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Cross-Protection against MERS-CoV by Prime-Boost Vaccination Using Viral Spike DNA and Protein.
J Virol. 2020 11 23; 94(24)JV

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.

Authors+Show Affiliations

Science Unit, International Vaccine Institute, Seoul, South Korea.Science Unit, International Vaccine Institute, Seoul, South Korea.Science Unit, International Vaccine Institute, Seoul, South Korea.Science Unit, International Vaccine Institute, Seoul, South Korea.Science Unit, International Vaccine Institute, Seoul, South Korea.Science Unit, International Vaccine Institute, Seoul, South Korea.Science Unit, International Vaccine Institute, Seoul, South Korea.Science Unit, International Vaccine Institute, Seoul, South Korea.Science Unit, International Vaccine Institute, Seoul, South Korea.Science Unit, International Vaccine Institute, Seoul, South Korea.Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.Science Unit, International Vaccine Institute, Seoul, South Korea.NKMAX Co., Ltd., Sungnam, South Korea.Department of Microbiology and Immunology, Graduate School of Medical Science, Brain Korea 21 Project, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.Science Unit, International Vaccine Institute, Seoul, South Korea mksong@ivi.int jokim@ivi.int.Science Unit, International Vaccine Institute, Seoul, South Korea mksong@ivi.int jokim@ivi.int.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32967955

Citation

Choi, Jung-Ah, et al. "Cross-Protection Against MERS-CoV By Prime-Boost Vaccination Using Viral Spike DNA and Protein." Journal of Virology, vol. 94, no. 24, 2020.
Choi JA, Goo J, Yang E, et al. Cross-Protection against MERS-CoV by Prime-Boost Vaccination Using Viral Spike DNA and Protein. J Virol. 2020;94(24).
Choi, J. A., Goo, J., Yang, E., Jung, D. I., Lee, S., Rho, S., Jeong, Y., Park, Y. S., Park, H., Moon, Y. H., Park, U., Seo, S. H., Lee, H., Lee, J. M., Cho, N. H., Song, M., & Kim, J. O. (2020). Cross-Protection against MERS-CoV by Prime-Boost Vaccination Using Viral Spike DNA and Protein. Journal of Virology, 94(24). https://doi.org/10.1128/JVI.01176-20
Choi JA, et al. Cross-Protection Against MERS-CoV By Prime-Boost Vaccination Using Viral Spike DNA and Protein. J Virol. 2020 11 23;94(24) PubMed PMID: 32967955.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cross-Protection against MERS-CoV by Prime-Boost Vaccination Using Viral Spike DNA and Protein. AU - Choi,Jung-Ah, AU - Goo,Junghyun, AU - Yang,Eunji, AU - Jung,Dae-Im, AU - Lee,Sena, AU - Rho,Semi, AU - Jeong,Yuji, AU - Park,Young-Shin, AU - Park,Hayan, AU - Moon,Young-Hye, AU - Park,Uni, AU - Seo,Sang-Hwan, AU - Lee,Hyeja, AU - Lee,Jae Myun, AU - Cho,Nam-Hyuk, AU - Song,Manki, AU - Kim,Jae-Ouk, Y1 - 2020/11/23/ PY - 2020/06/15/received PY - 2020/09/16/accepted PY - 2020/9/25/pubmed PY - 2020/9/25/medline PY - 2020/9/24/entrez KW - MERS-CoV KW - vaccines JF - Journal of virology JO - J Virol VL - 94 IS - 24 N2 - 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. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/32967955/Cross_Protection_against_MERS_CoV_by_Prime_Boost_Vaccination_Using_Viral_Spike_DNA_and_Protein_ L2 - http://jvi.asm.org/lookup/pmidlookup?view=long&pmid=32967955 DB - PRIME DP - Unbound Medicine ER -