SARS Vaccine Development

Jiang, Shibo; He, Yuxian; Liu, Shuwen

doi:10.3201/1107.050219

Cited by 187 publications

(179 citation statements)

References 40 publications

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“…protein and the cellular receptor ACE2, and that an independently folded RBD-Fc fusion protein can induce highly potent neutralizing Abs against SARS-CoV variants that have predominated in the 2002-2003 outbreak (38 -41). We proposed that the RBD of the S protein can be used for the development of a SARS vaccine, because it is not only a functional domain that mediates virus-receptor binding but also a critical neutralization determinant of SARS-CoV (47,48). However, the evolving genetic heterogeneity of SARS-CoV has raised concerns that viruses may have developed immune escape mechanisms to neutralization by Abs targeting the RBD (35).…”

Section: Discussionmentioning

confidence: 99%

Cross-Neutralization of Human and Palm Civet Severe Acute Respiratory Syndrome Coronaviruses by Antibodies Targeting the Receptor-Binding Domain of Spike Protein

et al. 2006

The Journal of Immunology

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The spike (S) protein of severe acute respiratory syndrome coronavirus (SARS-CoV) is considered as a protective Ag for vaccine design. We previously demonstrated that the receptor-binding domain (RBD) of S protein contains multiple conformational epitopes (Conf I-VI) that confer the major target of neutralizing Abs. Here we show that the recombinant RBDs derived from the S protein sequences of Tor2, GD03, and SZ3, the representative strains of human 2002–2003 and 2003–2004 SARS-CoV and palm civet SARS-CoV, respectively, induce in the immunized mice and rabbits high titers of cross-neutralizing Abs against pseudoviruses expressing S proteins of Tor2, GD03, and SZ3. We also demonstrate that the Tor2-RBD induced-Conf I-VI mAbs can potently neutralize both human SARS-CoV strains, Tor2 and GD03. However, only the Conf IV-VI, but not Conf I-III mAbs, neutralize civet SARS-CoV strain SZ3. All these mAbs reacted significantly with each of the three RBD variants (Tor2-RBD, GD03-RBD, and SZ3-RBD) that differ at several amino acids. Regardless, the Conf I-IV and VI epitopes were completely disrupted by single-point mutation of the conserved residues in the RBD (e.g., D429A, R441A, or D454A) and the Conf III epitope was significantly affected by E452A or D463A substitution. Interestingly, the Conf V epitope, which may overlap the receptor-binding motif and induce most potent neutralizing Abs, was conserved in these mutants. These data suggest that the major neutralizing epitopes of SARS-CoV have been apparently maintained during cross-species transmission, and that RBD-based vaccines may induce broad protection against both human and animal SARS-CoV variants.

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Section: Discussionmentioning

confidence: 99%

Cross-Neutralization of Human and Palm Civet Severe Acute Respiratory Syndrome Coronaviruses by Antibodies Targeting the Receptor-Binding Domain of Spike Protein

et al. 2006

The Journal of Immunology

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114

121

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“…Previously, we identified several S glycoprotein fragments, containing the RBD, which is a major SCV neutralization determinant (12)(13)(14)(15)(16)(17)(18), and residues critical for the binding of SCV to its receptor ACE2 (7,22). One of these fragments, containing residues 317-518, was cloned into a baculovirus vector, expressed in insect cells, and purified.…”

Section: Resultsmentioning

confidence: 99%

“…In the case of SCV entry, the spike (S) glycoprotein (7,8) binds to a receptor, angiotensin-converting enzyme 2 (ACE2) (9), through the receptor-binding site of its receptor-binding domain (RBD) (7,10,11). The RBD is an attractive target for neutralizing antibodies that could prevent SCV entry by blocking the attachment of ACE2 (12)(13)(14)(15)(16)(17)(18). To understand the structural mechanisms underlying SCV immunogenicity and neutralization and help in the design of vaccines capable of eliciting predetermined highly effective neutralizing antibodies, we used a retrovaccinology (19) approach based on the combination of phage display and x-ray crystallography.…”

mentioning

confidence: 99%

Structure of Severe Acute Respiratory Syndrome Coronavirus Receptor-binding Domain Complexed with Neutralizing Antibody

