18 results on '"Wanbo Tai"'
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2. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine
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Xiujuan Zhang, Yusen Zhou, Shibo Jiang, Jing Pu, Lanying Du, Wanbo Tai, Lei He, and Denis Voronin
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0301 basic medicine ,Antiserum ,biology ,viruses ,Viral Vaccine ,fungi ,Immunology ,HEK 293 cells ,COVID-19 ,cross-neutralization ,spike protein ,Immunotherapy ,Viral infection ,2019 novel coronavirus ,viral inhibitor ,SARS-CoV-2 ,receptor-binding domain ,virus diseases ,Plasma protein binding ,Virology ,body regions ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Infectious Diseases ,030220 oncology & carcinogenesis ,biology.protein ,Immunology and Allergy ,Antibody ,Binding site ,skin and connective tissue diseases ,Receptor ,Peptide sequence - Abstract
The outbreak of Coronavirus Disease 2019 (COVID-19) has posed a serious threat to global public health, calling for the development of safe and effective prophylactics and therapeutics against infection of its causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as 2019 novel coronavirus (2019-nCoV). The CoV spike (S) protein plays the most important roles in viral attachment, fusion and entry, and serves as a target for development of antibodies, entry inhibitors and vaccines. Here, we identified the receptor-binding domain (RBD) in SARS-CoV-2 S protein and found that the RBD protein bound strongly to human and bat angiotensin-converting enzyme 2 (ACE2) receptors. SARS-CoV-2 RBD exhibited significantly higher binding affinity to ACE2 receptor than SARS-CoV RBD and could block the binding and, hence, attachment of SARS-CoV-2 RBD and SARS-CoV RBD to ACE2-expressing cells, thus inhibiting their infection to host cells. SARS-CoV RBD-specific antibodies could cross-react with SARS-CoV-2 RBD protein, and SARS-CoV RBD-induced antisera could cross-neutralize SARS-CoV-2, suggesting the potential to develop SARS-CoV RBD-based vaccines for prevention of SARS-CoV-2 and SARS-CoV infection.
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- 2020
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3. The development of Nanosota-1 as anti-SARS-CoV-2 nanobody drug candidates
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Jian Shang, Joseph P. Gallant, Jian Zheng, Fang Li, Christopher Massey, Molly A. Vickers, Ke Shi, Aaron M. LeBeau, Lanying Du, Yushun Wan, Abby E. Odle, Stanley Perlman, Hideki Aihara, Wanbo Tai, and Gang Ye
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Drug ,Phage display ,QH301-705.5 ,Science ,media_common.quotation_subject ,ACE2 ,Hamster ,spike protein receptor-binding domain ,Plasma protein binding ,General Biochemistry, Genetics and Molecular Biology ,Virus ,crystal structures ,In vivo ,Biology (General) ,single-chain antibody from camelids ,media_common ,General Immunology and Microbiology ,biology ,Chemistry ,General Neuroscience ,COVID-19 ,General Medicine ,Virology ,Viral Receptor ,virus neutralization ,biology.protein ,Medicine ,Antibody - Abstract
Combating the COVID-19 pandemic requires potent and low-cost therapeutics. We identified a series of single-domain antibodies (i.e., nanobody), Nanosota-1, from a camelid nanobody phage display library. Structural data showed that Nanosota-1 bound to the oft-hidden receptor-binding domain (RBD) of SARS-CoV-2 spike protein, blocking viral receptor angiotensin-converting enzyme 2 (ACE2). The lead drug candidate possessing an Fc tag (Nanosota-1C-Fc) bound to SARS-CoV-2 RBD ~3000 times more tightly than ACE2 did and inhibited SARS-CoV-2 pseudovirus ~160 times more efficiently than ACE2 did. Administered at a single dose, Nanosota-1C-Fc demonstrated preventive and therapeutic efficacy against live SARS-CoV-2 infection in both hamster and mouse models. Unlike conventional antibodies, Nanosota-1C-Fc was produced at high yields in bacteria and had exceptional thermostability. Pharmacokinetic analysis of Nanosota-1C-Fc documented an excellent in vivo stability and a high tissue bioavailability. As effective and inexpensive drug candidates, Nanosota-1 may contribute to the battle against COVID-19.
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- 2021
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4. Novel virus-like nanoparticle vaccine effectively protects animal model from SARS-CoV-2 infection
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Stephanie A. Montgomery, Wanbo Tai, Marc K. Jenkins, Fang Li, Lanying Du, Ralph S. Baric, Xiujuan Zhang, Victoria K. Baxter, Mark T. Heise, Jian Shang, Qibin Geng, Chien Te K. Tseng, Yushun Wan, Sarah R. Leist, Kenneth H. Dinnon, Elizabeth J. Anderson, Juan Shi, Aleksandra Drelich, Sharon Taft-Benz, Audrey C. Knight, and Sung-Wook Hong
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RNA viruses ,Viral Diseases ,Immunogen ,Coronaviruses ,Physiology ,viruses ,Antibodies, Viral ,Biochemistry ,Mice ,Medical Conditions ,Immunogenicity, Vaccine ,Immune Physiology ,Public and Occupational Health ,Biology (General) ,Enzyme-Linked Immunoassays ,skin and connective tissue diseases ,Lung ,Pathology and laboratory medicine ,Vaccines ,Mice, Inbred BALB C ,Immune System Proteins ,biology ,Viral Vaccine ,virus diseases ,Animal Models ,Medical microbiology ,Vaccination and Immunization ,Infectious Diseases ,Experimental Organism Systems ,Viruses ,Female ,Angiotensin-Converting Enzyme 2 ,Antibody ,SARS CoV 2 ,Pathogens ,Research Article ,COVID-19 Vaccines ,SARS coronavirus ,Infectious Disease Control ,QH301-705.5 ,Immunology ,Mouse Models ,Research and Analysis Methods ,Microbiology ,complex mixtures ,Virus ,Antibodies ,Immune system ,Model Organisms ,Antigen ,Protein Domains ,Immunity ,Virology ,Vaccine Development ,Genetics ,Animals ,Humans ,Immunoassays ,Molecular Biology ,Medicine and health sciences ,Biology and life sciences ,fungi ,Organisms ,Viral pathogens ,Proteins ,COVID-19 ,Viral Vaccines ,Covid 19 ,RC581-607 ,biochemical phenomena, metabolism, and nutrition ,Antibodies, Neutralizing ,Microbial pathogens ,Disease Models, Animal ,HEK293 Cells ,Novel virus ,Drug Design ,biology.protein ,Immunologic Techniques ,Animal Studies ,Nanoparticles ,Parasitology ,Preventive Medicine ,Immunologic diseases. Allergy - Abstract
