Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments-The importance of immunofocusing in subunit vaccine design
Identifieur interne : 001E36 ( Main/Exploration ); précédent : 001E35; suivant : 001E37Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments-The importance of immunofocusing in subunit vaccine design
Auteurs : CUIQING MA [États-Unis] ; LILI WANG [États-Unis] ; XINRONG TAO [États-Unis] ; NARU ZHANG [États-Unis] ; YANG YANG [États-Unis] ; Chien-Te K. Tseng [États-Unis] ; FANG LI [États-Unis] ; YUSEN ZHOU [République populaire de Chine] ; SHIBO JIANG [États-Unis, République populaire de Chine] ; LANYING DU [États-Unis]Source :
- Vaccine [ 0264-410X ] ; 2014.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Vaccin.
English descriptors
- KwdEn :
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".
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Kimball Research Institute, New York Blood Center</s1><s2>New York, NY</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University</s1><s2>Shanghai</s2><s3>CHN</s3><sZ>9 aut.</sZ></inist:fA14><country>République populaire de Chine</country><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Lanying Du" sort="Lanying Du" uniqKey="Lanying Du" last="Lanying Du">LANYING DU</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Lindsley F. 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Kimball Research Institute, New York Blood Center</s1><s2>New York, NY</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Lili Wang" sort="Lili Wang" uniqKey="Lili Wang" last="Lili Wang">LILI WANG</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Lindsley F. Kimball Research Institute, New York Blood Center</s1><s2>New York, NY</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Xinrong Tao" sort="Xinrong Tao" uniqKey="Xinrong Tao" last="Xinrong Tao">XINRONG TAO</name><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Department of Microbiology and Immunology and Center for Biodefense and Emerging Disease, University of Texas Medical Branch</s1><s2>Galveston, TX</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Naru Zhang" sort="Naru Zhang" uniqKey="Naru Zhang" last="Naru Zhang">NARU ZHANG</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Lindsley F. Kimball Research Institute, New York Blood Center</s1><s2>New York, NY</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Yang Yang" sort="Yang Yang" uniqKey="Yang Yang" last="Yang Yang">YANG YANG</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Department of Pharmacology, University of Minnesota Medical School</s1><s2>Minneapolis, MN</s2><s3>USA</s3><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Minnesota</region></placeName></affiliation></author><author><name sortKey="Tseng, Chien Te K" sort="Tseng, Chien Te K" uniqKey="Tseng C" first="Chien-Te K." last="Tseng">Chien-Te K. Tseng</name><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Department of Microbiology and Immunology and Center for Biodefense and Emerging Disease, University of Texas Medical Branch</s1><s2>Galveston, TX</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Fang Li" sort="Fang Li" uniqKey="Fang Li" last="Fang Li">FANG LI</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Department of Pharmacology, University of Minnesota Medical School</s1><s2>Minneapolis, MN</s2><s3>USA</s3><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Minnesota</region></placeName></affiliation></author><author><name sortKey="Yusen Zhou" sort="Yusen Zhou" uniqKey="Yusen Zhou" last="Yusen Zhou">YUSEN ZHOU</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology</s1><s2>Beijing</s2><s3>CHN</s3><sZ>8 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Shibo Jiang" sort="Shibo Jiang" uniqKey="Shibo Jiang" last="Shibo Jiang">SHIBO JIANG</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Lindsley F. Kimball Research Institute, New York Blood Center</s1><s2>New York, NY</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University</s1><s2>Shanghai</s2><s3>CHN</s3><sZ>9 aut.</sZ></inist:fA14><country>République populaire de Chine</country><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Lanying Du" sort="Lanying Du" uniqKey="Lanying Du" last="Lanying Du">LANYING DU</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Lindsley F. Kimball Research Institute, New York Blood Center</s1><s2>New York, NY</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Vaccine</title><title level="j" type="abbreviated">Vaccine</title><idno type="ISSN">0264-410X</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Vaccine</title><title level="j" type="abbreviated">Vaccine</title><idno type="ISSN">0264-410X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Coronavirus</term><term>Protein</term><term>Subunit</term><term>Vaccine</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Coronavirus</term><term>Vaccin</term><term>Sousunité</term><term>Protéine</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Vaccin</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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".</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li><li>États-Unis</li></country><region><li>Minnesota</li><li>Texas</li><li>État de New York</li></region><settlement><li>Pékin</li></settlement></list><tree><country name="États-Unis"><region name="État de New York"><name sortKey="Cuiqing Ma" sort="Cuiqing Ma" uniqKey="Cuiqing Ma" last="Cuiqing Ma">CUIQING MA</name></region><name sortKey="Fang Li" sort="Fang Li" uniqKey="Fang Li" last="Fang Li">FANG LI</name><name sortKey="Lanying Du" sort="Lanying Du" uniqKey="Lanying Du" last="Lanying Du">LANYING DU</name><name sortKey="Lili Wang" sort="Lili Wang" uniqKey="Lili Wang" last="Lili Wang">LILI WANG</name><name sortKey="Naru Zhang" sort="Naru Zhang" uniqKey="Naru Zhang" last="Naru Zhang">NARU ZHANG</name><name sortKey="Shibo Jiang" sort="Shibo Jiang" uniqKey="Shibo Jiang" last="Shibo Jiang">SHIBO JIANG</name><name sortKey="Tseng, Chien Te K" sort="Tseng, Chien Te K" uniqKey="Tseng C" first="Chien-Te K." last="Tseng">Chien-Te K. Tseng</name><name sortKey="Xinrong Tao" sort="Xinrong Tao" uniqKey="Xinrong Tao" last="Xinrong Tao">XINRONG TAO</name><name sortKey="Yang Yang" sort="Yang Yang" uniqKey="Yang Yang" last="Yang Yang">YANG YANG</name></country><country name="République populaire de Chine"><noRegion><name sortKey="Yusen Zhou" sort="Yusen Zhou" uniqKey="Yusen Zhou" last="Yusen Zhou">YUSEN ZHOU</name></noRegion><name sortKey="Shibo Jiang" sort="Shibo Jiang" uniqKey="Shibo Jiang" last="Shibo Jiang">SHIBO JIANG</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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