Background. Middle East Respiratory Syndrome Coronavirus (MERS-CoV) emerged in 2012 causing Severe Acute Respiratory Disease and pneumonia, with ∼44% mortality in 136 cases till date. Design of vaccines to limit the virus spread or diagnostics to track newly emerging strains requires knowledge of antigenic and serological relationships of MERS-CoV to other coronaviruses.Methods. Using synthetic genomics and Venezuelan Equine Encephalitis Virus replicons (VRPs) expressing S and N proteins from MERS-CoV and other human and bat CoV`s, we characterize the antigenic (using western blots and ELISA) and serological responses (using Neutralization Assays) against two MERS-CoV isolates in comparison with other human and bat coronaviruses.Results. Serologic and neutralization responses against the S glycoprotein were primarily strain specific with very low level cross reactivity within, or across subgroups. Coronaviruses N proteins within, but not across subgroups, share cross-reactive epitopes with MERS-CoV isolates. Our findings were validated using MERS-CoV patient (NA 01) convalescent serum, and human serum to SARS-CoV, NL63 and OC43.Conclusions. Vaccine design for emerging coronaviruses should involve chimeric S protein containing neutralizing epitopes from multiple virus strains across subgroups, to reduce immune pathology, and diagnostic platform should include a panel of N and S proteins from phylogenetically distinct coronaviruses.