MERS-coronavirus: From discovery to intervention

Widagdo, W.; Okba, Nisreen M.A.; Stalin Raj, V.; Haagmans, Bart L.

Studies in Hong Kong during the SARS-CoV outbreak also indicated that infection with SARS-CoV was unlikely to result in an asymptomatic infection [49, 50] , explaining why active surveillance and quarantine were so effective in stopping the outbreak [4] . In case of MERS, asymptomatic MERS-CoV-infected individuals that spread the virus may fuel the ongoing outbreak as these are currently not identified by diagnostic screening. It is difficult to precisely assess the percentage of asymptomatic MERS-CoV infections in the human population, partly due to the lack of active serological surveillance and fully validated commercial serological assays. However, asymptomatic individuals who had contact with MERS patients have been identified using a combination of RT-PCR, ELISA, IFA and PRNT assays; suggesting that in case of MERS, the virus can indeed cause mild to asymptomatic infections [5, 36, 52] . In addition, subclinical MERS-CoV infection with long term excretion of MERS-CoV RNA has been reported [52] . Unlike severe MERS cases these patients are mostly young to middle-aged without underlying comorbidities. This group is primarily dominated by health care workers in the hospitals where MERS-CoV patients were admitted and secondly by family members having close contact with the severe MERS-CoV patients [5, 36] . In one contact tracing study, out of 280 individuals who had contact with MERS-CoV patients, 12 were concluded to have probable MERS-CoV infections. Only one out of these 12 contacts developed symptoms which later progressed to respiratory failure and fatal outcome, while the rest reported no symptoms [5] . Therefore, during an ongoing outbreak in a health care setting, it is imperative to protect the healthcare workers that are at high risk of acquiring the infection [36, 45] . In this scenario, prophylactic regimens, for example using humanized monoclonal antibodies, would be theoretically suitable to limit the spread of the virus. Monoclonal antibodies mostly have limited therapeutic efficacy despite promising in-vivo results, yet they might still serve as a potent prophylactic measure, as exemplified by palivizumab, a monoclonal antibody against respiratory syncytial virus. This antibody is effective in reducing the frequency of hospitalizations in children at high risk of infection, but its efficacy for treatment purposes has not been demonstrated [53] . The receptor binding domain (RBD) located within the S1 protein could serve as a target for humanized monoclonal antibodies. These antibodies have been generated using different approaches, i.e. from non-immune human peripheral blood mononuclear cells [54, 55] , from yeast cells expressing human antibodies [56] , from memory B cells obtained from infected humans [57] , or from mice immunized with the RBD domain of the S protein of MERS-CoV [58] . Several of these antibodies have been reported to be effective in-vitro and in-vivo [55] [56] [57] [58] [59] . One monoclonal antibody against MERS-CoV, m336, has been shown to be effective as a prophylactic agent in rabbits [60] . Inhibiting virus attachment could also be achieved by targeting the host receptor, DPP4. Unfortunately, commercially available DPP4 inhibitors that are marketed as type II diabetes mellitus drugs were not able to serve this purpose, since they do not bind to the RBD [56] . Monoclonal antibodies targeting DPP4, on the other hand, also may inhibit MERS-CoV attachment in vitro. One of these antibodies, YS110,