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SARS-CoV-2 prefusion spike protein stabilized by six rather than two prolines is more potent for inducing antibodies that neutralize viral variants of concern.
Lu, Mijia; Chamblee, Michelle; Zhang, Yuexiu; Ye, Chengjin; Dravid, Piyush; Park, Jun-Gyu; Mahesh, K C; Trivedi, Sheetal; Murthy, Satyapramod; Sharma, Himanshu; Cassady, Cole; Chaiwatpongsakorn, Supranee; Liang, Xueya; Yount, Jacob S; Boyaka, Prosper N; Peeples, Mark E; Martinez-Sobrido, Luis; Kapoor, Amit; Li, Jianrong.
  • Lu M; Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, 43210.
  • Chamblee M; Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, 43210.
  • Zhang Y; Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, 43210.
  • Ye C; Texas Biomedical Research Institute, San Antonio, TX, 78227.
  • Dravid P; Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205.
  • Park JG; Texas Biomedical Research Institute, San Antonio, TX, 78227.
  • Mahesh KC; Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205.
  • Trivedi S; Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205.
  • Murthy S; Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205.
  • Sharma H; Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205.
  • Cassady C; Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205.
  • Chaiwatpongsakorn S; Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205.
  • Liang X; Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, 43210.
  • Yount JS; Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH, 43210.
  • Boyaka PN; Infectious Disease Institute, The Ohio State University, Columbus, OH, 43210.
  • Peeples ME; Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, 43210.
  • Martinez-Sobrido L; Infectious Disease Institute, The Ohio State University, Columbus, OH, 43210.
  • Kapoor A; Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205.
  • Li J; Infectious Disease Institute, The Ohio State University, Columbus, OH, 43210.
Proc Natl Acad Sci U S A ; 119(35): e2110105119, 2022 08 30.
Article in English | MEDLINE | ID: covidwho-2000999
ABSTRACT
The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the main target for neutralizing antibodies (NAbs). The S protein trimer is anchored in the virion membrane in its prefusion (preS) but metastable form. The preS protein has been stabilized by introducing two or six proline substitutions, to generate stabilized, soluble 2P or HexaPro (6P) preS proteins. Currently, it is not known which form is the most immunogenic. Here, we generated recombinant vesicular stomatitis virus (rVSV) expressing preS-2P, preS-HexaPro, and native full-length S, and compared their immunogenicity in mice and hamsters. The rVSV-preS-HexaPro produced and secreted significantly more preS protein compared to rVSV-preS-2P. Importantly, rVSV-preS-HexaPro triggered significantly more preS-specific serum IgG antibody than rVSV-preS-2P in both mice and hamsters. Antibodies induced by preS-HexaPro neutralized the B.1.1.7, B.1.351, P.1, B.1.427, and B.1.617.2 variants approximately two to four times better than those induced by preS-2P. Furthermore, preS-HexaPro induced a more robust Th1-biased cellular immune response than preS-2P. A single dose (104 pfu) immunization with rVSV-preS-HexaPro and rVSV-preS-2P provided complete protection against challenge with mouse-adapted SARS-CoV-2 and B.1.617.2 variant, whereas rVSV-S only conferred partial protection. When the immunization dose was lowered to 103 pfu, rVSV-preS-HexaPro induced two- to sixfold higher antibody responses than rVSV-preS-2P in hamsters. In addition, rVSV-preS-HexaPro conferred 70% protection against lung infection whereas only 30% protection was observed in the rVSV-preS-2P. Collectively, our data demonstrate that both preS-2P and preS-HexaPro are highly efficacious but preS-HexaPro is more immunogenic and protective, highlighting the advantages of using preS-HexaPro in the next generation of SARS-CoV-2 vaccines.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Proline / Viral Vaccines / Vesicular Stomatitis / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / Vaccine Development Topics: Vaccines / Variants Limits: Animals / Humans Language: English Journal: Proc Natl Acad Sci U S A Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Proline / Viral Vaccines / Vesicular Stomatitis / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / Vaccine Development Topics: Vaccines / Variants Limits: Animals / Humans Language: English Journal: Proc Natl Acad Sci U S A Year: 2022 Document Type: Article