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Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments--the importance of immunofocusing in subunit vaccine design.
Vaccine. 2014 Oct 21; 32(46):6170-6176.V

Abstract

The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) is currently spreading among humans, making development of effective MERS vaccines a high priority. A defined receptor-binding domain (RBD) in MERS-CoV spike protein can potentially serve as a subunit vaccine candidate against MERS-CoV infections. To identify an ideal vaccine candidate, we have constructed five different versions of RBD fragments, S350-588-Fc, S358-588-Fc, S367-588-Fc, S367-606-Fc, and S377-588-Fc (their names indicate their residue range in the spike protein and their C-terminal Fc tag), and further investigated their receptor binding affinity, antigenicity, immunogenicity, and neutralizing potential. The results showed that S377-588-Fc is among the RBD fragments that demonstrated the highest DPP4-binding affinity and induced the highest-titer IgG antibodies in mice. In addition, S377-588-Fc elicited higher-titer neutralizing antibodies than all the other RBD fragments in mice, and also induced high-titer neutralizing antibodies in immunized rabbits. Structural analysis suggests that S377-588-Fc contains the stably folded RBD structure, the full receptor-binding site, and major neutralizing epitopes, such that additional structures to this fragment introduce non-neutralizing epitopes and may also alter the tertiary structure of the RBD. Taken together, our data suggest that the RBD fragment encompassing spike residues 377-588 is a critical neutralizing receptor-binding fragment and an ideal candidate for development of effective MERS vaccines, and that adding non-neutralizing structures to this RBD fragment diminishes its neutralizing potential. Therefore, in viral vaccine design, it is important to identify the most stable and neutralizing viral RBD fragment, while eliminating unnecessary and non-neutralizing structures, as a means of "immunofocusing".

Authors+Show Affiliations

Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA.Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA.Department of Microbiology and Immunology and Center for Biodefense and Emerging Disease, University of Texas Medical Branch, Galveston, TX, USA.Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA.Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, USA.Department of Microbiology and Immunology and Center for Biodefense and Emerging Disease, University of Texas Medical Branch, Galveston, TX, USA.Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, USA.State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA. Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai, China.Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25240756

Citation

Ma, Cuiqing, et al. "Searching for an Ideal Vaccine Candidate Among Different MERS Coronavirus Receptor-binding Fragments--the Importance of Immunofocusing in Subunit Vaccine Design." Vaccine, vol. 32, no. 46, 2014, pp. 6170-6176.
Ma C, Wang L, Tao X, et al. Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments--the importance of immunofocusing in subunit vaccine design. Vaccine. 2014;32(46):6170-6176.
Ma, C., Wang, L., Tao, X., Zhang, N., Yang, Y., Tseng, C. K., Li, F., Zhou, Y., Jiang, S., & Du, L. (2014). Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments--the importance of immunofocusing in subunit vaccine design. Vaccine, 32(46), 6170-6176. https://doi.org/10.1016/j.vaccine.2014.08.086
Ma C, et al. Searching for an Ideal Vaccine Candidate Among Different MERS Coronavirus Receptor-binding Fragments--the Importance of Immunofocusing in Subunit Vaccine Design. Vaccine. 2014 Oct 21;32(46):6170-6176. PubMed PMID: 25240756.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments--the importance of immunofocusing in subunit vaccine design. AU - Ma,Cuiqing, AU - Wang,Lili, AU - Tao,Xinrong, AU - Zhang,Naru, AU - Yang,Yang, AU - Tseng,Chien-Te K, AU - Li,Fang, AU - Zhou,Yusen, AU - Jiang,Shibo, AU - Du,Lanying, Y1 - 2014/09/19/ PY - 2014/05/25/received PY - 2014/07/20/revised PY - 2014/08/22/accepted PY - 2014/9/22/entrez PY - 2014/9/23/pubmed PY - 2015/4/22/medline KW - Critical neutralizing domain KW - Immunofocusing KW - MERS KW - MERS-CoV KW - Receptor-binding domain KW - Spike protein SP - 6170 EP - 6176 JF - Vaccine JO - Vaccine VL - 32 IS - 46 N2 - The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) is currently spreading among humans, making development of effective MERS vaccines a high priority. A defined receptor-binding domain (RBD) in MERS-CoV spike protein can potentially serve as a subunit vaccine candidate against MERS-CoV infections. To identify an ideal vaccine candidate, we have constructed five different versions of RBD fragments, S350-588-Fc, S358-588-Fc, S367-588-Fc, S367-606-Fc, and S377-588-Fc (their names indicate their residue range in the spike protein and their C-terminal Fc tag), and further investigated their receptor binding affinity, antigenicity, immunogenicity, and neutralizing potential. The results showed that S377-588-Fc is among the RBD fragments that demonstrated the highest DPP4-binding affinity and induced the highest-titer IgG antibodies in mice. In addition, S377-588-Fc elicited higher-titer neutralizing antibodies than all the other RBD fragments in mice, and also induced high-titer neutralizing antibodies in immunized rabbits. Structural analysis suggests that S377-588-Fc contains the stably folded RBD structure, the full receptor-binding site, and major neutralizing epitopes, such that additional structures to this fragment introduce non-neutralizing epitopes and may also alter the tertiary structure of the RBD. Taken together, our data suggest that the RBD fragment encompassing spike residues 377-588 is a critical neutralizing receptor-binding fragment and an ideal candidate for development of effective MERS vaccines, and that adding non-neutralizing structures to this RBD fragment diminishes its neutralizing potential. Therefore, in viral vaccine design, it is important to identify the most stable and neutralizing viral RBD fragment, while eliminating unnecessary and non-neutralizing structures, as a means of "immunofocusing". SN - 1873-2518 UR - https://www.unboundmedicine.com/medline/citation/25240756/Searching_for_an_ideal_vaccine_candidate_among_different_MERS_coronavirus_receptor_binding_fragments__the_importance_of_immunofocusing_in_subunit_vaccine_design_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0264-410X(14)01255-9 DB - PRIME DP - Unbound Medicine ER -