The key to battling the COVID-19 pandemic and its potential aftermath is to develop a variety of vaccines that are efficacious and safe, elicit lasting immunity, and cover a range of SARS-CoV-2 variants. Recombinant viral receptor-binding domains (RBDs) are safe vaccine candidates but often have limited efficacy due to the lack of virus-like immunogen display pattern. Here we have developed a novel virus-like nanoparticle (VLP) vaccine that displays 120 copies of SARS-CoV-2 RBD on its surface. This VLP-RBD vaccine mimics virus-based vaccines in immunogen display, which boosts its efficacy, while maintaining the safety of protein-based subunit vaccines. Compared to the RBD vaccine, the VLP-RBD vaccine induced five times more neutralizing antibodies in mice that efficiently blocked SARS-CoV-2 from attaching to its host receptor and potently neutralized the cell entry of variant SARS-CoV-2 strains, SARS-CoV-1, and SARS-CoV-1-related bat coronavirus. These neutralizing immune responses induced by the VLP-RBD vaccine did not wane during the two-month study period. Furthermore, the VLP-RBD vaccine effectively protected mice from SARS-CoV-2 challenge, dramatically reducing the development of clinical signs and pathological changes in immunized mice. The VLP-RBD vaccine provides one potentially effective solution to controlling the spread of SARS-CoV-2., Author summary Both mRNA-based and viral vector-based vaccines are currently being distributed to curtail the COVID-19 pandemic. Continued development of more varieties of SARS-CoV-2 vaccines will help battle the many variants of SARS-CoV-2. Here we have developed a virus-like particle (VLP) vaccine that combines the effectiveness of virus-based vaccines and safety of protein-based vaccines. Using the lumazine synthase nanoparticle protein as the structural scaffold and 120 copies of SARS-CoV-2 receptor-binding domain as the surface immunogen, this VLP vaccine induced high-titer neutralizing antibody responses in mice that lasted >2 months and potently inhibited SARS-CoV-2, SARS-CoV-1, and their variants. The VLP vaccine also protected mice from high-titer SARS-CoV-2 challenge. The novel VLP vaccine may contribute to the protection of the human population from SARS-CoV-2 and its variants.
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- 2021
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5. The Development of a Novel Nanobody Therapeutic for SARS-CoV-2
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Jian Shang, Aleksandra Drelich, Ke Shi, Stanley Perlman, Christopher Massey, Hideki Aihara, Chien Te K. Tseng, Lanying Du, Vivian Tat, Aaron M. LeBeau, Jian Zheng, Joseph P. Gallant, Yushun Wan, Gang Ye, Fang Li, Kempaiah Rayavara Kempaiah, Wanbo Tai, Abby E. Odle, and Molly A. Vickers
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Male ,Models, Molecular ,Drug ,Phage display ,drug pharmacokinetics ,Protein Conformation ,media_common.quotation_subject ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,ACE2 ,spike protein receptor-binding domain ,Mice, Transgenic ,Pharmacology ,spike protein ,Antibodies, Viral ,Article ,crystal structures ,Mice ,In vivo ,Animals ,Humans ,Medicine ,Pandemics ,single-chain antibody from camelids ,media_common ,Microbiology and Infectious Disease ,biology ,SARS-CoV-2 ,business.industry ,animal model ,COVID-19 ,Single-Domain Antibodies ,Antibodies, Neutralizing ,In vitro ,Virus ,COVID-19 Drug Treatment ,Bioavailability ,Mice, Inbred C57BL ,HEK293 Cells ,Viral Receptor ,virus neutralization ,Spike Glycoprotein, Coronavirus ,biology.protein ,Receptors, Virus ,Angiotensin-Converting Enzyme 2 ,receptor-binding domain ,Antibody ,business ,Research Article ,Protein Binding - Abstract
Combating the COVID-19 pandemic requires potent and low-cost therapeutics. We identified a novel series of single-domain antibodies (i.e., nanobody), Nanosota-1, from a camelid nanobody phage display library. Structural data showed thatNanosota-1bound to the oft-hidden receptor-binding domain (RBD) of SARS-CoV-2 spike protein, blocking out viral receptor ACE2. The lead drug possessing an Fc tag (Nanosota-1C-Fc) bound to SARS-CoV-2 RBD with a Kdof 15.7picomolar (∼3000 times more tightly than ACE2 did) and inhibited SARS-CoV-2 infection with an ND50of 0.16microgram/milliliter (∼6000 times more potently than ACE2 did). Administered at a single dose,Nanosota-1C-Fcdemonstrated preventive and therapeutic efficacy in hamsters subjected to SARS-CoV-2 infection. Unlike conventional antibody drugs,Nanosota-1C-Fcwas produced at high yields in bacteria and had exceptional thermostability. Pharmacokinetic analysis ofNanosota-1C-Fc documented a greater than 10-dayin vivohalf-life efficacy and high tissue bioavailability.Nanosota-1C-Fcis a potentially effective and realistic solution to the COVID-19 pandemic.Impact statementPotent and low-costNanosota-1drugs block SARS-CoV-2 infections bothin vitroandin vivoand act both preventively and therapeutically.
