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Kunjin Virus Replicon-based Vaccine Vectors: New Developments And Applications
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
The project is aimed towards further development of a unique gene expression and delivery system based on self-replicating RNA (replicon) of the nonvirulent Australian flavivirus Kunjin (KUN). A number of improvements in the design of KUN replicon vectors aimed to increase their efficiency and to optimize them for production of heterologous gene products with desired terminal sequences are proposed. Also proposed are improvements in the current KUN replicon packaging system and development of ne ....The project is aimed towards further development of a unique gene expression and delivery system based on self-replicating RNA (replicon) of the nonvirulent Australian flavivirus Kunjin (KUN). A number of improvements in the design of KUN replicon vectors aimed to increase their efficiency and to optimize them for production of heterologous gene products with desired terminal sequences are proposed. Also proposed are improvements in the current KUN replicon packaging system and development of new packaging systems for production of large amounts of virus-like particles (VLPs) containing KUN replicon RNA enclosed in KUN coat proteins for use as potential vaccines. The vaccine potentials of the curent and newly developed KUN vectors and VLPs will be evaluated in mice using respiratory syncytial virus as a model. An entirely new direction proposed in this application is generation of chimeric fowlpox virus-KUN replicon vectors which will combine the advantages of both systems and may result in the generation of an ultimate vaccine vector.Read moreRead less
Kunjin Replicons For Gene Therapy And Protein Manufacture
Funder
National Health and Medical Research Council
Funding Amount
$310,000.00
Summary
This grant seeks to provide proof of concept (PoC) for the use of the Kunjin replicon technology for gene therapy and protein production. (A) Protein production. Two Kunjin replicon constructs expressing green fluorescent protein (GFP) and secreted alkaline phosphatase (SEAP) are to be constructed and protein production monitored using FACS and SEAP bioactivity reporter kit (Roche), respectively. Protein production and biological activity of the proteins will be monitored in transient transfecti ....This grant seeks to provide proof of concept (PoC) for the use of the Kunjin replicon technology for gene therapy and protein production. (A) Protein production. Two Kunjin replicon constructs expressing green fluorescent protein (GFP) and secreted alkaline phosphatase (SEAP) are to be constructed and protein production monitored using FACS and SEAP bioactivity reporter kit (Roche), respectively. Protein production and biological activity of the proteins will be monitored in transient transfections and over an extended time period. Several cell lines, culture conditions and Kunjin replicon vector modifications will be tested. Arrangements have also been made to send the constructs to Roche, GSK, Eli Lilly, and Exelixis for side by side comparisons of this system with existing proprietary protein production echnologies. (B) Gene therapy. Two PoC gene therapy systems are proposed to be used for evaluation of Kunjin replicon vectors. (i) Tumours expressing granulocyte macrophage colony stimulating factor (GMCSF) by transfection cause the generation of anti-tumour CD8 T cells and subsequent tumour rejection. Current approaches include adoptive transfer of adeno-GM-CSF transfected tumour cells, a costly and laborious process resulting in only transient expression (Can. Imm. Immunother 2001 50:373). We intend to inject Kunjin replicon virus like particles into growing s.c. B16 melanomas and expect to see a high infection rate, a sustained high-level expression of GMCSF, and rejection of the tumour. In contrast to Kunjin, nearly all humans have antibody responses to adenovirus, and very high titres of adenovirus are required to obtain high infection and GM-CSF expression. Both factors limit adenovirus use in vivo. (ii) Transplant rejection can be inhibited by expression in the graft of CTLA4-Fc a reagent that blocks T cell co-stimulation enhancing allo-graft acceptance (Transplantation 2000 69:1806). High-level expression for over 100 days is expected to correlate with optimal graft acceptance. Our ability to use Kunjin to express beta galactosidase for several months in vivo without inflammation illustrates the potential for this approach (CIB ref 15). Initially we intend to use P815 cells injected i.p. into C57BL-6, where they are usually rejected within a few days. In contrast, P815 cells with Kunjin replicon-mediated CTLA4-Fc expression should survive for an extended period. Graft survival is easily monitored using FACS and anti-H-2d antibodies.Read moreRead less
In recent years it has become clear that certain white blood cells called CD8+ T lymphocytes or killer T cells are required to protect people against HIV. Unfortunately, current vaccines that produce or anti-HIV CD8 T cells only produce effective T cells for a short period. In this project we intend to test a novel vaccine vector called a Kunjin replicon, which promises to persistently produce or maintain effective T cells because the vaccine itself persists and continually immunises for extende ....In recent years it has become clear that certain white blood cells called CD8+ T lymphocytes or killer T cells are required to protect people against HIV. Unfortunately, current vaccines that produce or anti-HIV CD8 T cells only produce effective T cells for a short period. In this project we intend to test a novel vaccine vector called a Kunjin replicon, which promises to persistently produce or maintain effective T cells because the vaccine itself persists and continually immunises for extended periods. We intend to test the ability of this vaccine to persist and persistently produce effective CD8 T cells not only systemically in the blood system but also at mucosal surfaces, where HIV usually gains entry during sexual intercourse.Read moreRead less
Quantification Of Antigen Presentation To CD8 T Cells During Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$582,072.00
Summary
Knowledge of how virus-infected cells are detected by the bodyÍs immune system is fundamental to our understanding of virus infections and attempts to improve vaccines. We know that many proteins are displayed during virus infection but until now, the precise details of this display have only been worked out for very few proteins, studied one at a time. In this project we will apply cutting-edge technology to gain the first holistic view of how a virus-infected cell looks to the immune system.
