Alphavirus replicon vectors for prophylactic applications and cancer intervention

Alphavirus replicons represent self-replicating RNA molecules resembling alphaviral genomic RNA, except replicons encode antigen(s) of interest in place of an alphaviral structural polyprotein. Because viral structural genes are missing, replicon RNA cannot initiate replication of an alphavirus. However, due to the presence of intrinsic RNA-dependent RNA polymerase activity, replicons are capable of self-amplification in vitro and in vivo resulting in high levels of expression of antigen of interest. For vaccination or therapeutic purposes, replicons can be delivered in vivo by replicon particles. The latter represent viruslike particle vectors (VLPVs) that encapsidate replicon RNA and deliver it into target cells for antigen expression. The viruslike nature and self-replicating RNA features ensure efficient priming of innate immunity and adjuvant effect, while high-level expression provides antigen for induction of cell-mediated and humoral immune responses. Replicon vectors have been developed from several alphaviruses including Venezuelan equine encephalitis virus (VEEV), Semliki Forest virus (SFV), and Sindbis virus (SINV). Applications of replicon particles included prophylactic and therapeutic vaccines for infectious diseases and cancer, as well as adjuvants for enhancement of immune responses. In several preclinical models including nonhuman primates, alphavirus replicons have shown exceptional promise as safe and effective vaccines and adjuvants. Experimental replicon vaccines included vaccines against influenza, Ebola, Marburg, and Lassa viruses. Bivalent vaccines protecting from both Ebola and Lassa viruses have been also described. Protective effects have been reported for cancer indications after therapeutic vaccination with replicon vaccines expressing tumor-associated antigens. Clinical trials involving alphavirus replicons are underway. In this review, an attempt is made to summarize the state of the art of the alphavirus replicon-based technology for prophylactic and therapeutic applications. The advantages and challenges of the replicon technologies are presented, and the future of this promising platform is discussed.