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- 2020
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6. Biomechanical Characterization of SARS-CoV-2 Spike RBD and Human ACE2 Protein-Protein Interaction
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X. Frank Zhang, Wenpeng Cao, Lanying Du, Wonpil Im, Wanbo Tai, Chuqiao Dong, Seonghan Kim, and Decheng Hou
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Glycan ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,viruses ,Protein domain ,Biophysics ,Plasma protein binding ,Models, Biological ,Virus ,Article ,Protein–protein interaction ,03 medical and health sciences ,Molecular dynamics ,0302 clinical medicine ,Protein Domains ,Polysaccharides ,Humans ,Computer Simulation ,Receptor ,skin and connective tissue diseases ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,HEK 293 cells ,fungi ,Force spectroscopy ,virus diseases ,Single Molecule Imaging ,respiratory tract diseases ,Biomechanical Phenomena ,body regions ,HEK293 Cells ,Spike Glycoprotein, Coronavirus ,biology.protein ,Angiotensin-Converting Enzyme 2 ,030217 neurology & neurosurgery ,hormones, hormone substitutes, and hormone antagonists ,Protein Binding - Abstract
The current COVID-19 pandemic has led to a devastating impact across the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (the virus causing COVID-19) is known to use the receptor-binding domain (RBD) at viral surface spike (S) protein to interact with the angiotensin-converting enzyme 2 (ACE2) receptor expressed on many human cell types. The RBD-ACE2 interaction is a crucial step to mediate the host cell entry of SARS-CoV-2. Recent studies indicate that the ACE2 interaction with the SARS-CoV-2 S protein has a higher affinity than its binding with the structurally identical S protein of SARS-CoV-1, the virus causing the 2002-2004 SARS outbreak. However, the biophysical mechanism behind such binding affinity difference is unclear. This study utilizes combined single-molecule force spectroscopy and steered molecular dynamics (SMD) simulation approaches to quantify the specific interactions between SARS-CoV-2 or SARS-CoV-1 RBD and ACE2. Depending on the loading rates, the unbinding forces between SARS-CoV-2 RBD and ACE2 range from 70 to 105 pN and are 30-40% higher than those of SARS-CoV-1 RBD and ACE2 under similar loading rates. SMD results indicate that SARS-CoV-2 RBD interacts with the N-linked glycan on Asn90 of ACE2. This interaction is mostly absent in the SARS-CoV-1 RBD-ACE2 complex. During the SMD simulations, the extra RBD-N-glycan interaction contributes to a greater force and prolonged interaction lifetime. The observation is confirmed by our experimental force spectroscopy study. After removing N-linked glycans on ACE2, its mechanical binding strength with SARS-CoV-2 RBD decreases to a similar level of the SARS-CoV-1 RBD-ACE2 interaction. Together, the study uncovers the mechanism behind the difference in ACE2 binding between SARS-CoV-2 and SARS-CoV-1 and could help develop new strategies to block SARS-CoV-2 entry.
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- 2020
7. A vaccine inducing solely cytotoxic T lymphocytes fully prevents Zika virus infection and fetal damage
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Xiujuan Zhang, Denis Voronin, Lanying Du, Liang Qiao, Xinyi Wang, Ning Wang, Frank Gambino, Wanbo Tai, Juan Shi, and Yi Zhang
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0301 basic medicine ,Biology ,Major histocompatibility complex ,Transfection ,General Biochemistry, Genetics and Molecular Biology ,Zika virus ,DNA vaccination ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Fetus ,Cytotoxic T cell ,Animals ,Antibody-dependent enhancement ,Zika Virus Infection ,Viral Vaccines ,biology.organism_classification ,Virology ,CTL ,030104 developmental biology ,biology.protein ,Female ,Antibody ,030217 neurology & neurosurgery ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
As vaccine-induced non-neutralizing antibodies may cause antibody-dependent enhancement of Zika virus (ZIKV) infection, we test a vaccine that induces only specific cytotoxic T lymphocytes (CTLs) without specific antibodies. We construct a DNA vaccine expressing a ubiquitinated and rearranged ZIKV non-structural protein 3 (NS3). The protein is immediately degraded and processed in the proteasome for presentation via major histocompatibility complex (MHC) class I for CTL generation. We immunize Ifnar1-/- adult mice with the ubiquitin/NS3 vaccine, impregnate them, and challenge them with ZIKV. Our data show that the vaccine greatly reduces viral titers in reproductive organs and other tissues of adult mice. All mice immunized with the vaccine survived after ZIKV challenge. The vaccine remarkably reduces placenta damage and levels of pro-inflammatory cytokines, and it fully protects fetuses from damage. CD8+ CTLs are essential in protection, as demonstrated via depletion experiments. Our study provides a strategy to develop safe and effective vaccines against viral infections.
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- 2020
8. The Potency of an Anti-MERS Coronavirus Subunit Vaccine Depends on a Unique Combinatorial Adjuvant Formulation
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Sara Lustigman, Wanbo Tai, Parakkal Jovvian George, and Lanying Du
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0301 basic medicine ,adjuvant combination ,rASP-1 ,medicine.medical_treatment ,Immunology ,synergy ,lcsh:Medicine ,chemical and pharmacologic phenomena ,Biology ,Article ,03 medical and health sciences ,MERS-CoV ,0302 clinical medicine ,Immune system ,Drug Discovery ,medicine ,Pharmacology (medical) ,030212 general & internal medicine ,functional antibody responses ,Neutralizing antibody ,Pharmacology ,Immunogenicity ,lcsh:R ,Vaccine efficacy ,Virology ,Vaccination ,030104 developmental biology ,Infectious Diseases ,Immunization ,germinal center B cells ,adjuvants ,aluminum ,biology.protein ,T follicular helper cells ,Antibody ,receptor-binding domain ,Adjuvant - Abstract
Vaccination is one of the most successful strategies to prevent human infectious diseases. Combinatorial adjuvants have gained increasing interest as they can stimulate multiple immune pathways and enhance the vaccine efficacy of subunit vaccines. We investigated the adjuvanticity of Aluminum (alum) in combination with rASP-1, a protein adjuvant, using the Middle East respiratory syndrome coronavirus MERS-CoV receptor-binding-domain (RBD) vaccine antigen. A highly enhanced anti-MERS-CoV neutralizing antibody response was induced when mice were immunized with rASP-1 and the alum-adjuvanted RBD vaccine in two separate injection sites as compared to mice immunized with RBD + rASP-1 + alum formulated into a single inoculum. The antibodies produced also significantly inhibited the binding of RBD to its cell-associated receptor. Moreover, immunization with rASP-1 co-administered with the alum-adjuvanted RBD vaccine in separate sites resulted in an enhanced frequency of TfH and GC B cells within the draining lymph nodes, both of which were positively associated with the titers of the neutralizing antibody response related to anti-MERS-CoV protective immunity. Our findings not only indicate that this unique combinatorial adjuvanted RBD vaccine regimen improved the immunogenicity of RBD, but also point to the importance of utilizing combinatorial adjuvants for the induction of synergistic protective immune responses.
