Characterisation Of Anti-HBs Responses In Patients Undergoing Functional Hepatitis B Cure: Implication For Future Therapies
Funder
National Health and Medical Research Council
Funding Amount
$723,649.00
Summary
The hepatitis B virus causes liver cirrhosis and liver cancer. There is no cure for hepatitis B. However, a small number of patients can naturally rid themselves of the virus. We have identified 14 of these individuals and discovered that they have a unique immune response that is responsible for these “natural” cures. We plan to characterise this immune response and turn it into a therapeutic vaccine which can be used to cure patients who are still chronically infected.
A Polyepitope HPV16 E7 DNA Vaccine Restricted Through Multiple Class 1 Haplotypes Protects Against E7-expressing Tumour
Funder
National Health and Medical Research Council
Funding Amount
$218,244.00
Summary
Evidence that cervical cancer is caused by Human Papillomavirus is compelling. Once the virus enters the cells of the cervix, it produces a protein named E7 which functions to make the cells cancerous. Cervical cancer is the 5th commonest cause of death in women in Australia, and the major killer of women world-wide.The disease is particularly severe in those women whose immune systems are impaired, indicating immunological control of the cancerous cells . Current therapies including surgical re ....Evidence that cervical cancer is caused by Human Papillomavirus is compelling. Once the virus enters the cells of the cervix, it produces a protein named E7 which functions to make the cells cancerous. Cervical cancer is the 5th commonest cause of death in women in Australia, and the major killer of women world-wide.The disease is particularly severe in those women whose immune systems are impaired, indicating immunological control of the cancerous cells . Current therapies including surgical removal are frequently inadequate, and the r is no effective drug to combat the virus.These observations indicate that a vaccine is warranted, and that the E7 protein may be an ideal target for the vaccine. Cervical tumour cells are killed by specialised immune system cells named CTLs which recognise fragments of foreign antigen(E7) on their surface bound to selfMHC molecules. Our work has shown that multiple antigen fragments can be encoded and stitched together in a genetic vaccine which will stimulate CTLs to function in a number of 'self'molecule situations Our laboratory has developed several mouse models of human cervical cancer , and (along with others) has worked out which parts of the E7 protein are importatnt in developing an appropriate immune response to control tumour growth when given as a vaccine. One animal model consists of mice which are genetically engineered to produce several types of selfmolecules and also E7. Thes mice develop skin tumours as result of E7 expression. This system provides model of cervical epithelial tumours caused by E7 expression in women.Thus we can ask the questions o can we elicit CTL responses which function in the context of humanself ? o Will these CTL responses prevent the growth of E7-induced epithelial tumours? The OUTCOME of the project will be a vaccine which will prevent the establishment of cervical cancer which can progress directly into clinical trials in women bearing appropriate selfmolecules.Read moreRead less
Polynucleotide Vaccine Based On Targeted Delivery To Antigen Presenting Cells
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
We have previously generated a vaccine for breast and other adenocarcinomas by linking a breast cancer associated protein, MUC-1, to a sugar called mannan. This complex was capable of eradicating tumours in mice and its efficacy has been evaluated in human clinical trials (12 in total). As an extension to these studies we have now found that this sugar, mannan, can be used to deliver DNA to immune cells. The current project will evaluate a DNA vaccine for breast cancer.
The growing momentum towards elimination of malaria and the need to control of drug-resistant parasites means that new drugs and vaccines are needed. In this Fellowship I will use the human malaria challenge system that I have developed to test whether new drugs and vaccines for malaria are working sufficiently well to justify their full development. In this system healthy volunteers are deliberately infected with malaria and then cured before they become unwell.
Discovery Of Long CD8+ T Cell Epitopes Uncovers A Hidden Reservoir Of Immunodominant, Anti-tumour Responses
Funder
National Health and Medical Research Council
Funding Amount
$480,127.00
Summary
Stimulating killer T cells to eliminate tumours has been one of the ultimate yet elusive goals of cancer vaccine development. Vaccines aimed at stimulating killer T cells are similar to those generated under natural conditions. However, special strategies are needed to vaccinate beneficial killer T cells that are not normally part of the natural immunity. In this project, we will explore such a scenario and dissect the related mechanisms contributing to such differential immune outcomes.
