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
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.
Host Genes Controlling Flavivirus Infection: New Insights And Application For Developing Highly Effective Kunjin Replicon-based Ebola Vaccine
Funder
National Health and Medical Research Council
Funding Amount
$736,995.00
Summary
The applications is aimed at identifying new host genes controlling infection with West Nile virus and other medically important flaviviruses such as dengue and Japanese encephalitis. For this, we will use novel in vivo RNAi screening approach with virus libraries encoding artificial microRNAs (amirs) targeting whole mouse genome. We will then apply amiR technology to produce highly effective Kujniin replicon-based Ebola vaccine candidate that has shown promising results in trails in primates.
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
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
Co-administration Of DNA Encoding Co-stimulatory Molecules Enhances The Efficacy Of Immune Response To Foreign Antigen
Funder
National Health and Medical Research Council
Funding Amount
$182,000.00
Summary
Vaccines to prevent or treat infectious diseases and some cancers are urgently needed. Infected cells and some cancer cells display unique proteins which the body's immune system can recognises as 'foreign'. The body will then mount an immune response, which, if successful, will eradicate the infected or cancerous cells. Dendritic cells (DCs) initiate the body's immune response by instructing other immune cells to mount a response. For a vaccine to be successful it is important that the vaccine ....Vaccines to prevent or treat infectious diseases and some cancers are urgently needed. Infected cells and some cancer cells display unique proteins which the body's immune system can recognises as 'foreign'. The body will then mount an immune response, which, if successful, will eradicate the infected or cancerous cells. Dendritic cells (DCs) initiate the body's immune response by instructing other immune cells to mount a response. For a vaccine to be successful it is important that the vaccine activates the DCs in the right way. We propose to activate DCs by vaccinating with DNA encoding recently identified costimulatory molecules, as well as DNA encoding the foreign antigen. Our earlier work leads us to believe that this will enhance the immune response, and lead to a more effective state of immunityRead moreRead less