This may be in part owing to stringent safety requirements that must be met for viruses, that in their natural state have the potential to be human pathogens, to be used as viral vaccine vectors that may replicate in vivo in a manner similar to their wild-type parental viruses. Another reason may be fear of risk of spontaneous recombination between virus vectors and naturally occurring viral relatives in the ecosystems in which the vaccine is used. Even if APVs are not generally expected to replicate in mammals, the vaccine vectors may reach bird populations via animal populations. It is also possible that the vector, through spontaneous recombination and mutation events, may restore its replication competence. To cater for this, the aim during design and development of a virus vector is always to introduce at least two gene deletions crucial for viral to undergo a full replication cycle to assure a very low probability that replication competence could be restored. To our knowledge, such reversions have not been identified in clinical trials of APV-vectored vaccines. In addition to concerns regarding reversion or recombination, another safety signal was recently identified in an in vitro experiment that showed APV replication in cell clones derived from embryonic bovine trachea [53] and Syrian baby hamster kidney (BHK) cells. In this experiment, infectious IMV was observed; indicating complete virus replication had taken place [54] . These findings are in contrast to the general dogma that APVs are restricted to infection of cells of avian origin, and are an indication that there is still more to learn about the replication mechanisms and virus-host interactions of these viruses, including evasion of immune responses, cell tropism and host range mechanisms.