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- 2020
9. Engineering a stable CHO cell line for the expression of a MERS-coronavirus vaccine antigen
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Mun Peak Nyon, Shibo Jiang, Lanying Du, Bi Hung Peng, Jeroen Pollet, Wanbo Tai, Abdullah Algaissi, Kevin S. Naceanceno, Christopher A. Seid, Chien Te K. Tseng, Ulrich Strych, Maria Elena Bottazzi, Anurodh S. Agrawal, and Peter J. Hotez
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0301 basic medicine ,medicine.medical_treatment ,Protein subunit ,Genetic Vectors ,Gene Expression ,CHO Cells ,Article ,law.invention ,03 medical and health sciences ,Epitopes ,Mice ,Immune system ,Cricetulus ,Immunogenicity, Vaccine ,law ,medicine ,Animals ,Neutralizing antibody ,Antigens, Viral ,biology ,General Immunology and Microbiology ,General Veterinary ,Chemistry ,Chinese hamster ovary cell ,Public Health, Environmental and Occupational Health ,Viral Vaccines ,Virology ,Recombinant Proteins ,3. Good health ,Immunoglobulin Fc Fragments ,030104 developmental biology ,Infectious Diseases ,Monoclonal ,biology.protein ,Recombinant DNA ,Middle East Respiratory Syndrome Coronavirus ,Molecular Medicine ,Antibody ,Coronavirus Infections ,Genetic Engineering ,Adjuvant ,Protein Processing, Post-Translational - Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) has infected at least 2040 patients and caused 712 deaths since its first appearance in 2012, yet neither pathogen-specific therapeutics nor approved vaccines are available. To address this need, we are developing a subunit recombinant protein vaccine comprising residues 377–588 of the MERS-CoV spike protein receptor-binding domain (RBD), which, when formulated with the AddaVax adjuvant, it induces a significant neutralizing antibody response and protection against MERS-CoV challenge in vaccinated animals. To prepare for the manufacture and first-in-human testing of the vaccine, we have developed a process to stably produce the recombinant MERS S377-588 protein in Chinese hamster ovary (CHO) cells. To accomplish this, we transfected an adherent dihydrofolate reductase-deficient CHO cell line (adCHO) with a plasmid encoding S377-588 fused with the human IgG Fc fragment (S377-588-Fc). We then demonstrated the interleukin-2 signal peptide-directed secretion of the recombinant protein into extracellular milieu. Using a gradually increasing methotrexate (MTX) concentration to 5 μM, we increased protein yield by a factor of 40. The adCHO-expressed S377-588-Fc recombinant protein demonstrated functionality and binding specificity identical to those of the protein from transiently transfected HEK293T cells. In addition, hCD26/dipeptidyl peptidase-4 (DPP4) transgenic mice vaccinated with AddaVax-adjuvanted S377-588-Fc could produce neutralizing antibodies against MERS-CoV and survived for at least 21 days after challenge with live MERS-CoV with no evidence of immunological toxicity or eosinophilic immune enhancement. To prepare for large scale-manufacture of the vaccine antigen, we have further developed a high-yield monoclonal suspension CHO cell line.
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- 2018
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10. Highly conserved M2e and hemagglutinin epitope-based recombinant proteins induce protection against influenza virus infection
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Shibo Jiang, Shihui Sun, Guangyu Zhao, Pei Li, Lanying Du, Lei He, Wanbo Tai, Nianping Song, Yan Guo, and Yusen Zhou
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0301 basic medicine ,Hemagglutinin Glycoproteins, Influenza Virus ,Antibodies, Viral ,Influenza A Virus, H7N9 Subtype ,medicine.disease_cause ,Epitope ,Conserved sequence ,law.invention ,Mice ,Influenza A Virus, H1N1 Subtype ,0302 clinical medicine ,law ,030212 general & internal medicine ,Mice, Inbred BALB C ,Vaccines, Synthetic ,Protection ,biology ,TCID50, 50% tissue culture infectious dose ,Immunogenicity ,Vaccination ,Hemagglutinin fusion peptide ,3. Good health ,HA-FP, hemagglutinin fusion peptide ,Infectious Diseases ,CPE, cytopathic effect ,Influenza Vaccines ,Vaccines, Subunit ,Recombinant DNA ,Female ,Immunology ,Hemagglutinin (influenza) ,IPTG, isopropyl-β-d-thiogalactopyranoside ,Microbiology ,Article ,Antigenic drift ,Virus ,Viral Proteins ,03 medical and health sciences ,Orthomyxoviridae Infections ,medicine ,Animals ,Influenza A Virus, H5N1 Subtype ,Virology ,Universal vaccines ,M2e, extracellular domain of M2 ,Influenza A virus subtype H5N1 ,030104 developmental biology ,M2e ,biology.protein ,Influenza virus - Abstract
Highly pathogenic influenza viruses continue to cause serious threat to public health due to their pandemic potential, calling for an urgent need to develop effective, safe, convenient, and universal vaccines against influenza virus infection. In this study, we constructed two recombinant protein vaccines, 2H5M2e-2H7M2e-H5FP-H7FP (hereinafter M2e-FP-1) and 2H5M2e-H5FP-2H7M2e-H7FP (hereinafter M2e-FP-2), by respectively linking highly conserved sequences of two molecules of ectodomain of M2 (M2e) and one molecule of fusion peptide (FP) epitope of hemagglutinin (HA) of H5N1 and H7N9 influenza viruses in different orders. The Escherichia coli-expressed M2e-FP-1 and M2e-FP-2 proteins induced similarly high-titer M2e-FP-specific antibodies in the immunized mice. Importantly, both proteins were able to prevent lethal challenge of heterologous H1N1 influenza virus, with significantly reduced viral titers and alleviated pathological changes in the lungs, as well as increased body weight and complete survivals, in the challenge mice. Taken together, our study demonstrates that highly conserved M2e and FP epitope of HA of H5N1 and H7N9 influenza viruses can be used as important targets for development of safe and economical universal influenza vaccines, and that the position of H7N9 M2e and H5N1 HA epitope sequences in the vaccine components has no significant effects on the immunogenicity and efficacy of M2e-FP-based subunit vaccines.
