Replicon RNA Viral Vectors as Vaccines

Abstract

Single-stranded RNA viruses of both positive and negative polarity have been used as vectors for vaccine development. In this context, alphaviruses, flaviviruses, measles virus and rhabdoviruses have been engineered for expression of surface protein genes and antigens. Administration of replicon RNA vectors has resulted in strong immune responses and generation of neutralizing antibodies in various animal models. Immunization of mice, chicken, pigs and primates with virus-like particles, naked RNA or layered DNA/RNA plasmids has provided protection against challenges with lethal doses of infectious agents and administered tumor cells. Both prophylactic and therapeutic efficacy has been achieved in cancer immunotherapy. Moreover, recombinant particles and replicon RNAs have been encapsulated by liposomes to improve delivery and targeting. Replicon RNA vectors have also been subjected to clinical trials. Overall, immunization with self-replicating RNA viruses provides high transient expression levels of antigens resulting in generation of neutralizing antibody responses and protection against lethal challenges under safe conditions.

mRNA as a Transformative Technology for Vaccine Development to Control Infectious Diseases

“…Self-amplifying mRNA vaccines are commonly based on the engineered RNA genome of positive-sense single-stranded RNA viruses, such as alphaviruses, flaviviruses, and picornaviruses. 81,82 In all cases, the mRNA mimics the replicative features of positive-sense singlestranded RNA viruses with the goal of increasing the duration and magnitude of the expression, as well as subsequent immunogenicity of the encoded antigen. The best-studied self-amplified mRNA molecules are derived from alphavirus genomes, such as those of the Sindbis virus (SINV), Semliki Forest virus (SFV), and Venezuelan equine encephalitis viruses (VEEVs) (reviewed in Ljungberg and Liljeström 83 and Atkins et al 84 ).…”

“…Alternatively, self-amplifying RNA can also be produced directly in target cells, for example, by delivering a pDNA expressing the alphavirus-derived RDRP complex and the antigen of interest into such target cells, which has been reviewed elsewhere. 82 The efficacy of alphavirus VRPs as vaccine in preclinical models and humans has been previously described and has been largely attributed to the production of high levels of correctly processed heterologous proteins and to their ability to deliver antigen to a variety of cell types, including antigen-presenting cells. [95][96][97][98][99][100][101][102][103] Activation of DCs upon VRPs infection results in a wave of cytokine secretion and subsequently a robust adjuvanting effect, which markedly amplifies the magnitude of vaccine-elicited adaptive immune responses.…”

Promising approaches for the treatment and prevention of viral respiratory illnesses

“…116 To enhance immunogenicity, RNA vaccines have been encapsulated in nanoparticles, achieving sterilizing immunity for Zika virus in mice, 117 as well as being incorporated into virus-based self-replicating constructs known as replicons. 118,119 Active IFV vaccination already forms the core of the global strategy against severe seasonal and pandemic influenza. Trivalent and more recent quadrivalent vaccines are largely efficacious in healthy adults provided an adequate match between circulating and vaccine strains.…”

Expression kinetics and innate immune response after electroporation and lipid nanoparticle mediated delivery of a self-amplifying mRNA in the skin of mice

“…Sa-RNAs based on e.g. VEEV have been evaluated in the past as a possible new vaccination platform [6,[39][40][41][42]. However, the in vivo expression kinetics and especially the inherent innate immunity of VEEV-based sa-RNAs have not been studied in detail.…”