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-Reference-Cited by-全球学者库

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

Published:2022-08-22 Issue:35 Volume:119 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Lu Mijia¹^ORCID,Chamblee Michelle¹,Zhang Yuexiu¹,Ye Chengjin²^ORCID,Dravid Piyush³^ORCID,Park Jun-Gyu²^ORCID,Mahesh KC³,Trivedi Sheetal³,Murthy Satyapramod³,Sharma Himanshu³^ORCID,Cassady Cole³,Chaiwatpongsakorn Supranee³^ORCID,Liang Xueya¹,Yount Jacob S.⁴⁵,Boyaka Prosper N.¹⁵^ORCID,Peeples Mark E.³⁵⁶^ORCID,Martinez-Sobrido Luis²,Kapoor Amit³⁵⁶^ORCID,Li Jianrong¹⁵

Affiliation:

1. Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, 43210

2. Texas Biomedical Research Institute, San Antonio, TX, 78227

3. Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, 43205

4. Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH, 43210

5. Infectious Disease Institute, The Ohio State University, Columbus, OH, 43210

6. Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, 43210

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 (10 4 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 10 3 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.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2110105119

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