br Introduction The Middle East respiratory syndrome coronav

Introduction The Middle East respiratory syndrome coronavirus (MERS-CoV) is the only lineage C betacoronavirus known to infect humans (Annan et al., 2013; Anthony et al., 2013; van Boheemen et al., 2012). Similarly to severe acute respiratory syndrome coronavirus (SARS-CoV), MERS-CoV infection can result in acute respiratory distress syndrome and organ dysfunction, including progressive renal function impairment (Zaki et al., 2012). According to the World Health Organization, by the end of 12 August 2015, a total of 1401 cases had been laboratory confirmed, with at least 500 deaths following MERS-CoV infection. Among them, 186 MERS-CoV infection cases, including 36 deaths, had been reported by the Republic of Korea (http://www.who.int/csr/don/12-august-2015-mers-saudi-arabia/en/). These recent clustered cases firstly sprang up outside the Arabian Peninsula, indicating the potential human-to-human transmission of MERS-CoV. To date, no specific antiviral drug exists for MERS-CoV infection and supportive treatment is the mainstay of management (Zumla et al., 2015). Ribavirin and interferon alfa-2b exhibited potential in a rhesus macaque model (Falzarano et al., 2013a,b), but in a retrospective cohort study, ribavirin and interferon alfa-2a therapy was associated with significantly improved survival at 14days, but not at 28days in patients with severe MERS-CoV infection (Omrani et al., 2014). Besides, specific peptide fusion inhibitors of MERS-CoV (Lu et al., 2014), convalescent sera from recovered patient and human monoclonal neutralising rosmarinic acid (Jiang et al., 2014; Tang et al., 2014; Ying et al., 2014) provided a novel approach to MERS-CoV treatment. However, more data are needed from animal studies and carefully done clinical studies (Zumla et al., 2015). Therefore, developing a prophylactic vaccine against MERS-CoV infection remains a priority (Papaneri et al., 2015). Considerable evidence has proved that recombinant receptor binding domain (rRBD)-based subunit vaccine is a promising candidate vaccine against the SARS-CoV infection. As rRBD of SARS-CoV Spike protein induced strong neutralisation antibody and long-term protective immunity in rabbits and mice and completely protected immunized mice from SARS-CoV infection (Zhu et al., 2013). Furthermore, high titres of neutralisation antibodies in non-human primates (NHP) were induced by vaccination with the rRBD of SARS-CoV (Wang et al., 2012). Experience using rRBD-based subunit vaccines against SARS could inform the design of a rRBD-based MERS vaccine. Several human neutralising antibodies targeting the RBD of the MERS-CoV spike protein, have been identified from the naïve-antibody library (Tang et al., 2014; Ying et al., 2014), suggesting that RBD contains epitopes that can induce nAbs and therefore may represent a target antigen against MERS-CoV. Our group and others have confirmed rRBD protein induced strong neutralising antibody responses against MERS-CoV infection in mice and rabbits (Du et al., 2013; Lan et al., 2014; Ma et al., 2014; Mou et al., 2013; Zhang et al., 2015). Although the rRBD subunit vaccine is a highly potent neutraliser of antibodies and T-cell immune responses, no formulation has been tested on a higher animal model with MERS-CoV challenge to verify its prophylactic efficacy (Gretebeck and Subbarao, 2015). Recently, MERS-CoV infection and disease animal models have been developed (Agrawal et al., 2015; de Wit et al., 2013a,b; Falzarano et al., 2014; Munster et al., 2013; Pascal et al., 2015; Yao et al., 2013; Zhao et al., 2014), including a rhesus macaque model of naturally permissive MERS-CoV disease (de Wit et al., 2013a,b; Munster et al., 2013; Yao et al., 2013). We herein evaluate a rRBD subunit vaccine in a rhesus macaque model, to identify a prophylactic approach that could be used in humans to prevent MERS-CoV infection.
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Discussion The MERS virus, which emerged in 2012, is now considered a threat to global public health. Developing an effective vaccine is important to control MERS-CoV infection. To date, virus-vector vaccines, such as recombinant modified vaccinia virus Ankara (MVA), which expresses full-length MERS-CoV spike protein (MVA-MERS-S), and recombinant adenoviral vectors encoding the full-length MERS-CoV S protein (Ad5.MERS-S) and the S1 extracellular domain of S protein (Ad5.MERS-S1), have been developed and tested for their ability to induce virus-neutralising antibodies in mice (Kim et al., 2014; Song et al., 2013; Volz et al., 2015). Besides, the rRBD subunit vaccine confers a highly potent neutralising antibody and T-cell immune response in mice (Zhang et al., 2014). However, few studies have been assessed in response to MERS-CoV challenge to verify their efficacy, due to a lack of animal models. For example, mice (Coleman et al., 2014; Scobey et al., 2013), hamsters (de Wit et al., 2013a,b) and ferrets (Raj et al., 2014) had not been proved to infect with MERS-CoV naturally. Recently, a small animal model of MERS-CoV infection was developed by transducing mice with an adenovirus vector expressing human DPP4 (Zhao et al., 2014). However, MERS-CoV infection in this model is highly dependent on the transduction of cells and the level of DPP4 expression from the adenovirus vector, and therefore does not necessarily reflect the natural disease process (Falzarano et al., 2014). More recently a transgenic mouse model of MERS-CoV has been published (Agrawal et al., 2015). However, in this model, all cells of the mouse express human DPP4. This kind of non-physiological expression patterns resulted in extensive brain infection of MERS-CoV and rapidly succumbs to infection in mice. Moreover, a novel humanized mouse model of MERS-CoV infection was developed, though the mice were not acquired by routine technology (Pascal et al., 2015). Encouragingly, rhesus macaque models are naturally permissive to MERS-CoV disease, and more closely mimic the disease course in human patients (de Wit et al., 2013a,b; Munster et al., 2013; Yao et al., 2013). Furthermore, the effects of interferon-α2b and ribavirin treatment have been evaluated in these models (Falzarano et al., 2013a,b). Therefore, we herein assessed rRBD vaccine efficacy in a NHP model.