Prabakaran

Gan

Yang

et al. 2006

Journal of Biological Chemistry

254

297

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The severe acute respiratory syndrome coronavirus (SARSCoV, or SCV), which caused a world-wide epidemic in 2002 and 2003, binds to a receptor, angiotensin-converting enzyme 2 (ACE2), through the receptor-binding domain (RBD) of its envelope (spike, S) glycoprotein. The RBD is very immunogenic; it is a major SCV neutralization determinant and can elicit potent neutralizing antibodies capable of out-competing ACE2. However, the structural basis of RBD immunogenicity, RBD-mediated neutralization, and the role of RBD in entry steps following its binding to ACE2 have not been elucidated. By mimicking immune responses with the use of RBD as an antigen to screen a large human antibody library derived from healthy volunteers, we identified a novel potent cross-reactive SCV-neutralizing monoclonal antibody, m396, which competes with ACE2 for binding to RBD, and determined the crystal structure of the RBD-antibody complex at 2.3-Å resolution. The antibody-bound RBD structure is completely defined, revealing two previously unresolved segments (residues 376 -381 and 503-512) and a new disulfide bond (between residues 378 and 511). Interestingly, the overall structure of the m396-bound RBD is not significantly different from that of the ACE2-bound RBD. The antibody epitope is dominated by a 10-residue-long protruding ␤6 -␤7 loop with two putative ACE2-binding hotspot residues (Ile-489 and Tyr-491). These results provide a structural rationale for the function of a major determinant of SCV immunogenicity and neutralization, the development of SCV therapeutics based on the antibody paratope and epitope, and a retrovaccinology approach for the design of anti-SCV vaccines. The available structural information indicates that the SCV entry may not be mediated by ACE2-induced conformational changes in the RBD but may involve other conformational changes or/and yet to be identified coreceptors.The severe acute respiratory syndrome coronavirus (SARS-CoV, or SCV) 4 infected more than 8000 humans with a fatality rate of ϳ10% (1-4). Although there have been no recent outbreaks, the need to develop potent therapeutics and vaccines against a re-emerging SCV or a related virus remains of high priority. The amazingly rapid pace of SARS research for the last few years has resulted in a wealth of information for the virus, especially about its interactions with the host leading to disease and immune responses, which could also be helpful for the development of strategies to cope with other viral pathogens including influenza and HIV.Entry of viruses into animal cells is initiated by binding to cell-surface-associated receptors and can be prevented by neutralizing antibodies (nAbs) targeting the virus receptor-binding site (5, 6). In the case of SCV entry, the spike (S) glycoprotein (7, 8) binds to a receptor, angiotensin-converting enzyme 2 (ACE2) (9), through the receptor-binding site of its receptor-binding domain (RBD) (7, 10, 11). The RBD is an attractive target for neutralizing antibodies that could prevent SCV entry by blocking the a...

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“…We have previously identified fragments containing the receptorbinding domain (RBD), which is a major SARS-CoV neutralization determinant (23,(28)(29)(30)(31)(32)(33), and residues critical for its binding to ACE2 (34,35). One of these fragments containing residues 317-518 was cloned into a baculovirus expression vector, expressed in insect cells, and purified.…”

mentioning

confidence: 99%

Potent cross-reactive neutralization of SARS coronavirus isolates by human monoclonal antibodies

Zhu

Chakraborti

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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298

328

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SARS Vaccine Development

Cited by 187 publications

References 40 publications

Cross-Neutralization of Human and Palm Civet Severe Acute Respiratory Syndrome Coronaviruses by Antibodies Targeting the Receptor-Binding Domain of Spike Protein

Cross-Neutralization of Human and Palm Civet Severe Acute Respiratory Syndrome Coronaviruses by Antibodies Targeting the Receptor-Binding Domain of Spike Protein

Structure of Severe Acute Respiratory Syndrome Coronavirus Receptor-binding Domain Complexed with Neutralizing Antibody

Potent cross-reactive neutralization of SARS coronavirus isolates by human monoclonal antibodies

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