AbstractSARS-CoV-2 transmission from humans to animals has been reported for many domesticated species, including cats, dogs and minks. Identification of novel spike gene mutations appearing in minks has raised major concerns about potential immune evasion and challenges for the global vaccine strategy. The genetic variant, known as “cluster-five”, arose among farmed minks in Denmark and resulted in a complete shutdown of the world’s largest mink production. However, the functional properties of this new variant are not established. Here we present functional data on the Y453F cluster-five receptor-binding domain (RBD) and show that it does not decrease established humoral immunity or affect the neutralizing response in a vaccine model based on wild-type RBD or spike. However, it binds the human ACE-2 receptor with a four-fold higher affinity suggesting an enhanced transmission capacity and a possible challenge for viral control.