Experimental DNA-launched live-attenuated vaccines against infections caused by Flavi-and alphaviruses

Abstract

DNA vaccines represent a promising technology due to their safety, ease of production, genetic stability, no need for cold chain, and activation of innate immunity by recombinant DNA produced in bacterial cells. However, so far there are no licensed DNA vaccines for prevention of human infectious diseases. While a few DNA vaccines have been recently approved for veterinary applications, low immunogenicity in humans is the major obstacle for clinical applications. In contrast, live-attenuated vaccines are among the most cost-effective and broadly used public health interventions. They represent approximately 60 % of all licensed vaccines and provide long-term immunity following a single-dose vaccination. Live-attenuated vaccines have their own limitations including the need for bio-containment during production, cold chain requirements, and safety concerns due to the possibility of reversion, especially for RNA viruses. Here we describe a novel infectious DNA (iDNA ®) vaccine technology which combines advantages of naked DNA vaccination and live-attenuated vaccine efficacy. Using yellow fever 17D vaccine, an experimental IND vaccine TC-83 against Venezuelan equine encephalitis virus (VEEV), and live-attenuated chikungunya (CHIK) 181/25 vaccine candidate, we have provided proof-of-concept evidence that these vaccines can be launched from DNA and induce specific immune responses against pathogenic RNA viruses. The iDNA vaccine technology is based on the transcription of the full-length genomic RNA of the live-attenuated virus from plasmid DNA in vitro and in vivo. A few ng of iDNA encoding the full-length genomic RNA are required to initiate the replication of the vaccine virus in vitro. The in vivo-generated viral RNA initiates limited replication of the vaccine virus, which in turn leads to efficient immunization. Electroporation in vivo has induced specific immune responses against pathogenic viruses and protected mice against fatal disease. DNA-launched vaccine is manufactured in vaccinated individuals and does not require traditional vaccine manufacturing facility and technology. If successful in further testing, this technology can dramatically change the way we make vaccines as well as vaccination practice.