle, Olivia; Wirchnianski, Ariel S; Bortz, Robert H; Laudermilch, Ethan; Fels, J Maximilian; Mengotto, Amanda; Malonis, Ryan J; Georgiev, George I; Quiroz, Jose A; Wrapp, Daniel; Wang, Nianshuang; Dye, Kathryn E; Barnhill, Jason; Dye, John M; McLellan, Jason S; Daily, Johanna P; Lai, Jonathan R; Herbert, Andrew S; Walker, Laura M; Chandran, Kartik; Jangra, Rohit K.
  • Haslwanter D; Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, New York, USA.
  • Dieterle ME; Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, New York, USA.
  • Wec AZ; Adimab LLC, Lebanon, New Hampshire, USA.
  • O'Brien CM; U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA.
  • Sakharkar M; The Geneva Foundation, Tacoma, Washington, USA.
  • Florez C; Adimab LLC, Lebanon, New Hampshire, USA.
  • Tong K; Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, New York, USA.
  • Rappazzo CG; Department of Chemistry and Life Science, United States Military Academy at West Point, West Point, New York, USA.
  • Lasso G; Department of Biochemistry, Albert Einstein College of Medicine, New York, New York, USA.
  • Vergnolle O; Adimab LLC, Lebanon, New Hampshire, USA.
  • Wirchnianski AS; Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, New York, USA.
  • Bortz RH; Department of Biochemistry, Albert Einstein College of Medicine, New York, New York, USA.
  • Laudermilch E; Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, New York, USA.
  • Fels JM; Department of Biochemistry, Albert Einstein College of Medicine, New York, New York, USA.
  • Mengotto A; Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, New York, USA.
  • Malonis RJ; Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, New York, USA.
  • Georgiev GI; Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, New York, USA.
  • Quiroz JA; Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, New York, New York, USA.
  • Wrapp D; Department of Biochemistry, Albert Einstein College of Medicine, New York, New York, USA.
  • Wang N; Department of Biochemistry, Albert Einstein College of Medicine, New York, New York, USA.
  • Dye KE; Department of Biochemistry, Albert Einstein College of Medicine, New York, New York, USA.
  • Barnhill J; Department of Molecular Biosciences, The University of Texas at Austingrid.89336.37, Austin, Texas, USA.
  • Dye JM; Department of Molecular Biosciences, The University of Texas at Austingrid.89336.37, Austin, Texas, USA.
  • McLellan JS; Department of Science, Mount St. Mary's University, Emmitsburg, Maryland, USA.
  • Daily JP; Department of Chemistry and Life Science, United States Military Academy at West Point, West Point, New York, USA.
  • Lai JR; Department of Radiology and Radiological Services, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
  • Herbert AS; U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA.
  • Walker LM; Department of Molecular Biosciences, The University of Texas at Austingrid.89336.37, Austin, Texas, USA.
  • Chandran K; Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, New York, USA.
  • Jangra RK; Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, New York, New York, USA.
mBio ; 12(5): e0247321, 2021 10 26.
Article in English | MEDLINE | ID: covidwho-1450586
ABSTRACT
Most known SARS-CoV-2 neutralizing antibodies (nAbs), including those approved by the FDA for emergency use, inhibit viral infection by targeting the receptor-binding domain (RBD) of the spike (S) protein. Variants of concern (VOC) carrying mutations in the RBD or other regions of S reduce the effectiveness of many nAbs and vaccines by evading neutralization. Therefore, therapies that are less susceptible to resistance are urgently needed. Here, we characterized the memory B-cell repertoire of COVID-19 convalescent donors and analyzed their RBD and non-RBD nAbs. We found that many of the non-RBD-targeting nAbs were specific to the N-terminal domain (NTD). Using neutralization assays with authentic SARS-CoV-2 and a recombinant vesicular stomatitis virus carrying SARS-CoV-2 S protein (rVSV-SARS2), we defined a panel of potent RBD and NTD nAbs. Next, we used a combination of neutralization-escape rVSV-SARS2 mutants and a yeast display library of RBD mutants to map their epitopes. The most potent RBD nAb competed with hACE2 binding and targeted an epitope that includes residue F490. The most potent NTD nAb epitope included Y145, K150, and W152. As seen with some of the natural VOC, the neutralization potencies of COVID-19 convalescent-phase sera were reduced by 4- to 16-fold against rVSV-SARS2 bearing Y145D, K150E, or W152R spike mutations. Moreover, we found that combining RBD and NTD nAbs did not enhance their neutralization potential. Notably, the same combination of RBD and NTD nAbs limited the development of neutralization-escape mutants in vitro, suggesting such a strategy may have higher efficacy and utility for mitigating the emergence of VOC. IMPORTANCE The U.S. FDA has issued emergency use authorizations (EUAs) for multiple investigational monoclonal antibody (MAb) therapies for the treatment of mild to moderate COVID-19. These MAb therapeutics are solely targeting the receptor-binding domain of the SARS-CoV-2 spike protein. However, the N-terminal domain of the spike protein also carries crucial neutralizing epitopes. Here, we show that key mutations in the N-terminal domain can reduce the neutralizing capacity of convalescent-phase COVID-19 sera. We report that a combination of two neutralizing antibodies targeting the receptor-binding and N-terminal domains may be beneficial to combat the emergence of virus variants.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antibodies, Neutralizing / RNA-Binding Motifs / SARS-CoV-2 / COVID-19 / Mutation Topics: Vaccines / Variants Limits: Humans Language: English Journal: MBio Year: 2021 Document Type: Article Affiliation country: MBio.02473-21

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antibodies, Neutralizing / RNA-Binding Motifs / SARS-CoV-2 / COVID-19 / Mutation Topics: Vaccines / Variants Limits: Humans Language: English Journal: MBio Year: 2021 Document Type: Article Affiliation country: MBio.02473-21