There is an unmet medical need for a prophylactic vaccine against herpes simplex virus (HSV). DNA vaccines and cutaneous vaccination have been tried for many applications, but few reports combine this vaccine composition and administration route. We compared DNA administration using the Nanopatch™, a solid microprojection device coated with vaccine comprised of thousands of short (110 μm) densly-packed projections (70 μm spacing), to standard intramuscular DNA vaccination in a mouse model of vaginal HSV-2 infection. A dose-response relationship was established for immunogenicity and survival in both vaccination routes. Appropriate doses administered by Nanopatch™ were highly immunogenic and enabled mouse survival. Vaginal HSV-2 DNA copy number day 1 post challenge correlated with survival, indicating that vaccine-elicited acquired immune responses can act quickly and locally. Solid, short, densely-packed arrays of microprojections applied to the skin are thus a promising route of administration for DNA vaccines.
"Furthermore, in order to forgo the requirement for animal models for in vivo studies of cutaneous DNA vaccination, a human skin organ culture ex vivo system has been developed for analyzing expression levels and immunological activation over a prolonged period of 72 hours . Another study examined the effects of DNA vaccination of plasmids that encode a low dose of the vaginal herpes simplex virus (HSV) protein gD2, and proved that the immune response was comparable to that of conventional intramuscular DNA vaccination at a high dose, and provided protection against lethal challenge with vaginal HSV-2 in a mouse model . In another study, positively charged poly (lactic-co-glycolic) acid nanoparticles were coated with DNA plasmid solution expressing anthrax protective antigen, and the vaccine solution was used to immunize mice by dripping the solution onto skin that were pretreated with microneedle rollers . "
[Show abstract][Hide abstract] ABSTRACT: In today's medical industry, the range of vaccines that exist for administration in humans represents an eclectic variety of forms and immunologic mechanisms. Namely, these are the live attenuated viruses, inactivated viruses, subunit proteins, and virus-like particles for treating virus-caused diseases, as well as the bacterial-based polysaccharide, protein, and conjugated vaccines. Currently, a new approach to vaccination is being investigated with the concept of DNA vaccines. As an alternative delivery route to enhance the vaccination efficacy, microneedles have been devised to target the rich network of immunologic antigen-presenting cells in the dermis and epidermis layers under the skin. Numerous studies have outlined the parameters of microneedle delivery of a wide range of vaccines, revealing comparable or higher immunogenicity to conventional intramuscular routes, overall level of stability, and dose-sparing advantages. Furthermore, recent mechanism studies have begun to successfully elucidate the biological mechanisms behind microneedle vaccination. This paper describes the current status of microneedle vaccine research.
"ELISAs were performed as previously described . Antibody titers for the unchallenged animals immunized as for the ELISPOT assay study were calculated as follows: splines were fitted to the dilution data in GraphPad Prism 5 and the inverse of the dilution required to give an OD of 0.5 was taken as the titer. "
[Show abstract][Hide abstract] ABSTRACT: While there are a number of licensed veterinary DNA vaccines, to date, none have been licensed for use in humans. Here, we demonstrate that a novel technology designed to enhance the immunogenicity of DNA vaccines protects against lethal herpes simplex virus 2 (HSV-2) challenge in a murine model. Polynucleotides were modified by use of a codon optimization algorithm designed to enhance immune responses, and the addition of an ubiquitin-encoding sequence to target the antigen to the proteasome for processing and to enhance cytotoxic T cell responses. We show that a mixture of these codon-optimized ubiquitinated and non-ubiquitinated constructs encoding the same viral envelope protein, glycoprotein D, induced both B and T cell responses, and could protect against lethal viral challenge and reduce ganglionic latency. The optimized vaccines, subcloned into a vector suitable for use in humans, also provided a high level of protection against the establishment of ganglionic latency, an important correlate of HSV reactivation and candidate endpoint for vaccines to proceed to clinical trials.
PLoS ONE 10/2013; 8(10):e76407. DOI:10.1371/journal.pone.0076407 · 3.23 Impact Factor
"Nanopatch microprojections are of extremely high density (>20,000 cm−2), distinguishing them from other reported microneedle patch technologies with densities of <5000 cm−2
. Using a spring-loaded applicator for dynamic delivery , we have delivered a broad range of microprojection-coated vaccines by Nanopatch, including plasmid DNA, virus like particle, split virion, recombinant protein and killed virus , –. In the case of a split virion influenza vaccine, Nanopatch-induced Haemagglutinin Antigen (HA)-specific antibody responses were equivalent to those induced by intramuscular injection with only 1/100th of the vaccine dose . "
[Show abstract][Hide abstract] ABSTRACT: The disadvantages of needle-based immunisation motivate the development of simple, low cost, needle-free alternatives. Vaccine delivery to cutaneous environments rich in specialised antigen-presenting cells using microprojection patches has practical and immunological advantages over conventional needle delivery. Additionally, stable coating of vaccine onto microprojections removes logistical obstacles presented by the strict requirement for cold-chain storage and distribution of liquid vaccine, or lyophilised vaccine plus diluent. These attributes make these technologies particularly suitable for delivery of vaccines against diseases such as malaria, which exerts its worst effects in countries with poorly-resourced healthcare systems. Live viral vectors including adenoviruses and poxviruses encoding exogenous antigens have shown significant clinical promise as vaccines, due to their ability to generate high numbers of antigen-specific T cells. Here, the simian adenovirus serotype 63 and the poxvirus modified vaccinia Ankara - two vectors under evaluation for the delivery of malaria antigens to humans - were formulated for coating onto Nanopatch microprojections and applied to murine skin. Co-formulation with the stabilising disaccharides trehalose and sucrose protected virions during the dry-coating process. Transgene-specific CD8(+) T cell responses following Nanopatch delivery of both vectors were similar to intradermal injection controls after a single immunisation (despite a much lower delivered dose), though MVA boosting of pre-primed responses with Nanopatch was found to be less effective than the ID route. Importantly, disaccharide-stabilised ChAd63 could be stored for 10 weeks at 37°C with less than 1 log10 loss of viability, and retained single-dose immunogenicity after storage. These data support the further development of microprojection patches for the deployment of live vaccines in hot climates.
PLoS ONE 07/2013; 8(7):e67888. DOI:10.1371/journal.pone.0067888 · 3.23 Impact Factor
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