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- 2017
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11. Cross-neutralization of SARS coronavirus-specific antibodies against bat SARS-like coronaviruses
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Wanbo Tai, Cheng Peng, Shibo Jiang, Xing-Yi Ge, Leiping Zeng, Lanying Du, and Zhengli Shi
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0301 basic medicine ,030106 microbiology ,Cross Reactions ,Antibodies, Viral ,Chlorocebus aethiops ,General Biochemistry, Genetics and Molecular Biology ,Epitope ,Virus ,03 medical and health sciences ,Epitopes ,Mice ,Antigen ,Neutralization Tests ,Chiroptera ,Animals ,Letter to the Editor ,Antigens, Viral ,Vero Cells ,General Environmental Science ,Binding Sites ,biology ,Antibodies, Monoclonal ,biology.organism_classification ,Virology ,Antibodies, Neutralizing ,Specific antibody ,030104 developmental biology ,Severe acute respiratory syndrome-related coronavirus ,Spike Glycoprotein, Coronavirus ,Vero cell ,biology.protein ,Receptors, Virus ,Severe acute respiratory syndrome coronavirus ,Antibody ,General Agricultural and Biological Sciences - Published
- 2017
12. Rational Design of Zika Virus Subunit Vaccine with Enhanced Efficacy
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Lei He, Guangyu Zhao, Fang Li, Lanying Du, Jiawei Chen, Yusen Zhou, Wanbo Tai, Qibin Geng, and Yuehong Chen
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Protein subunit ,Immunology ,epitope shielding ,Antibodies, Viral ,Microbiology ,Epitope ,Zika virus ,law.invention ,03 medical and health sciences ,Epitopes ,Mice ,0302 clinical medicine ,Immune system ,Protein Domains ,Viral Envelope Proteins ,law ,Neutralization Tests ,Pregnancy ,Virology ,Vaccines and Antiviral Agents ,Animals ,Humans ,glycan probe ,Neutralizing antibody ,030304 developmental biology ,0303 health sciences ,biology ,Zika Virus Infection ,domain III ,Viral Vaccines ,vaccine efficacy ,Zika Virus ,Vaccine efficacy ,biology.organism_classification ,Antibodies, Neutralizing ,3. Good health ,envelope protein ,Disease Models, Animal ,intrinsic limitation of subunit vaccine designs ,Insect Science ,Vaccines, Subunit ,biology.protein ,Recombinant DNA ,Female ,Antibody ,030217 neurology & neurosurgery - Abstract
Viral subunit vaccines generally show low efficacy. In this study, we revealed an intrinsic limitation of subunit vaccine designs: artificially exposed surfaces of subunit vaccines contain epitopes unfavorable for vaccine efficacy. More specifically, we identified an epitope on Zika virus (ZIKV) envelope protein domain III (EDIII) that is buried in the full-length envelope protein but becomes exposed in recombinant EDIII. We further shielded this epitope with a glycan, and the resulting mutant EDIII vaccine demonstrated significantly enhanced efficacy over the wild-type EDIII vaccine in protecting animal models from ZIKV infections. Therefore, the intrinsic limitation of subunit vaccines can be overcome through shielding these artificially exposed unfavorable epitopes. The engineered EDIII vaccine generated in this study is a promising vaccine candidate that can be further developed to battle ZIKV infections., Zika virus (ZIKV) infection in pregnant women can lead to fetal deaths and malformations. We have previously reported that ZIKV envelope protein domain III (EDIII) is a subunit vaccine candidate with cross-neutralization activity; however, like many other subunit vaccines, its efficacy is limited. To improve the efficacy of this subunit vaccine, we identified a nonneutralizing epitope on ZIKV EDIII surrounding residue 375, which is buried in the full-length envelope protein but becomes exposed in recombinant EDIII. We then shielded this epitope with an engineered glycan probe. Compared to the wild-type EDIII, the mutant EDIII induced significantly stronger neutralizing antibodies in three mouse strains and also demonstrated significantly improved efficacy by fully protecting mice, particularly pregnant mice and their fetuses, against high-dose lethal ZIKV challenge. Moreover, the mutant EDIII immune sera significantly enhanced the passive protective efficacy by fully protecting mice against lethal ZIKV challenge; this passive protection was positively associated with neutralizing antibody titers. We further showed that the enhanced efficacy of the mutant EDIII was due to the shielding of the immunodominant nonneutralizing epitope surrounding residue 375, which led to immune refocusing on the neutralizing epitopes. Taken together, the results of this study reveal that an intrinsic limitation of subunit vaccines is their artificially exposed immunodominant nonneutralizing epitopes, which can be overcome through glycan shielding. Additionally, the mutant ZIKV protein generated in this study is a promising subunit vaccine candidate with high efficacy in preventing ZIKV infections in mice. IMPORTANCE Viral subunit vaccines generally show low efficacy. In this study, we revealed an intrinsic limitation of subunit vaccine designs: artificially exposed surfaces of subunit vaccines contain epitopes unfavorable for vaccine efficacy. More specifically, we identified an epitope on Zika virus (ZIKV) envelope protein domain III (EDIII) that is buried in the full-length envelope protein but becomes exposed in recombinant EDIII. We further shielded this epitope with a glycan, and the resulting mutant EDIII vaccine demonstrated significantly enhanced efficacy over the wild-type EDIII vaccine in protecting animal models from ZIKV infections. Therefore, the intrinsic limitation of subunit vaccines can be overcome through shielding these artificially exposed unfavorable epitopes. The engineered EDIII vaccine generated in this study is a promising vaccine candidate that can be further developed to battle ZIKV infections.
