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Hepatitis C Vaccine Preparedness Study: Investing In Infectious Disease Prevention
Funder
National Health and Medical Research Council
Funding Amount
$820,767.00
Summary
Injecting drug users (IDU) are a key target group for new vaccines designed to prevent hepatitis C virus (HCV) infection. This study will establish the feasibility of conducting HCV vaccine trials in IDUs by answering key scientific questions, generating data to inform trial design and evaluation, establishing a partnership between leading international researchers and the peak Australian body for people who inject drugs, and providing the foundation for a global HCV prevention trial network.
Characterization Of Neutralizing Antibody Responses In HCV Infected Individuals.
Funder
National Health and Medical Research Council
Funding Amount
$478,076.00
Summary
Hepatitis C virus is a major human pathogen infecting 200 million people world-wide. Currently, there is no vaccine to prevent infection and treatment regimes are only partially effective. IInitial HCV infection is frequently asymptomatic and 30% of people spontaneously clear the virus. The remaining 70% of people develop a life-long chronic infection that causes progressive liver disease, cirrhosis and in some cases liver cancer. The reason why some people are able to clear virus has been attri ....Hepatitis C virus is a major human pathogen infecting 200 million people world-wide. Currently, there is no vaccine to prevent infection and treatment regimes are only partially effective. IInitial HCV infection is frequently asymptomatic and 30% of people spontaneously clear the virus. The remaining 70% of people develop a life-long chronic infection that causes progressive liver disease, cirrhosis and in some cases liver cancer. The reason why some people are able to clear virus has been attributed to the development of a strong cellular immune response and antibody is belived to play a monir role in achieving viral clearance. However, measurememnt of antibody responses in HCV infected pateints is routinely performed using conventional diagnostic tests that do not measure antibody that can help neutralize and clear virus. We have developed an assay that accurately measures the level of NAb in patient sera. We have found that chronically infected patients have broadly reactive neutralizing antibodies but that patients who clear virus, naturally or through treatment do not have broadly reactive neutralizing antibodies. Possibly explaining this phenomenon is that early during infection, antibody is frequently specific only to the infecting virus therefore to detect neutralizing antibodies, homologous viral sequences must be examined. In addition, we have found evidence that HCV can evade neutralzing antibodies through masking of sites to which antibodies bind. We propose to explore whether acutely infected patients develop NAb to autologous viral sequences, and how do these viral sequences and the antibody titre change throughout the course of infection and treatment. We also plan to determine the mechanism of neutralization resistance through the use of mutagenesis of resistant HCV glycoproteins. These studies are aimed at gaining a thorough understanding of the true role of antibody in HCV infection and its influence on viral evolution.Read moreRead less
Role Of The Hepatitis C Virus Glycoprotein E2 Variable Regions In Viral Entry And Antibody Mediated Neutralization.
Funder
National Health and Medical Research Council
Funding Amount
$542,462.00
Summary
The first stage of Hepatitis C Virus replication involves attaching to liver cells. This study is aimed at understanding how the virus attaches to liver cells and how antibodies raised during infection, block this interaction. In addition, this study aims to examine how the virus modulates its structure to evade the immne system, allowing the virus to establish chronic infections. The results of this study will guide future vaccine design for HCV.
