Combination of these two mAbs demonstrated a synergistic effect in neutralization. neutralizing mAbs bind to receptor binding motif of MERS-CoV spike protein, despite the full-length spike was used as panning antigen. This demonstrates that the RBM is dominant in the selection systems, suggesting the RBM as a critical target for the development of MERS-CoV vaccines and therapeutics. Coronavirus S1 is responsible for virus attachment to cellular receptor, while S2 is responsible for viral and cellular membrane fusion. S2 is more conserved than S1 protein, suggesting that the S2 epitope may provide broader nAbs. The combination of Abs targeting divergent epitopes, that we termed divergent combination immunotherapy, would be more potent to prevent viral infection and neutralization escape . Another interesting finding is that 8/12 of these mAbs used IGHV1C69 germline gene. IGHV1C69 germline gene has been reported preferentially used by many antiviral mAbs . Finally, all these mAbs bind to RBD with nanomolar to picomolar affinities, but they showed different neutralization potencies according to each study. This is most likely because virus, cells and experiment conditions were different in each lab, or these potent mAbs do have different neutralization potencies despite they bind to closed epitopes with similar affinities. Most importantly, studies need to be conducted to verify if these mAbs can prevent MERS-CoV infection developed a mouse model for MERS by transducing human DPP4 into mouse lungs with adenoviral vectors to sensitize mice for infection . After MERS-CoV infection, virus could be detected in lungs but cleared by days 6C8 in young mice and days 10C14 in old mice; young mice failed to gain weight while aged mice lost weight. Several strains of immunocompromised mice were persistently infected, but did not lost weight. This suggested that this mouse model may recapitulate the respiratory disease observed in mild or moderate human cases but not the fatal cases or the occasionally occurring kidney disease. This model can be difficult as an evaluative model for therapeutics since clinical signs are mild; pathology and viral replication are limited. Falzarano tested the common marmoset as a MERS-CoV model. After MERS-CoV inoculation combined via intranasal, ADL5747 intratracheal, oral and ocular routes, most of the marmosets developed respiratory diseases that ranged from moderate to severe as indicated by progressive severe pneumonia with extensive lung pathology. Two out of nine animals had to be euthanized due to the severity of disease. Viral loads in the lungs were up to 1000-times higher than those in the rhesus macaque lungs and did not decrease between 3 and 6 dpi. Viral RNA was also detected in the blood of infected marmosets, suggesting a more systemic dissemination. This is the first animal model for MERS-CoV that showed severe to lethal disease. Common marmosets may be the best model for evaluating the efficacy of vaccines and treatment strategies to date. However the availability is limited. Conclusion The ADL5747 high fatality rate and epidemic of MERS emphasizes the need for effective vaccine Rabbit Polyclonal to SIK or antivirals. Recently identified human neutralizing mAbs have shown potent neutralizing activities Assessment of these mAbs in relevant animal models is yet to be conducted before clinical trials. It is worth to note that all ADL5747 human neutralizing mAbs mentioned above were identified from phage/yeast-displayed antibody libraries. This is particularly important when early access to patient specimens is problematic, in part because of government, regulatory and biocontainment restrictions. All these mAbs, despite being identified from different library with different methods, target the RBD of MERS-CoV S protein and have a similar mechanism of neutralization, blocking the interaction of MERS-CoV spike with its receptor DPP4. These mAbs have nanomolar to picomolar binding affinities to MERS-CoV RBD. They appear to recognize adjacent but nonoverlapping epitopes, suggesting that these mAb cocktails, while being directed to a similar region on S1 may still be sufficient for divergent combination immunotherapy. In addition, therapeutic approaches should not be limited to the combination of different antiMERS-CoV mAbs, but rather include the combination of mAbs with MERS-CoV inhibitors. We expect that ADL5747 these efforts will result in some potent therapeutic approaches to treat MERS patients and prevent MERS-CoV infection.