Flaviviruses are the agents of many mosquito-transmitted infections such as encephalitis and dengue. Hepatitis C virus is a member of the same virus family. Using Australian flavivirus Kunjin as a model and advanced techniques in molecular biology, biochemistry and electron micriscopy, the research at SASVRC has established international leadership in the area of flavivirus RNA replication and ultrastructure of virus-infected cells. The objectives of this application are to advance further our u ....Flaviviruses are the agents of many mosquito-transmitted infections such as encephalitis and dengue. Hepatitis C virus is a member of the same virus family. Using Australian flavivirus Kunjin as a model and advanced techniques in molecular biology, biochemistry and electron micriscopy, the research at SASVRC has established international leadership in the area of flavivirus RNA replication and ultrastructure of virus-infected cells. The objectives of this application are to advance further our understanding of how the flavivirus RNA replication complex synthesizes RNA and how this RNA is specifically packaged to produce infectious virus. To achieve these goals we will employ state-of-the-art molecular biology techniques based on manipulations with infectious complementary DNA copy of Kunjin virus RNA. The intimate understanding of these mechanisms in flavivirus replication should facilitate the design of efficient antiviral drugs by specifically targeting unique events in RNA replication and-or packaging. This may assist in the development of antiviral drugs for treatment of infections caused by other higly pathogenic flaviviruses in Australia, such as dengue, Japanese encephalitis and Murray Valley encephalitis, and in the rest of the wirld such as New York strain of West Nile virus as well as the related heptitis C virus. Understanding the mechanisms of Kunjin virus replication and assembly will also aid in the further development of this virus as a safe vaccine vector against other viruses, e.g. HIV, and diseases such as cancer.Read moreRead less
Development Of Hepatitis B Surface Antigen As A Generic Vector For The Delivery Of Foreign CTL Epitopes.
Funder
National Health and Medical Research Council
Funding Amount
$439,642.00
Summary
Many kinds of cancer and infections display unique proteins which the body's immune system can recognise as ' foreign', and mount an immune response which, if correctly harnessed, will kill the cancer or infected cells . A way to harness the immune response is to vaccinate with these unique proteins. However, new ways need to be found to deliver the unique proteins to produce the maximal possible anti- cancer or pathogen response, and one that is long lived. In particular one needs to stimulate ....Many kinds of cancer and infections display unique proteins which the body's immune system can recognise as ' foreign', and mount an immune response which, if correctly harnessed, will kill the cancer or infected cells . A way to harness the immune response is to vaccinate with these unique proteins. However, new ways need to be found to deliver the unique proteins to produce the maximal possible anti- cancer or pathogen response, and one that is long lived. In particular one needs to stimulate the cellular arm of the immune response to produce killer cells named CTLs which specifically kill cancer or infected cells. In this project we plan to use an already-licensed human vaccine - the Hepatitis B surface antigen vaccine , or HBsAG, - and genetically modify it to contain important regions of cancer or pathogen proteins termed 'epitopes'. We surmise that immunisation with these modified HBsAg will elicit powerful CTL responses which will killer cancer or infected cells.Read moreRead less