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Cross-Protection against MERS-CoV by Prime-Boost Vaccination Using Viral Spike DNA and Protein

Authors
 Jung-Ah Choi  ;  Junghyun Goo  ;  Eunji Yang  ;  Dae-Im Jung  ;  Sena Lee  ;  Semi Rho  ;  Yuji Jeong  ;  Young-Shin Park  ;  Hayan Park  ;  Young-Hye Moon  ;  Uni Park  ;  Sang-Hwan Seo  ;  Hyeja Lee  ;  Jae Myun Lee  ;  Nam-Hyuk Cho  ;  Manki Song  ;  Jae-Ouk Kim 
Citation
 JOURNAL OF VIROLOGY, Vol.94(24) : e01176, 2020-11 
Journal Title
JOURNAL OF VIROLOGY
ISSN
 0022-538X 
Issue Date
2020-11
MeSH
Animals ; Antibodies, Neutralizing / immunology ; Antibodies, Viral / immunology ; Coronavirus Infections / immunology* ; Coronavirus Infections / mortality ; Coronavirus Infections / prevention & control* ; Coronavirus Infections / virology ; Cross Protection* ; Disease Models, Animal ; Female ; Humans ; Immunity, Cellular ; Immunization, Secondary ; Immunogenicity, Vaccine ; Mice ; Middle East Respiratory Syndrome Coronavirus / immunology* ; Plasmids / administration & dosage ; Plasmids / genetics ; Plasmids / immunology ; Spike Glycoprotein, Coronavirus / genetics ; Spike Glycoprotein, Coronavirus / immunology* ; Vaccination ; Vaccines, DNA / administration & dosage ; Vaccines, DNA / immunology* ; Viral Vaccines / administration & dosage ; Viral Vaccines / immunology*
Keywords
MERS-CoV ; vaccines
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory illness and has a high mortality of ∼34%. However, since its discovery in 2012, an effective vaccine has not been developed for it. To develop a vaccine against multiple strains of MERS-CoV, we targeted spike glycoprotein (S) using prime-boost vaccination with DNA and insect cell-expressed recombinant proteins for the receptor-binding domain (RBD), S1, S2, SΔTM, or SΔER. Our S subunits were generated using an S sequence derived from the MERS-CoV EMC/2012 strain. We examined humoral and cellular immune responses of various combinations with DNA plasmids and recombinant proteins in mice. Mouse sera immunized with SΔER DNA priming/SΔTM protein boosting showed cross-neutralization against 15 variants of S-pseudovirions and the wild-type KOR/KNIH/002 strain. In addition, these immunizations provided full protection against the KOR/KNIH/002 strain challenge in human DPP4 knock-in mice. These findings suggest that vaccination with the S subunits derived from one viral strain can provide cross-protection against variant MERS-CoV strains with mutations in S. DNA priming/protein boosting increased gamma interferon production, while protein-alone immunization did not. The RBD subunit alone was insufficient to induce neutralizing antibodies, suggesting the importance of structural conformation. In conclusion, heterologous DNA priming with protein boosting is an effective way to induce both neutralizing antibodies and cell-mediated immune responses for MERS-CoV vaccine development. This study suggests a strategy for selecting a suitable platform for developing vaccines against MERS-CoV or other emerging coronaviruses.IMPORTANCE Coronavirus is an RNA virus with a higher mutation rate than DNA viruses. Therefore, a mutation in S-protein, which mediates viral infection by binding to a human cellular receptor, is expected to cause difficulties in vaccine development. Given that DNA-protein vaccines promote stronger cell-mediated immune responses than protein-only vaccination, we immunized mice with various combinations of DNA priming and protein boosting using the S-subunit sequences of the MERS-CoV EMC/2012 strain. We demonstrated a cross-protective effect against wild-type KOR/KNIH/002, a strain with two mutations in the S amino acids, including one in its RBD. The vaccine also provided cross-neutralization against 15 different S-pseudotyped viruses. These suggested that a vaccine targeting one variant of S can provide cross-protection against multiple viral strains with mutations in S. The regimen of DNA priming/Protein boosting can be applied to the development of other coronavirus vaccines.
Files in This Item:
T202006346.pdf Download
DOI
10.1128/JVI.01176-20
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Lee, Jae Myun(이재면) ORCID logo https://orcid.org/0000-0002-5273-3113
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/182621
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