Advances in MERS-CoV Vaccines and Therapeutics Based on the Receptor-Binding Domain
Abstract
:1. Introduction
2. MERS-CoV S Protein RBD
3. Recent Advances in the Development of Vaccines Based on the MERS-CoV S-Protein RBD
4. Recent Advances in the Development of Therapeutics Based on the MERS-CoV S-Protein RBD
4.1. MERS-CoV S-Protein RBD-Targeting mAbs
4.2. Nanobodies Targeting the MERS-CoV S-protein RBD
5. Potential Challenges and Future Perspectives
Author Contributions
Acknowledgments
Conflicts of Interest
References
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Name | Functionality and Antigenicity | Immunogenicity in Induction of Antibody Response | Immunogenicity in Induction of Cellular Immune Response | Protective Immunity | Ref. |
---|---|---|---|---|---|
RBD-[SSG]-FR and RBD-FR nanoparticles | Bind to DPP4 receptor; antisera block RBD-hDPP4 binding | Induce MERS-CoV RBD-specific antibodies (IgG, IgG1, IgG2a, IgG2b, IgA) in mice | Elicit MERS-CoV RBD-specific T-cell responses (IFN-γ, TNF-α) in mouse splenocytes | N/A | [89] |
sVLP (spherical virus-like particle) | N/A | Induces MERS-CoV RBD-specific antibodies (IgG) in mice, neutralizing pseudotyped MERS-CoV (1:320) | Elicits MERS-CoV RBD-specific cellular immune response (IFN-γ, IL-2, IL-4) in mouse splenocytes | N/A | [90] |
rRBD (recombinant RBD) | N/A | Induces MERS-CoV RBD-specific antibodies (IgG, IgG1, IgG2a) in mice or NHPs, neutralizing pseudotyped (1:800 to 1:1,600) and live (EMC2012: 1:269 to 1:363) MERS-CoV | Elicits MERS-CoV RBD-specific cellular immune response (TNF-α, IFN-γ, IL-2, IL-4, IL-6) in mouse splenocytes or monkey PBMCs | Partially protects NHPs from MERS-CoV (EMC2012: 6.5 × 107 TCID50) infection with alleviated pneumonia and decreased viral load | [88,91] |
RBD (S377-588)-Fc | Binds strongly to soluble and cell-associated hDPP4 or cDPP4 receptors and MERS-CoV RBD-specific neutralizing mAbs (Mersmab1, m336, m337, m338) | Induces MERS-CoV S1-specific antibodies (IgG, IgG1, IgG2a) in mice and rabbits, cross-neutralizing 17 pseudotyped (>1:104), 2 live (EMC2012, London1-2012: ≥1:103) MERS-CoV, and 5 mAb escape mutants (>1:104) | Elicits MERS-CoV S1-specific cellular immune responses (IFN-γ, IL-2) in mouse splenocytes | Protects Ad5/hDPP4-transduced BALB/c mice and hDPP4-Tg mice (67% survival rate) from challenge by MERS-CoV (EMC2012: 105 PFU for BALB/c; 103–104 TCID50 for Tg), without toxicity or immune enhancement | [92,95,96,97,98,99] |
2012-RBD 2013-RBD 2014-RBD 2015-RBD Camel-RBD | Bind strongly to hDPP4 and cDPP4 receptors and MERS-CoV RBD-specific mAbs (Mersmab1, m336, m337, m338) with high affinity | Induce MERS-CoV S1-specific antibodies (IgG, IgG1, IgG2a) in mice, potently cross-neutralizing 17 pseudotyped (≥1:104), 2 live (EMC2012, London1-2012: >1:102) MERS-CoV, and 5 mAb escape mutants (≥1:104) | N/A | N/A | [100] |
RBD-Fd | Binds strongly to soluble and cell-associated hDPP4 receptors and MERS-CoV RBD-specific mAbs (Mersmab1, m336, m337, m338) | Induces robust and long-term MERS-CoV S1-specific antibodies (IgG, IgG1, IgG2a) in mice, neutralizing at least 9 pseudotyped (>1:104) and live (EMC2012: >1:103) MERS-CoV | N/A | Protects hDPP4-Tg mice (83% survival rate) from lethal MERS-CoV (EMC2012: 104 TCID50) challenge | [94] |
RBD (T579N) | Binds strongly to soluble and cell-associated hDPP4 receptors and MERS-CoV RBD-specific mAbs (hHS-1, m336, m337, m338) | Induces highly potent neutralizing antibodies in mice against live MERS-CoV (EMC2012: >1:3 × 103) | N/A | Significantly enhances efficacy in fully protecting hDPP4-Tg mice (100% survival rate) from lethal MERS-CoV (EMC2012: 104 TCID50) challenge | [93] |
