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
Development Of An Immunotherapy Against Kgp Of Porphyromonas Gingivalis
Funder
National Health and Medical Research Council
Funding Amount
$495,710.00
Summary
Chronic periodontitis is an inflammatory disease of the supporting tissues of the teeth associated with specific bacteria, which results in the destruction of tooth support and ultimately leads to tooth loss. This project aims to develop an immunotherapy against the major virulence factor produced by bacteria associated with the disease. The immunotherapy will be evaluated in animal models of disease.
Mimetics Of Natural Triggers Of Innate Immunity As Vaccines
Funder
National Health and Medical Research Council
Funding Amount
$241,650.00
Summary
Knowledge of what properties of an antigen allow it to induce an immune response is central to our understanding of how we fight disease and how we can vaccinate effectively against disease. The fact that an antigen is foreign to the host is not in itself sufficient for it to initiate the series of events that must take place in order to activate B and T lymphocytes, the cells involved in immunity. For vaccine purposes, antigens must be delivered with substances called adjuvants to be effective. ....Knowledge of what properties of an antigen allow it to induce an immune response is central to our understanding of how we fight disease and how we can vaccinate effectively against disease. The fact that an antigen is foreign to the host is not in itself sufficient for it to initiate the series of events that must take place in order to activate B and T lymphocytes, the cells involved in immunity. For vaccine purposes, antigens must be delivered with substances called adjuvants to be effective. There is very little known about how adjuvants actually work but many of the highly effective experimental adjuvants contain an immunostimulant which is usually either whole dead bacteria or components of the cell walls of bacteria or other organisms. From evidence emerging in the literature and our own experimental observations, we have begun to understand the requirements for and the chain of events leading to immune response induction. The interaction of certain lipid-containing groups, present on antigens from pathogenic organisms, with a specialised type of cell, the dendritic cell, is a key event in this process. We have designed synthetic mimics of lipid-containing moieties from bacteria and coupled them to unrelated parts of viral proteins. We showed that these lipopeptides can elicit potent anti-viral immune responses and long lived memory responses. The experiments outlined in this proposal will examine the interaction of these and other second generation lipopeptides with dendritic cells. We will determine whether these can bind to particular molecules on the dendritic cell surface to initiate a specific series of signals leading to immune induction and if so we will seek to use different lipid groups to trigger the immune response in different and predictable ways. The outcomes of this work may have a major impact on the design of new vaccines as well as increase our understanding of how the immune system is triggered to respond to invading organisms.Read moreRead less
The aim of this project is to develop mathematical models and computer software capable of predicting immune responses to infection and disease. This “artificial immune system” should lead to improved vaccine design and better understanding of what causes the immune system to attack its own body, causing autoimmune disease, or fail to respond, causing immunodeficiency. This enabling science could then lead to improvements in treatment for a range of conditions of clinical importance.
Stability Engineering Of Human Antibody Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$421,104.00
Summary
Therapeutic monoclonal antibodies are among the fastest growing class of drugs with more than $30 billion sales in 2011. Unfortunately, antibodies often display limited stability and a tendency to aggregate. This greatly hinders their development and results in high failure rates of otherwise promising candidates. We have recently identified mutations that render human antibodies resistant to aggregation. Here we apply this technology to a monoclonal antibody candidate developed by a leading pha ....Therapeutic monoclonal antibodies are among the fastest growing class of drugs with more than $30 billion sales in 2011. Unfortunately, antibodies often display limited stability and a tendency to aggregate. This greatly hinders their development and results in high failure rates of otherwise promising candidates. We have recently identified mutations that render human antibodies resistant to aggregation. Here we apply this technology to a monoclonal antibody candidate developed by a leading pharmaceutical company.Read moreRead less