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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
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
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
Immunodominance In Vaccinia Virus And Recombinant Vaccinia Vaccines
Funder
National Health and Medical Research Council
Funding Amount
$388,455.00
Summary
When confronted with an invading microbe, the human immune system does not recognise its overall shape. Instead, the microbe is chopped up into tiny fragments, called peptides, and these can be recognised by special cells of the immune system called T cells which orchestrate a response. We have a good understanding of this chopping process and can predict many of these peptides, but this is only part of the story. Not all peptides will be recognized by a T cell. Further, through processes we do ....When confronted with an invading microbe, the human immune system does not recognise its overall shape. Instead, the microbe is chopped up into tiny fragments, called peptides, and these can be recognised by special cells of the immune system called T cells which orchestrate a response. We have a good understanding of this chopping process and can predict many of these peptides, but this is only part of the story. Not all peptides will be recognized by a T cell. Further, through processes we do not understand well, T cells that recognize only a few out of the many peptides will dominate an entire immune response. As a result, immune responses are focused in such a way that they recognize only a tiny portion of an invading microbe. Focusing of immune responses also occurs during immunization with vaccines. Some new, genetically engineered vaccines use a harmless microbe to carry small parts of more dangerous pathogens. The parts chosen will not cause any disease by themselves, so the whole vaccine is safe. Vaccines built in this way are in clinical trials for diseases such as AIDS and malaria, but do not work as well as was hoped. These new vaccines are largely made up of the carrier and the parts of the microbe we wish to immunize against (e.g. a part of the AIDS virus) will be only a small fraction of the whole vaccine. Ideally we would like the immune system to focus on this small part of our choosing, but the few studies done suggest that this is not the case. In this project we will study vaccines that use a carrier called vaccinia virus. We will test to what extent immune responses are focused inappropriately. We will then genetically alter the virus and use new immunisation strategies to try and shift the focus of the immune response so that it targets the right parts of the vaccine. The ultimate aim is to improve vaccines, but in the process we may learn more about how the immune system chooses its targets.Read moreRead less