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- 2019
13. Enhanced Ability of Oligomeric Nanobodies Targeting MERS Coronavirus Receptor-Binding Domain
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Yusen Zhou, Shihui Sun, Guangyu Zhao, Jiangfan Li, Lanying Du, Yuehong Chen, Wanbo Tai, Yaning Gao, Junfeng Li, and Lei He
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0301 basic medicine ,Hot Temperature ,medicine.medical_treatment ,viruses ,lcsh:QR1-502 ,therapeutic antibodies ,medicine.disease_cause ,Antibodies, Viral ,lcsh:Microbiology ,MERS-CoV ,Pepsin ,Urea ,Coronavirus ,biology ,Chemistry ,virus diseases ,nanobodies ,3. Good health ,Chaotropic agent ,Infectious Diseases ,Middle East Respiratory Syndrome Coronavirus ,Receptors, Virus ,Antibody ,receptor-binding domain ,Protein Binding ,Camelus ,Middle East respiratory syndrome coronavirus ,030106 microbiology ,Virus ,Article ,03 medical and health sciences ,Protein Domains ,Neutralization Tests ,cross-neutralization ,Virology ,medicine ,Animals ,Humans ,Protease ,COVID-19 ,Single-Domain Antibodies ,medicine.disease ,Molecular biology ,Antibodies, Neutralizing ,Pepsin A ,030104 developmental biology ,biology.protein ,Middle East respiratory syndrome ,Receptors, Coronavirus - Abstract
Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV), an infectious coronavirus first reported in 2012, has a mortality rate greater than 35%. Therapeutic antibodies are key tools for preventing and treating MERS-CoV infection, but to date no such agents have been approved for treatment of this virus. Nanobodies (Nbs) are camelid heavy chain variable domains with properties distinct from those of conventional antibodies and antibody fragments. We generated two oligomeric Nbs by linking two or three monomeric Nbs (Mono-Nbs) targeting the MERS-CoV receptor-binding domain (RBD), and compared their RBD-binding affinity, RBD–receptor binding inhibition, stability, and neutralizing and cross-neutralizing activity against MERS-CoV. Relative to Mono-Nb, dimeric Nb (Di-Nb) and trimeric Nb (Tri-Nb) had significantly greater ability to bind MERS-CoV RBD proteins with or without mutations in the RBD, thereby potently blocking RBD–MERS-CoV receptor binding. The engineered oligomeric Nbs were very stable under extreme conditions, including low or high pH, protease (pepsin), chaotropic denaturant (urea), and high temperature. Importantly, Di-Nb and Tri-Nb exerted significantly elevated broad-spectrum neutralizing activity against at least 19 human and camel MERS-CoV strains isolated in different countries and years. Overall, the engineered Nbs could be developed into effective therapeutic agents for prevention and treatment of MERS-CoV infection.
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- 2019
14. Single-dose treatment with a humanized neutralizing antibody affords full protection of a human transgenic mouse model from lethal Middle East respiratory syndrome (MERS)-coronavirus infection
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Shihui Sun, Yusen Zhou, Lanying Du, Hongjie Qiu, Yufei Wang, Jiannan Feng, Wanbo Tai, Guangyu Zhao, He Xiao, and Yan Guo
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0301 basic medicine ,viruses ,Antibodies, Viral ,medicine.disease_cause ,Lethal infection ,Epitope ,Epitopes ,Mice ,MERS-CoV ,Humanized monoclonal antibody ,Neutralizing antibody ,Protection ,biology ,virus diseases ,3. Good health ,Middle East Respiratory Syndrome Coronavirus ,Receptors, Virus ,Female ,Coronavirus Infections ,Protein Binding ,Genetically modified mouse ,medicine.drug_class ,Middle East respiratory syndrome coronavirus ,Dipeptidyl Peptidase 4 ,Transgene ,030106 microbiology ,Mice, Transgenic ,Cross Reactions ,Antibodies, Monoclonal, Humanized ,Monoclonal antibody ,Article ,Cell Line ,03 medical and health sciences ,Neutralization Tests ,Virology ,medicine ,Animals ,Humans ,Dipeptidyl peptidase-4 ,Pharmacology ,medicine.disease ,Antibodies, Neutralizing ,Receptor-binding domain ,respiratory tract diseases ,Treatment ,Disease Models, Animal ,030104 developmental biology ,biology.protein ,Middle East respiratory syndrome - Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is continuously spreading and causing severe and fatal acute respiratory disease in humans. Prophylactic and therapeutic strategies are therefore urgently needed to control MERS-CoV infection. Here, we generated a humanized monoclonal antibody (mAb), designated hMS-1, which targeted the MERS-CoV receptor-binding domain (RBD) with high affinity. hMS-1 significantly blocked MERS-CoV RBD binding to its viral receptor, human dipeptidyl peptidase 4 (hDPP4), potently neutralized infection by a prototype MERS-CoV, and effectively cross-neutralized evolved MERS-CoV isolates through recognizing highly conserved RBD epitopes. Notably, single-dose treatment with hMS-1 completely protected hDPP4 transgenic (hDPP4-Tg) mice from lethal infection with MERS-CoV. Taken together, our data suggest that hMS-1 might be developed as an effective immunotherapeutic agent to treat patients infected with MERS-CoV, particularly in emergent cases.
