RNA-based viral vectors

Abstract

The advent of reverse genetic approaches to manipulate the genomes of both positive (+) and negative (−) sense RNA viruses allowed researchers to harness these genomes for basic research. Manipulation of positive sense RNA virus genomes occurred first largely because infectious RNA could be transcribed directly from cDNA versions of the RNA genomes. Manipulation of negative strand RNA virus genomes rapidly followed as more sophisticated approaches to provide RNA-dependent RNA polymerase complexes coupled with negative-strand RNA templates were developed. These advances have driven an explosion of RNA virus vaccine vector development. That is, development of approaches to exploit the basic replication and expression strategies of RNA viruses to produce vaccine antigens that have been engineered into their genomes. This study has led to significant preclinical testing of many RNA virus vectors against a wide range of pathogens as well as cancer targets. Multiple RNA virus vectors have advanced through preclinical testing to human clinical evaluation. This review will focus on RNA virus vectors designed to express heterologous genes that are packaged into viral particles and have progressed to clinical testing.

Keywords:

• alphavirus
• flavivirus
• orthomyxovirus
• paramyxovirus
• reverse genetics
• rhabdovirus
• RNA virus vector

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Chimeric flaviviruses and live attenuated influenza vaccines (orthomyxoviruses) have achieved regulatory approval for use in humans, while chimeric flaviviruses and alphavirus replicons have reached approval in veterinary animals.

• Recombinant alphavirus replicon, chimeric flavivirus, paramyxovirus and vaccines are advancing through human clinical trials supported by preclinical efficacy against a wide variety of infectious disease and cancer targets.

• Rational design of flavivirus-, alphavirus- and rhabdovirus-based vaccines has increased vector safety that will support continued testing of these vector platforms.

• Most flavivirus and paramyxovirus vector development has focused on the expression of sequences derived from other flaviviruses or paramyxoviruses, respectively; these chimeric vectors offer increased attenuation and great promise for development of vaccines against some of the most important insect-borne and pediatric respiratory illnesses known to man.

• The oncolytic nature of many RNA viruses (ex paramyxoviruses and rhabdoviruses) that can be manipulated through reverse genetics represents a significant advancement in cancer treatment. New and continued clinical evaluation of these oncolytic viruses will likely shape the future of cancer therapy.