Journal
CELL
Volume 182, Issue 3, Pages 722-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.06.035
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Funding
- National Natural Science Foundation of China, China (NSFC) [81991494]
- National Science and Technology Major Project, China [2016YFE0205800, 2018ZX10101004]
- Strategic Priority Research Program of the CAS, China [XDPB0301]
- Youth Innovation Promotion Association CAS, China [2018113]
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Vaccines are urgently needed to control the ongoing pandemic COVID-19 and previously emerging MERS/ SARS caused by coronavirus (CoV) infections. The CoV spike receptor-binding domain (RBD) is an attractive vaccine target but is undermined by limited immunogenicity. We describe a dimeric form of MERS-CoV RBD that overcomes this limitation. The RBD-dimer significantly increased neutralizing antibody (NAb) titers compared to conventional monomeric form and protected mice against MERS-CoV infection. Crystal structure showed RBD-dimer fully exposed dual receptor-binding motifs, the major target for NAbs. Structureguided design further yielded a stable version of RBD-dimer as a tandem repeat single-chain (RBD-sc-dimer) which retained the vaccine potency. We generalized this strategy to design vaccines against COVID-19 and SARS, achieving 10- to 100-fold enhancement of NAb titers. RBD-sc-dimers in pilot scale production yielded high yields, supporting their scalability for further clinical development. The framework of immunogen design can be universally applied to other beta-CoV vaccines to counter emerging threats.
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