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
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.
Defining Mechanisms Of Follistatin-mediated Muscle Adaptation, For Treatment Of Frailty And Muscle-related Diseases
Funder
National Health and Medical Research Council
Funding Amount
$557,478.00
Summary
Physical frailty-weakness is one of the most common symptoms of serious illness and a key cause of death. I propose to study a new model of skeletal muscle growth, to learn more about the causes of wasting in muscle-related diseases. The work will identify cell mechanisms that cause loss of muscle strength, and will help develop novel treatment approaches to prevent or reverse physical frailty in illness. New therapies to combat frailty are vital to improve the health of our community.
The In Vitro Culture Of Hepatitis C Virus And Approaches To The Control Of Replication
Funder
National Health and Medical Research Council
Funding Amount
$452,310.00
Summary
HCV is a major cause of liver disease and around 200 million people are currently infected worldwide, including 200,000 Australians. HCV differs to other flaviviruses. Most notably, around 80% of individuals develop a persistent infection, accounting for the large number of carriers. This infection is probably life-long and 40-50% of carriers will develop serious liver disease, including liver cancer. HCV is currently the leading single indicator for liver transplantation in the western world. T ....HCV is a major cause of liver disease and around 200 million people are currently infected worldwide, including 200,000 Australians. HCV differs to other flaviviruses. Most notably, around 80% of individuals develop a persistent infection, accounting for the large number of carriers. This infection is probably life-long and 40-50% of carriers will develop serious liver disease, including liver cancer. HCV is currently the leading single indicator for liver transplantation in the western world. These carriers can also transmit the virus to uninfected individuals. Screening in the blood banks has reduced transmission after blood transfusion to virtually zero. However, although individuals who share contaminated needles represent a major high risk population, around 30% of carriers have no acknowledged transmission risk factors, and transmission to patients in hospitals has been recognised. As a result, it is clear that members of the general population may still become infected. It has been estimated that there are 10,000 new cases each year in Australia. The best available treatment is a combination of interferon-alpha and ribavirin, but this is only successful in 40-50% of carriers. Moreover, many patients fail to tolerate these drugs and the cost restricts treatment to a small proportion of carriers. As a result,only approx 6,500 carriers have been treated in Australia. A huge backlog in the liver clinics and the resistant nature of the virus in 50% of patients in Australia mean that these patients will not be treated unless new therapies are developed. The most effective means to prevent virus infections is by vaccination. Thus the development of novel antivirals and a vaccine for HCV are priorities. Since the cost of a single liver transplant is $100,000 the development of such agents is likely to be cost effective. However, it is necessary to develop suitable cell culture systems to test putative antiviral agents.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