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Woolloongabba, Australia

Flesch I.E.A.,Australian National University | Woo W.-P.,Queensland Institute of Medical Research | Woo W.-P.,Coridon Pty Ltd. | Wang Y.,Australian National University | And 5 more authors.
Journal of Immunology

Previous studies of CD8+ T cell immunodominance after primary virus infection of F1 mice compared with their inbred parents have generally concluded that no dramatic changes occur. In this study, we revisit this issue using vaccinia virus (VACV), which has a large genome, a recently defined immunodominance hierarchy in mice, and is a candidate vector for vaccines.We found that immunogenicity of VACV peptides defined using inbred mice was highly variable in F1 progeny: some peptides were equally immunogenic in F1 and inbred, whereas others elicited responses that were reduced by >90% in F1 mice. Furthermore, the dominance of a peptide in the relevant inbred parent did not predict whether it would be poorly immunogenic in F1 mice. This result held using F1 hybrids of MHC-congenic mice, suggesting that MHC differences alone were responsible. It was also extended to foreign epitopes expressed by an rVACVvaccine. F 1 mice were less able to mount responses to the poorly immunogenic peptides when used as a sole immunogen, ruling out immunodomination. In addition, conserved TCR Vβ usage between inbred and F1 mice did not always correlate with strong responses in F1 mice. However, direct estimation of naive precursor numbers showed that these were reduced in F1 compared with inbred mice for specificities that were poorly immunogenic in the hybrids. These data have implications for our understanding of the extent to which MHC diversity alters the range of epitopes that are immunogenic in outbred populations. Copyright © 2009 by The American Association of Immunologists, Inc. Source

Dutton J.L.,Coridon Pty Ltd. | Li B.,Coridon Pty Ltd. | Woo W.-P.,Coridon Pty Ltd. | Marshak J.O.,University of Washington | And 9 more authors.

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. © 2013 Dutton et al. Source

Nelson J.,VGXI Inc. | Rodriguez S.,VGXI Inc. | Finlayson N.,Coridon Pty Ltd. | Williams J.,Nature Technology Corporation | Carnes A.,Nature Technology Corporation
Human Vaccines and Immunotherapeutics

Two DNA vaccine plasmids encoding Herpes simplex virus type 2 (HSV-2) glycoprotein D, NTC8485-02-gD2and NTC8485-02-UgD2tr, were produced at large scale under current good manufacturing practice (cGMP) for use in a Phase I human clinical trial. These DNA vaccines incorporate the regulatory agency compliant, minimal, antibiotic-free (AF) NTC8485 mammalian expression vector. Plasmid yields of > 1 g/L were achieved using the HyperGRO™ fed-batch fermentation process, with successful scale up from 10 L process development scale to 320 L culture volume for cGMP production. The DNA vaccines were purified using a low residence time, high shear lysis process and AIRMIX™ technology, followed by chromatographic purification. This combination of optimized plasmid vector, high yield upstream production, and efficient downstream purification resulted in purified HSV-2 DNA vaccines with > 99% total supercoiled plasmid, ≤ 0.2% RNA, ≤ 0.1% host cell genomic DNA, and ≤ 0.1 endotoxin units per mg. © 2013 Landes Bioscience. Source

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