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- 2016
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15. A Novel Nanobody Targeting Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Receptor-Binding Domain Has Potent Cross-Neutralizing Activity and Protective Efficacy against MERS-CoV
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Enqi Du, Jiawei Chen, Jiangfan Li, Yuehong Chen, Kaiyuan Ji, Ruiwen Fan, Lei He, Yufei Wang, Guangyu Zhao, Fang Li, Shibo Jiang, Wanbo Tai, Yan Guo, Shihui Sun, Yusen Zhou, Jian Shang, Lanying Du, and Hongjie Qiu
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0301 basic medicine ,Middle East respiratory syndrome coronavirus ,viruses ,030106 microbiology ,Immunology ,Biology ,medicine.disease_cause ,Antibodies, Viral ,Microbiology ,Epitope ,03 medical and health sciences ,Epitopes ,Mice ,In vivo ,Neutralization Tests ,Virology ,medicine ,Animals ,Humans ,Binding site ,Receptor ,Mice, Inbred BALB C ,Binding Sites ,virus diseases ,Spike Protein ,Single-Domain Antibodies ,Antibodies, Neutralizing ,respiratory tract diseases ,030104 developmental biology ,Insect Science ,Spike Glycoprotein, Coronavirus ,biology.protein ,Middle East Respiratory Syndrome Coronavirus ,Antibody ,Coronavirus Infections ,Conformational epitope ,Protein Binding - Abstract
The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) continues to infect humans and camels, calling for efficient, cost-effective, and broad-spectrum strategies to control its spread. Nanobodies (Nbs) are single-domain antibodies derived from camelids and sharks and are potentially cost-effective antivirals with small size and great expression yield. In this study, we developed a novel neutralizing Nb (NbMS10) and its human-Fc-fused version (NbMS10-Fc), both of which target the MERS-CoV spike protein receptor-binding domain (RBD). We further tested their receptor-binding affinity, recognizing epitopes, cross-neutralizing activity, half-life, and efficacy against MERS-CoV infection. Both Nbs can be expressed in yeasts with high yield, bind to MERS-CoV RBD with high affinity, and block the binding of MERS-CoV RBD to the MERS-CoV receptor. The binding site of the Nbs on the RBD was mapped to be around residue Asp539, which is part of a conserved conformational epitope at the receptor-binding interface. NbMS10 and NbMS10-Fc maintained strong cross-neutralizing activity against divergent MERS-CoV strains isolated from humans and camels. Particularly, NbMS10-Fc had significantly extended half-life in vivo; a single-dose treatment of NbMS10-Fc exhibited high prophylactic and therapeutic efficacy by completely protecting humanized mice from lethal MERS-CoV challenge. Overall, this study proves the feasibility of producing cost-effective, potent, and broad-spectrum Nbs against MERS-CoV and has produced Nbs with great potentials as anti-MERS-CoV therapeutics.IMPORTANCE Therapeutic development is critical for preventing and treating continual MERS-CoV infections in humans and camels. Because of their small size, nanobodies (Nbs) have advantages as antiviral therapeutics (e.g., high expression yield and robustness for storage and transportation) and also potential limitations (e.g., low antigen-binding affinity and fast renal clearance). Here, we have developed novel Nbs that specifically target the receptor-binding domain (RBD) of MERS-CoV spike protein. They bind to a conserved site on MERS-CoV RBD with high affinity, blocking RBD's binding to MERS-CoV receptor. Through engineering a C-terminal human Fc tag, the in vivo half-life of the Nbs is significantly extended. Moreover, the Nbs can potently cross-neutralize the infections of diverse MERS-CoV strains isolated from humans and camels. The Fc-tagged Nb also completely protects humanized mice from lethal MERS-CoV challenge. Taken together, our study has discovered novel Nbs that hold promise as potent, cost-effective, and broad-spectrum anti-MERS-CoV therapeutic agents.
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- 2018
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16. Critical neutralizing fragment of Zika virus EDIII elicits cross-neutralization and protection against divergent Zika viruses
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Lanying Du, Lei He, Guangyu Zhao, Pei Li, Chuming Luo, Haiyan Zhao, Wanbo Tai, Shibo Jiang, Shihun Sun, Yusen Zhou, Daved H. Fremont, Yufei Wang, and Fang Li
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0301 basic medicine ,Microcephaly ,Epidemiology ,Cross Protection ,Immunology ,Antibodies, Viral ,Microbiology ,Article ,Zika virus ,law.invention ,03 medical and health sciences ,Mice ,Immunogenicity, Vaccine ,Viral Envelope Proteins ,Interferon ,law ,Virology ,Drug Discovery ,medicine ,Animals ,Humans ,biology ,Zika Virus Infection ,Immunogenicity ,Immunization, Passive ,Viral Vaccines ,General Medicine ,Zika Virus ,medicine.disease ,biology.organism_classification ,Antibodies, Neutralizing ,Recombinant Proteins ,Titer ,030104 developmental biology ,Infectious Diseases ,Immunization ,Immunoglobulin G ,Vaccines, Subunit ,biology.protein ,Recombinant DNA ,Parasitology ,Antibody ,medicine.drug - Abstract
Zika virus (ZIKV) infection remains a serious health threat due to its close association with congenital Zika syndrome (CZS), which includes microcephaly and other severe birth defects. As no vaccines are available for human use, continuous effort is needed to develop effective and safe vaccines to prevent ZIKV infection. In this study, we constructed three recombinant proteins comprising, respectively, residues 296–406 (E296-406), 298–409 (E298-409), and 301–404 (E301-404) of ZIKV envelope (E) protein domain III (EDIII) fused with a C-terminal Fc of human IgG. Our results demonstrated that E298-409 induced the highest titer of neutralizing antibodies against infection with nine ZIKV strains isolated from different hosts, countries, and time periods, and it maintained long-term anti-ZIKV immunogenicity to induce neutralizing antibodies. Pups born to mice immunized with E298-409 were fully protected against lethal challenge with two epidemic human ZIKV strains, 2015/Honduras (R103451) and 2015/Colombia (FLR). Passive transfer of anti-E298-409 mouse sera protected pups born to naive mice, as well as type I interferon receptor-deficient adult A129 mice, from lethal challenge with human ZIKV strains R103451 and FLR, and this protection was positively correlated with neutralizing antibodies. These data suggest that the critical neutralizing fragment (i.e., a fragment that can induce highly potent neutralizing antibodies against divergent ZIKV strains) of ZIKV EDIII is a good candidate for development as an effective and safe ZIKV subunit vaccine to protect pregnant mothers and their fetuses against ZIKV infection. The E298-409-specific antibodies can be used for passive immunization to prevent ZIKV infection in newborns or immunocompromised adults.