A NOVEL APPROACH FOR TARGETING DNA TO DENDRITIC CELLS IN VIVO FOR VACCINE DEVELOPMENT AND CANCER IMMUNOTHERAPY
Funder
National Health and Medical Research Council
Funding Amount
$430,250.00
Summary
The use of genetic material, known as DNA, as a vaccine, has been a relatively new advance in vaccination technology with potential for combating many infectious diseases and cancers. The use of DNA has the advantage that it can be easily manipulated to develop new vaccines that have the desired preventative and-or immunotherapeutic effect. For optimal effect, however, the DNA to be used as a vaccine needs to be targeted to specific cell types in the body. Evidence suggests that a minor populati ....The use of genetic material, known as DNA, as a vaccine, has been a relatively new advance in vaccination technology with potential for combating many infectious diseases and cancers. The use of DNA has the advantage that it can be easily manipulated to develop new vaccines that have the desired preventative and-or immunotherapeutic effect. For optimal effect, however, the DNA to be used as a vaccine needs to be targeted to specific cell types in the body. Evidence suggests that a minor population of cells known as dendritic cells, which are present in blood and other tissues, play an important role in eliciting the effects of DNA vaccines. However, current methods for delivering DNA to these cells often lack selectivity in delivery, and-or use viruses to deliver the DNA. This can pose the risk of allergic type reactions and-or possibly cause tumours. The use of small membranous vesicles known as liposomes, made of phospholipids, has recently attracted considerable interest as DNA delivery vehicles, since these are considered safe, and have the potential to deliver large quantities of DNA. Although DNA can easily be packaged inside liposomes, it is has not been easy to target the liposomes and their contents (eg. encapsulated DNA) to specific cells (such as dendritic cells) within the body. We have recently produced a novel chelator lipid molecule which can be used to conveniently attach onto the liposome surface specific targeting molecules, such as engineered forms of antibody fragments, that can target or steer the liposomes together with their payload (eg. the DNA), directly to dendritic cells. This project will test the potential for using such targeted liposomes as DNA vaccines by examining whether liposomes containing DNA for a model antigen can be used in vaccinations to inhibit the growth and metastasis of a highly metastatic tumour (melanoma) in mice.Read moreRead less
Low-Cost Portable Inhalation Therapy Platform For Needle-Free DNA-Based Influenza Vaccination
Funder
National Health and Medical Research Council
Funding Amount
$524,644.00
Summary
Influenza affects a large proportion of the global population and can result in many deaths in a pandemic. A DNA influenza vaccine overcomes the possibility of severe side effects associated with commonly used vaccines based on weakened viruses and can be rapidly produced and easily transported without refrigeration. DNA vaccines are however unstable and difficult to deliver. We propose to address this with a low-cost and portable handheld device which allows the vaccine to simply be inhaled.
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.
The Mechanisms Of Establishing, Maintaining Immunological Memory And Immunodominance Hierarchy
Funder
National Health and Medical Research Council
Funding Amount
$234,750.00
Summary
The hallmark of the adaptive immune response is the development of specific immunological memory following the first confrontation with a microorganism. Memory T cells are capable of responding rapidly upon subsequent exposure to the same microbes thus providing protective immunity. This proposal aims to investigate how cytotoxic T cells establish memory following their primary encounter with microorganisms. The proposal will dissect the relationship between memory T cell formation and the amoun ....The hallmark of the adaptive immune response is the development of specific immunological memory following the first confrontation with a microorganism. Memory T cells are capable of responding rapidly upon subsequent exposure to the same microbes thus providing protective immunity. This proposal aims to investigate how cytotoxic T cells establish memory following their primary encounter with microorganisms. The proposal will dissect the relationship between memory T cell formation and the amount-length of antigen exposure; and the influence on memory induction from various immune modulators (cytokines) at the time of antigen encounter. Using a range of sophisticated detection methods, very early memory T cells will be identified in the primary response and tracked through their differentiation into long-term memory pool. Experiments will determine how T cells against particular determinants are selected from the primary immune response, retained in the memory pool and recalled in the subsequent challenges. The properties of antigen processing of various determinants will be correlated with the immunodominance hierarchy in the primary and memory response. Taken together the proposed project is central to understanding how memory T cells are created and what rules govern their stability. The project is highly relevant to vaccine design against tumours and pathogensRead moreRead less
Immunopathogenesis And Manipulation Of The HIV Reservoir
Funder
National Health and Medical Research Council
Funding Amount
$494,732.00
Summary
Kelleher is a Clinical immunologist with a globally recognised, sustained track record of translational research which has impacted both on our understanding of HIV immunopathogenesis and on the way HIV infection is treated. He will conduct a series of studies that encompass basic scientific techniques through to pivotal pre-clinical and clinical studies that will provide a pathway towards control of HIV-infection without daily therapy.