Name | Source | Binding MERS-CoV RBD | Structure Available | In vitro Anti-MERS-CoV Activity | In vivo Protection | Ref. |
---|---|---|---|---|---|---|
MERS-GD27 MERS-GD33 mAbs | Human | Kd: 0.775 nM (for MERS-GD27) and 0.575 nM (for MERS-GD33). Recognize RBD residues L506, D510, E513, W535, E536, D539, E540, W553 (for MERS-GD27), R511, and A556 (for MERS-GD33) | Yes, crystal structure for the Fab–RBD complex | IC50: 0.001 µg/mL against pseudotyped MERS-CoV; 0.001 µg/mL against live MERS-CoV; both mAbs have synergistic effect against pseudotyped MERS-CoV with reduced IC50 by 0.499-fold (for MERS-GD27) or 6.05-fold (for MERS-GD33) vs individual mAbs | MERS-GD27 prophylactically and therapeutically protects hDPP4-Tg mice against MERS-CoV (EMC2012: 3 LD50) with 60% and 40% survival rates, respectively | [112,113] |
MCA1 mAb | Human | Recognizes RBD residues D510, W535, E536, D539, Y540, R542, and Q544 | Yes, crystal structure for the Fab–RBD complex | IC50: 0.39 µg/mL against live MERS-CoV (EMC2012) | Prophylactically and therapeutically (5–20 mg/kg) inhibits MERS-CoV (EMC2012: 5 × 106 TCID50) replication in common marmosets, improving clinical outcomes and reducing lung disease and viral replication | [114] |
JC57-14 mAb | Macaque | Recognizes RBD residues W535, E536, D539, Y540, and R542 | Yes, crystal structure for the Fab–RBD complex | IC50: 0.0084 µg/mL against pseudotyped MERS-CoV and 0.07 µg/mL against live MERS-CoV (EMC2012), cross-neutralizing 8 pseudotyped MERS-CoVs | N/A | [102] |
CDC2-C2 mAb | Human | Recognizes RBD residues F506, D509, W535, E536, D539, Y540, and R542 | Yes, crystal structure for the Fab–RBD complex | IC50: 0.0057 µg/mL against pseudotyped MERS-CoV and 0.058 µg/mL against live MERS-CoV (EMC2012), cross-neutralizing 10 pseudotyped MERS-CoVs | Prophylactically (20 mg/kg) protects hDPP4-Tg mice against MERS-CoV (EMC2012: 106 TCID50) in lungs with 100% survival rate | [102] |
MERS-4 mAb | Human | Recognizes RBD residues L507, L545, S546, P547, G549; binds RBD from outside of the RBD DPP4-binding interface | Yes, crystal structure for the Fab–RBD complex | Has synergistic neutralization effect with MERS-27, m336, and 5F9 mAbs against pseudotyped MERS-CoV, with the reduction of IC50 by 2.6-fold (for MERS-4 + m336) and 15.21-fold (for MERS-4 + 5F9) | N/A | [115] |
VHH-83 HCAb-83 VHHs | Dromedary | Kd: 0.1 nM (for VHH-83) and 2.5 pM (for HCAb-83). Recognizes RBD residue D539 | N/A | PRNT50: 0.0012–0.0014 µg/mL against live MERS-CoV (EMC2012) | HCAb-83 (200 µg) prophylactically protects hDPP4-Tg mice (K18) against MERS-CoV (EMC2012: 105 PFU) in lungs with 100% survival rate | [116] |
NbMS10 NbMS10-Fc VHHs | Llama | Kd: 0.87 nM (for NbMS10) and 0.35 nM (for NbMS10-Fc). Recognize RBD residue D539 | N/A | IC50: 0.003–0.979 µg/ml (for NbMS10) and 0.003–0.067 µg/ml (for NbMS10-Fc) in cross-neutralizing ≥11 pseudotyped MERS-CoVs | NbMS10-Fc (10 mg/kg) prophylactically and therapeutically protects hDPP4-Tg mice against MERS-CoV (EMC2012, 105.3 TCID50) with 100% survival rate | [117] |
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Zhou, Y.; Yang, Y.; Huang, J.; Jiang, S.; Du, L. Advances in MERS-CoV Vaccines and Therapeutics Based on the Receptor-Binding Domain. Viruses 2019, 11, 60. https://doi.org/10.3390/v11010060
Zhou Y, Yang Y, Huang J, Jiang S, Du L. Advances in MERS-CoV Vaccines and Therapeutics Based on the Receptor-Binding Domain. Viruses. 2019; 11(1):60. https://doi.org/10.3390/v11010060
Chicago/Turabian StyleZhou, Yusen, Yang Yang, Jingwei Huang, Shibo Jiang, and Lanying Du. 2019. "Advances in MERS-CoV Vaccines and Therapeutics Based on the Receptor-Binding Domain" Viruses 11, no. 1: 60. https://doi.org/10.3390/v11010060