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- 2017
17. Recombinant Receptor-Binding Domains of Multiple Middle East Respiratory Syndrome Coronaviruses (MERS-CoVs) Induce Cross-Neutralizing Antibodies against Divergent Human and Camel MERS-CoVs and Antibody Escape Mutants
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Shibo Jiang, Wanbo Tai, Lanying Du, Yufei Wang, Stanley Perlman, Fang Li, Craig Fett, Yusen Zhou, and Guangyu Zhao
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0301 basic medicine ,Models, Molecular ,viruses ,Gene Expression ,medicine.disease_cause ,Antibodies, Viral ,Protein Structure, Secondary ,Mice ,Mice, Inbred BALB C ,biology ,Immunogenicity ,Vaccination ,Recombinant Proteins ,Spike Glycoprotein, Coronavirus ,Middle East Respiratory Syndrome Coronavirus ,Receptors, Virus ,Female ,Antibody ,Coronavirus Infections ,Plasmids ,Protein Binding ,Virus genetics ,Antigenicity ,Camelus ,medicine.drug_class ,Middle East respiratory syndrome coronavirus ,Dipeptidyl Peptidase 4 ,Immunology ,Cross Reactions ,Monoclonal antibody ,Microbiology ,Virus ,03 medical and health sciences ,Neutralization Tests ,Virology ,Vaccines and Antiviral Agents ,medicine ,Animals ,Humans ,Protein Interaction Domains and Motifs ,Immune Evasion ,Binding Sites ,Viral Vaccines ,medicine.disease ,Antibodies, Neutralizing ,030104 developmental biology ,Insect Science ,Mutation ,biology.protein ,Middle East respiratory syndrome - Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) binds to cellular receptor dipeptidyl peptidase 4 (DPP4) via the spike (S) protein receptor-binding domain (RBD). The RBD contains critical neutralizing epitopes and serves as an important vaccine target. Since RBD mutations occur in different MERS-CoV isolates and antibody escape mutants, cross-neutralization of divergent MERS-CoV strains by RBD-induced antibodies remains unknown. Here, we constructed four recombinant RBD (rRBD) proteins with single or multiple mutations detected in representative human MERS-CoV strains from the 2012, 2013, 2014, and 2015 outbreaks, respectively, and one rRBD protein with multiple changes derived from camel MERS-CoV strains. Like the RBD of prototype EMC2012 (EMC-RBD), all five RBDs maintained good antigenicity and functionality, the ability to bind RBD-specific neutralizing monoclonal antibodies (MAbs) and the DPP4 receptor, and high immunogenicity, able to elicit S-specific antibodies. They induced potent neutralizing antibodies cross-neutralizing 17 MERS pseudoviruses expressing S proteins of representative human and camel MERS-CoV strains identified during the 2012-2015 outbreaks, 5 MAb escape MERS-CoV mutants, and 2 live human MERS-CoV strains. We then constructed two RBDs mutated in multiple key residues in the receptor-binding motif (RBM) of RBD and demonstrated their strong cross-reactivity with anti-EMC-RBD antibodies. These RBD mutants with diminished DPP4 binding also led to virus attenuation, suggesting that immunoevasion after RBD immunization is accompanied by loss of viral fitness. Therefore, this study demonstrates that MERS-CoV RBD is an important vaccine target able to induce highly potent and broad-spectrum neutralizing antibodies against infection by divergent circulating human and camel MERS-CoV strains. IMPORTANCE MERS-CoV was first identified in June 2012 and has since spread in humans and camels. Mutations in its spike (S) protein receptor-binding domain (RBD), a key vaccine target, have been identified, raising concerns over the efficacy of RBD-based MERS vaccines against circulating human and camel MERS-CoV strains. Here, we constructed five vaccine candidates, designated 2012-RBD, 2013-RBD, 2014-RBD, 2015-RBD, and Camel-RBD, containing single or multiple mutations in the RBD of representative human and camel MERS-CoV strains during the 2012-2015 outbreaks. These RBD-based vaccine candidates maintained good functionality, antigenicity, and immunogenicity, and they induced strong cross-neutralizing antibodies against infection by divergent pseudotyped and live MERS-CoV strains, as well as antibody escape MERS-CoV mutants. This study provides impetus for further development of a safe, highly effective, and broad-spectrum RBD-based subunit vaccine to prevent MERS-CoV infection.
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- 2016
18. Introduction of neutralizing immunogenicity index to the rational design of MERS coronavirus subunit vaccines
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Yang Yang, Lanying Du, Shihui Sun, Stanley Perlman, Wanbo Tai, Guangyu Zhao, Chien Te K. Tseng, Fang Li, Qing Zhu, Yusen Zhou, Chang Liu, Shibo Jiang, and Xinrong Tao
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0301 basic medicine ,Glycan ,Immunogen ,Middle East respiratory syndrome coronavirus ,viruses ,Science ,Protein subunit ,030106 microbiology ,General Physics and Astronomy ,Biology ,medicine.disease_cause ,Antibodies, Viral ,General Biochemistry, Genetics and Molecular Biology ,Epitope ,Article ,03 medical and health sciences ,Mice ,Immune system ,medicine ,Animals ,Humans ,Mice, Inbred BALB C ,Multidisciplinary ,Immunogenicity ,Viral Vaccines ,General Chemistry ,Virology ,Antibodies, Neutralizing ,Recombinant Proteins ,3. Good health ,Protein Subunits ,030104 developmental biology ,HEK293 Cells ,Immunology ,Spike Glycoprotein, Coronavirus ,Vaccines, Subunit ,biology.protein ,Middle East Respiratory Syndrome Coronavirus ,Antibody ,Coronavirus Infections - Abstract
Viral subunit vaccines often contain immunodominant non-neutralizing epitopes that divert host immune responses. These epitopes should be eliminated in vaccine design, but there is no reliable method for evaluating an epitope's capacity to elicit neutralizing immune responses. Here we introduce a new concept ‘neutralizing immunogenicity index' (NII) to evaluate an epitope's neutralizing immunogenicity. To determine the NII, we mask the epitope with a glycan probe and then assess the epitope's contribution to the vaccine's overall neutralizing immunogenicity. As proof-of-concept, we measure the NII for different epitopes on an immunogen comprised of the receptor-binding domain from MERS coronavirus (MERS-CoV). Further, we design a variant form of this vaccine by masking an epitope that has a negative NII score. This engineered vaccine demonstrates significantly enhanced efficacy in protecting transgenic mice from lethal MERS-CoV challenge. Our study may guide the rational design of highly effective subunit vaccines to combat MERS-CoV and other life-threatening viruses., Viral subunit vaccines contain epitopes that elicit non-neutralizing immune responses. Here, Du et al. mask an immunodominant non-neutralizing epitope on a MERS coronavirus subunit vaccine with a glycan probe, leading to significantly improved efficacy of the vaccine.
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- 2016
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