Viral vector-driven trans-encapsidation of replicon RNAs as a rapid approach for the development of safe and economically attractive anti-enterovirus vaccines

Multiple enteroviruses are associated with life-threatening and economically important diseases, yet licensed vaccines are available only against poliovirus (worldwide) and enterovirus A71 (China). Both live attenuated and inactivated anti-poliovirus vaccines, while highly successful in preventing the disease, have important shortcomings. Live vaccine strains are inherently genetically unstable and can regain virulence, leading to re-emergence of paralytic disease. Inactivated vaccine does not induce the mucosal immunity sufficient to interrupt viral transmission and is made from virulent strains, presenting a biosafety challenge. Recent alternatives, such as new vaccine strains with improved genetic stability and VLP-based vaccines, only partially address these concerns. Here, we investigated another approach to the development of anti-enterovirus vaccines based on efficient trans-encaspidation of replication-competent enterovirus RNAs coding for only the non-structural proteins (replicons) by Newcastle Disease virus vectors expressing enterovirus capsid proteins. Thus, the encapsidated replicon production is driven by effectively replicating enterovirus RNA and the NDV vector. This system is easily scalable and can be adapted to any cell culture provided it can be infected by both the enterovirus and NDV. Unlike the empty VLPs, the encapsidated replicons recapitulate the stability and antigenicity of native enterovirus particles, but cannot propagate beyond the originally infected cell. The protective efficacy of an encapsidated poliovirus replicon immunization was similar to that of the licensed Sabin vaccine strain in a murine model. This approach can easily be adapted to any enterovirus, allowing the rapid development of new, affordable vaccine candidates.