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An Engineered Receptor-Binding Domain Improves the Immunogenicity of Multivalent SARS-CoV-2 Vaccines.
Guo, Yan; He, Wenhui; Mou, Huihui; Zhang, Lizhou; Chang, Jing; Peng, Shoujiao; Ojha, Amrita; Tavora, Rubens; Parcells, Mark S; Luo, Guangxiang; Li, Wenhui; Zhong, Guocai; Choe, Hyeryun; Farzan, Michael; Quinlan, Brian D.
  • Guo Y; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, USA.
  • He W; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, USA.
  • Mou H; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, USA.
  • Zhang L; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, USA.
  • Chang J; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, USA.
  • Peng S; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, USA.
  • Ojha A; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, USA.
  • Tavora R; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, USA.
  • Parcells MS; Department of Animal and Food Sciences, University of Delaware, Newark, Delaware, USA.
  • Luo G; Department of Microbiology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA.
  • Li W; National Institute of Biological Sciences, Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China.
  • Zhong G; Scripps Research SZBL Chemical Biology Institute, Shenzhen Bay Laboratory, Shenzhen, China.
  • Choe H; School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
  • Farzan M; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, USA.
  • Quinlan BD; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, USA mfarzan@scripps.edu bquinlan@scripps.edu.
mBio ; 12(3)2021 05 11.
Article in English | MEDLINE | ID: covidwho-1225697
ABSTRACT
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates viral entry into cells expressing angiotensin-converting enzyme 2 (ACE2). The S protein engages ACE2 through its receptor-binding domain (RBD), an independently folded 197-amino-acid fragment of the 1,273-amino-acid S-protein protomer. The RBD is the primary SARS-CoV-2 neutralizing epitope and a critical target of any SARS-CoV-2 vaccine. Here, we show that this RBD conjugated to each of two carrier proteins elicited more potent neutralizing responses in immunized rodents than did a similarly conjugated proline-stabilized S-protein ectodomain. Nonetheless, the native RBD is expressed inefficiently, limiting its usefulness as a vaccine antigen. However, we show that an RBD engineered with four novel glycosylation sites (gRBD) is expressed markedly more efficiently and generates a more potent neutralizing responses as a DNA vaccine antigen than the wild-type RBD or the full-length S protein, especially when fused to multivalent carriers, such as a Helicobacter pylori ferritin 24-mer. Further, gRBD is more immunogenic than the wild-type RBD when administered as a subunit protein vaccine. Our data suggest that multivalent gRBD antigens can reduce costs and doses, and improve the immunogenicity, of all major classes of SARS-CoV-2 vaccines.IMPORTANCE All available vaccines for coronavirus disease 2019 (COVID-19) express or deliver the full-length SARS-CoV-2 spike (S) protein. We show that this antigen is not optimal, consistent with observations that the vast majority of the neutralizing response to the virus is focused on the S-protein receptor-binding domain (RBD). However, this RBD is not expressed well as an independent domain, especially when expressed as a fusion protein with a multivalent scaffold. We therefore engineered a more highly expressed form of the SARS-CoV-2 RBD by introducing four glycosylation sites into a face of the RBD normally occluded in the full S protein. We show that this engineered protein, gRBD, is more immunogenic than the wild-type RBD or the full-length S protein in both genetic and protein-delivered vaccines.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Immunogenicity, Vaccine / Receptors, Coronavirus / Angiotensin-Converting Enzyme 2 / COVID-19 Vaccines Type of study: Observational study / Prognostic study Topics: Vaccines Limits: Animals / Female / Humans Language: English Year: 2021 Document Type: Article Affiliation country: MBio.00930-21

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Immunogenicity, Vaccine / Receptors, Coronavirus / Angiotensin-Converting Enzyme 2 / COVID-19 Vaccines Type of study: Observational study / Prognostic study Topics: Vaccines Limits: Animals / Female / Humans Language: English Year: 2021 Document Type: Article Affiliation country: MBio.00930-21