Chimeric Virus-like Particles (VLPs) Displaying H1, H3 And H5 Haemagglutinins - Construction And Immunogenicity
Funder
National Health and Medical Research Council
Funding Amount
$207,543.00
Summary
Virus-like particles (VLPs) provoke strong immune responses in the body. We have developed a novel VLP system that allows the production of VLPs containing foreign vaccine antigens of much larger size than previously possible, and have shown that these VLPs provoke strong immune responses in mice without the use of adjuvants. The capacity of these VLPs is large enough to accommodate the most important vaccine antigen of influenza, the haemagglutinin (HA) molecule. We will test whether VLPs can b ....Virus-like particles (VLPs) provoke strong immune responses in the body. We have developed a novel VLP system that allows the production of VLPs containing foreign vaccine antigens of much larger size than previously possible, and have shown that these VLPs provoke strong immune responses in mice without the use of adjuvants. The capacity of these VLPs is large enough to accommodate the most important vaccine antigen of influenza, the haemagglutinin (HA) molecule. We will test whether VLPs can be produced containing each of the three most important HA types _ H1 and H3 that are currently circulating in man, and H5 (avian) that is considered a pandemic threat. VLPs will be tested for their ability to induce neutralizing antibody and cellular immune responses in mice, and for their ability to protect ferrets from influenza infection. If successful, the HA-VLP system would provide a method for the rapid production of new influenza vaccines using large-scale fermentation technology as for hepatitis B and many other vaccines, rather than eggs or cell culture as used for current influenza vaccines.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
Vaccine To Prevent Influenza Virus And Bacterial Super-infection.
Funder
National Health and Medical Research Council
Funding Amount
$707,717.00
Summary
Influenza viruses have the ability to pre-dispose infected hosts toward secondary bacterial complications. The mortality of viral infections that are complicated by a concurrent, or subsequent, bacterial infection (known as a super-infection), is often greater than that of either the virus or the bacteria alone. We will develop a novel multi-pathogen vaccine candidate against the major upper respiratory tract pathogens - Influenza A and Streptococcus pyogenes to prevent super-infections.
Novel Generic Vaccine Approaches Applied For The Prevention Of Hepatitis C And Influenza Virus Infections.
Funder
National Health and Medical Research Council
Funding Amount
$392,328.00
Summary
For the induction of good immune responses, antigens should be delivered in several copies on a defined particle. The small envelope protein (HBsAg) encoded by the hepatitis B virus (HBV) has the capacity to self-assemble with host derived lipids into VLPs. HBsAg VLPs are the sole component of one of the most successful vaccines, and clinical trials have shown that they are a successful delivery system for foreign epitopes or protein domains. Hepatitis C virus (HCV) and Influenza viruses are maj ....For the induction of good immune responses, antigens should be delivered in several copies on a defined particle. The small envelope protein (HBsAg) encoded by the hepatitis B virus (HBV) has the capacity to self-assemble with host derived lipids into VLPs. HBsAg VLPs are the sole component of one of the most successful vaccines, and clinical trials have shown that they are a successful delivery system for foreign epitopes or protein domains. Hepatitis C virus (HCV) and Influenza viruses are major human pathogens. HCV has infected 200 million people worldwide, and there is no effective vaccine available. Influenza continues to affect thousands of people each year causing epidemics with severe morbidity and considerable mortality. Current influenza vaccines are mostly inactivated formulations and they exhibit poor immunogenicity in immunological naive persons such as children and in the elderly. The influenza vaccines are not optimal for stimulation of cell-mediated immunity. We propose to use particulate antigens as a delivery platform for influenza and HCV-specific epitopes with the focus to develop approaches to target various HCV and influenza strains, including H5N1 bird influenza. We have successfully produced modified VLPs containing HCV-specific sequences, which are able to induce anti-HCV antibodies with neutralising capacity. We hypothesise that the design of VLPs with an appropriate set of HCV-specific antigens will enhance the neutralising capacity of anti-HCV sera and this may overcome strain specificity. This application will exploit a prototype delivery system to induce antibody and also cellular responses against a variety of HCV- and influenza specific target sequences (epitopes). The outcome of this study will be a prototype multivalent vaccine to a range of HCV- and influenza-specific epitopes. As a delivery system this will be ideal for vaccination against agents that are highly variable.Read moreRead less
Enabling Technologies For Design And Delivery Of Novel Vaccines Against Infectious Diseases And Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$925,346.00
Summary
This grant will support research necessary to develop the next generation of vaccines. These will combat diseases caused by bacteria and viruses and can also be used to fight cancer. The broad range of application is made possible through the incorporation of simple molecular features that activate the immune system. The intellectual property that has been developed is protected by a patent portfolio some patents of which are already licenced to the pharmaceutical industry.