Human neutralizing antibodies against MERS coronavirus: implications for future immunotherapy

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Date: July 2015
From: Immunotherapy(Vol. 7, Issue 6)
Publisher: Future Medicine Ltd.
Document Type: Editorial
Length: 2,332 words
Lexile Measure: 1650L

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Author(s): Xian-Chun Tang aff1 , Wayne A Marasco [*] aff1

Keywords:

animal model; biodefense; emerging pathogen; human monoclonal antibodies; humoral immunity; IGHV1-69; MERS-CoV; passive immunotherapy; spike protein; zoonosis

Middle East respiratory syndrome coronavirus (MERS-CoV) was first reported in September 2012 [1 ]. Dromedary camels are a putative source for human MERS-CoV since dromedaries have shown high rates of seropositivity ([greater than]90%) in serum samples collected over 30 years ago and virus was recently isolated from camels [2 ]. The high prevalence of MERS-CoV infection in camels and the difficulty of eliminating this virus reservoir suggest that the recurrence of MERS is very likely to occur. Indeed, during early 2015 an increasing number of MERS cases in the Kingdom of Saudi Arabia have been seen. As of 11 March 2015, 1060 confirmed cases, including at least 394 related deaths have officially been reported to WHO [3 ]. The high mortality rate (˜37%) and ongoing epidemic have raised concern of a more widespread regional outbreak or even global spread.

Since this virus was reported, tremendous efforts have been made in the search for effective anti-MERS-CoV agents. Combinations of treatment with IFN-[alpha]2b and ribavirin were reported to improve clinical outcomes in MERS-CoV-infected rhesus macaques [4 ]. A synthesized peptide (HR2P) was found to inhibit MERS-CoV replication and its S protein mediated cell-cell fusion [5 ]. Some compounds with anti-MERS-CoV activity in cell culture were found by screening small libraries of US FDA approved drugs [6,7 ]. Neutralizing antibodies (nAbs) could be used in an outbreak setting for the prophylaxis and early treatment of emerging viral pathogens. During SARS outbreak, convalescent plasma from recovered SARS patients have been shown to help clearing SARS-CoV efficiently [8,9 ]. Convalescent sera were recommended for MERS treatment by the International Severe Acute Respiratory and Emerging Infection Consortium [10 ]. Monoclonal antibodies (mAbs) have demonstrated host protection against viral infections [11 ]. In this review, we summarize the recent progress in potential therapeutic mAbs and animal models for MERS.

Current nAbs against MERS-CoV

In April 2014, three independent studies reported the identification of human nAbs against MERS-CoV [12-14 ]. In our study, seven nAbs were identified from a well-characterized phage-displayed scFv library [12 ]. The panning target was full-length Spike incorporated on the surface of paramagnetic proteoliposomes and mammalian cells. This kind of bait was used to mimic the native structure of Spike protein on viral particles. With this panning strategy, seven nAbs were identified and all bound to the receptor-binding domain (RBD) in S1 of MERS-CoV with nanomolar-picomolar binding affinities. A competition assay revealed that these seven mAbs could be categorized into three groups and bind to at least three distinct epitopes. One epitope is located centrally in RBD and another two are flanking. All seven mAbs can neutralize pseudotyped and live MERS-CoV infection in cell culture through a mechanism of blocking the interaction between MERS-CoV S protein and its hDPP4 receptor. Virus evolution under nAb pressure was further investigated by identifying escape mutants. Interestingly, all the escape mutations were...

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Gale Document Number: GALE|A422428331