A Truncated Receptor-Binding Domain of MERS-CoV Spike Protein Potently Inhibits MERS-CoV Infection and Induces Strong Neutralizing Antibody Responses: Implication for Developing Therapeutics and Vaccines

Abstract

An emerging respiratory infectious disease with high mortality, Middle East respiratory syndrome (MERS), is caused by a novel coronavirus (MERS-CoV). It was first reported in 2012 in Saudi Arabia and has now spread to eight countries. Development of effective therapeutics and vaccines is crucial to save lives and halt the spread of MERS-CoV. Here, we show that a recombinant protein containing a 212-amino acid fragment (residues 377-588) in the truncated receptor-binding domain (RBD: residues 367–606) of MERS-CoV spike (S) protein fused with human IgG Fc fragment (S377-588-Fc) is highly expressed in the culture supernatant of transfected 293T cells. The purified S377-588-Fc protein efficiently binds to dipeptidyl peptidase 4 (DPP4), the receptor of MERS-CoV, and potently inhibited MERS-CoV infection, suggesting its potential to be further developed as a therapeutic modality for treating MERS-CoV infection and saving the patients’ lives. The recombinant S377-588-Fc is able to induce in the vaccinated mice strong MERS-CoV S-specific antibodies, which blocks the binding of RBD to DPP4 receptor and effectively neutralizes MERS-CoV infection. These findings indicate that this truncated RBD protein shows promise for further development as an effective and safe vaccine for the prevention of MERS-CoV infection.

Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection

“…Type I IFN and ribavirin have been reported to ameliorate disease in infected macaques (15), and small molecules targeting diverse intracellular pathways have been shown to inhibit MERS-CoV in vitro (16)(17)(18). Furthermore, experimental immunogens can elicit an anti-MERS-CoV response (19,20). However, no MERS-CoV targeting therapeutic has been demonstrated to function in vivo, partly because of limited small animal models of infection (21)(22)(23).…”

Putative suppressing effect of IgG Fc-conjugated haemagglutinin (HA) stalk of influenza virus H7N9 on the neutralizing immunogenicity of Fc-conjugated HA head: implication for rational design of HA-based influenza vaccines

“…We have previously demonstrated that the Fc-conjugated RBD-containing H5N1 influenza vaccine induces strong cross-protection (Du et al, 2013c). We have also shown that vaccines based on the RBD of spike proteins of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus elicit highly potent neutralizing antibody responses that protect animals from viral challenges (He et al, 2004;Du et al, 2007Du et al, , 2008Du et al, , 2009Du et al, , 2013aMa et al, 2014;Zhang et al, 2015).…”

Current advancements and potential strategies in the development of MERS-CoV vaccines

“…The induction of neutralizing activity by a recombinant protein fragment containing residues 377–662 of MERS-CoV RBD has also been demonstrated. Particularly, a truncated 212-amino acid RBD fragment containing residues 377–588 (inside RBD: residues 367–606) of MERS-CoV S protein induced strong MERS-CoV S-specific antibodies in vaccinated mice, blocking the binding of MERS-CoV RBD to viral receptor DPP4 and effectively neutralizing MERS-CoV infection, thus providing promise for further development as an effective and safe MERS vaccine [56–57]. …”

“…Since the RBD of SARS-CoV contains multiple neutralizing epitopes, RBD-based SARS subunit vaccines covering these neutralizing epitopes are able to induce potent neutralizing antibodies completely preventing SARS-CoV challenge [50, 51]. Similarly, it has been shown that the RBD of MERS-CoV induced strong neutralizing antibody responses against infection of MERS-CoV [56, 57] and that the MERS-CoV RBD does, indeed, contain several important neutralizing epitopes [93]. Accordingly, further optimization of the RBD and development of optimized RBD-based MERS subunit vaccines containing multiple neutralizing epitopes would be desirable and feasible to improve the vaccine efficacy.…”