Abstract
Nucleic acid-based vaccines such as viral vectors, plasmid DNA (pDNA), and mRNA are being developed as a means to address limitations of both live-attenuated and subunit vaccines. DNA vaccines have been shown to be potent in a wide variety of animal species and several products are now licensed for commercial veterinary but not human use. Electroporation delivery technologies have been shown to improve the generation of T and B cell responses from synthetic DNA vaccines in many animal species and now in humans. However, parallel RNA approaches have lagged due to potential issues of potency and production. Many of the obstacles to mRNA vaccine development have recently been addressed, resulting in a revival in the use of non-amplifying and self-amplifying mRNA for vaccine and gene therapy applications. In this paper, we explore the utility of EP for the in vivo delivery of large, self-amplifying mRNA, as measured by reporter gene expression and immunogenicity of genes encoding HIV envelope protein. These studies demonstrated that EP delivery of self-amplifying mRNA elicited strong and broad immune responses in mice, which were comparable to those induced by EP delivery of pDNA.
Highlights
In 1990, Wolff et al [1] demonstrated that direct injection of messenger RNA or plasmidDNA into the skeletal muscle of a mouse resulted in expression of the encoded protein
Older DNA vaccines have been shown to be immunogenic in a wide variety of animal species and several products are licensed for commercial veterinary use
In contrast to the RNA, mice injected with a low dose (1 μg) of naked plasmid DNA (pDNA) showed levels of secreted alkaline phosphatase (SEAP) expression that were indistinguishable from baseline (Figure 1B), but substantial enhancements in SEAP expression was observed when pDNA was delivered by EP
Summary
In 1990, Wolff et al [1] demonstrated that direct injection of messenger RNA (mRNA) or plasmidDNA (pDNA) into the skeletal muscle of a mouse resulted in expression of the encoded protein. Older DNA vaccines have been shown to be immunogenic in a wide variety of animal species and several products are licensed for commercial veterinary use. These include a West Nile virus vaccine for horses [2], an infectious hematopoietic necrosis virus vaccine for fish [3], a melanoma cancer vaccine for dogs [4], and a growth hormone releasing hormone gene therapy with electroporation delivery for pigs [5]. The most promising approaches to overcome these limitations include facilitation of pDNA delivery by electroporation (EP) [9]; and stimulation of the immune system via the use of genetic adjuvants [10,11,12,13]
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