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Improved Vaccines Against Tuberculosis Based On Dendritic Cell Manipulation
Funder
National Health and Medical Research Council
Funding Amount
$257,036.00
Summary
The incidence of tuberculosis (TB) is increasing throughout the world. BCG, the only currently available vaccine is only partially protective and better vaccines are urgently required to help limit the spread of TB. We have recently prepared naked DNA vaccines with the genes for three mycobacterial proteins and found that they partially protected against lung TB in mice. Further improvement is required and this project is to design and test improved DNA vaccines. Vaccines will be more effective ....The incidence of tuberculosis (TB) is increasing throughout the world. BCG, the only currently available vaccine is only partially protective and better vaccines are urgently required to help limit the spread of TB. We have recently prepared naked DNA vaccines with the genes for three mycobacterial proteins and found that they partially protected against lung TB in mice. Further improvement is required and this project is to design and test improved DNA vaccines. Vaccines will be more effective if they generate stronger cellular immune response to mycobacteria. Dendritic cells (DC) are the major cells that present mycobacterial antigens to T lymphocytes and thus stimulate T lymphocytes to generate immune responses that protect against TB. Therefore the aim of this project is to identify ways to manipulate DC to improve their ability to activate protective immunity. We will target membrane molecules on DC to activate the antigen- presenting function of these cells by fusing the genes for mycobacterial proteins to genes either for antibodies to surface molecules on DC or receptors for these molecules. These novel DNA vaccines will be tested for their effects on DC function and their capacity to stimulate the protective pattern of immunity in mice. The cytokine environment at the time of stimulation will be modified by giving the DNA vaccine together with two cytokine-expressing vaccines, to 'push' the T lymphocytes to respond more vigorously. Finally, we shall test whether a combination of the new DNA vaccines and BCG is more effective than BCG at protecting against virulent TB infection.Read moreRead less
Efficacy Of Asexual Blood-stage Antigens And Antigen Combinations For Vaccination Of Mice Against Plasmodium Chabaudi.
Funder
National Health and Medical Research Council
Funding Amount
$286,320.00
Summary
The development of a vaccine against malaria is one of the world's major public health priorities. Over the last two decades much progress has been made towards the development of a malaria vaccine but none is yet available that is suitable for use in humans. Many parasite molecules have been identified that are considered potential components of a malaria vaccine and some of these have already reach the stage of being tested in early clinical trials. However, a major problem confronting the fie ....The development of a vaccine against malaria is one of the world's major public health priorities. Over the last two decades much progress has been made towards the development of a malaria vaccine but none is yet available that is suitable for use in humans. Many parasite molecules have been identified that are considered potential components of a malaria vaccine and some of these have already reach the stage of being tested in early clinical trials. However, a major problem confronting the field of malaria vaccine development is finding the resources necessary to test the large number of antigens and antigen combinations that are considered of potential value. One way to gain information that will help to determine which antigens and antigen combinations should have priority for testing in clinical trials is to carry out vaccine trials in monkeys or mice using malaria parasites that infect these species. We will use Plasmodium chabaudi infections in the mouse to examine the ability of three antigens from the disease causing blood stages of the parasite to induce antibody responses that prevent the development of severe malaria. We will determine whether antigen combinations provide better protection than single antigens when mice are challenged with a variety of parasite strains. Detailed analyses of the antibody responses will be carried out to determine if combining antigens changes the response in a way that may help or hinder vaccine efficacy.Read moreRead less
Immunological Mechanisms Of Clinical Responsiveness To Immunotherapy For Metastatic Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$480,750.00
Summary
There have been no major improvements in the treatment of most metastasizing, solid tumours in the last several decades. One avenue that has received much attention is boosting a cancer patient's immune system with an anti-cancer vaccine, so that it destroys just the cancerous cells. This has proved an elusive goal, and no treatment has ever been shown to be of repeated worth, in the complete resolution of multiple sites of metastatic disease, until now. Two consecutive trials of our dendritic c ....There have been no major improvements in the treatment of most metastasizing, solid tumours in the last several decades. One avenue that has received much attention is boosting a cancer patient's immune system with an anti-cancer vaccine, so that it destroys just the cancerous cells. This has proved an elusive goal, and no treatment has ever been shown to be of repeated worth, in the complete resolution of multiple sites of metastatic disease, until now. Two consecutive trials of our dendritic cell based vaccine, which uses only cells from the patient to be treated, have each shown a 15% complete, durable, response rate. The remissions have now lasted longer than 3 years in patients otherwise expected to survive less than 1 year, with no serious side effects observed in any of the patients treated. It is likely that part of the success of this treatment is that it targets unique mutations in the patient's own cancer cells, in combination with a powerful immune stimulation from the dendritic cells. In contrast, most carefully run trials, now and in the recent past, have attempted to use more generic targets, common to many patients' cancers. The problem with this approach is likely to be that the patient is tolerant to these, since the targets are common, self proteins. At variance with all previous trials, we found an exact correlation between durable clinical responses and the degree of anti-tumour immunity displayed by the patients T cells. This grant proposal is based on the reasoning that, by studying in depth the characteristics of this successful immune response, in patients with complete, durable, clinical responses, we will be able to make major improvements in the formulation of the therapy.Read moreRead less
Streptococcus pneumoniae (the pneumococcus) is an important human pathogen, which is responsible for the deaths of millions of children each year in developing countries. The high morbidity and mortality associated with pneumococcal disease is also being exacerbated by the rate at which this organism is acquiring resistance to multiple antibiotics. Existing pneumococcal polysaccharide vaccines are poorly immunogenic in young children and only provide cover against a limited range of serotypes. S ....Streptococcus pneumoniae (the pneumococcus) is an important human pathogen, which is responsible for the deaths of millions of children each year in developing countries. The high morbidity and mortality associated with pneumococcal disease is also being exacerbated by the rate at which this organism is acquiring resistance to multiple antibiotics. Existing pneumococcal polysaccharide vaccines are poorly immunogenic in young children and only provide cover against a limited range of serotypes. Serotype coverage is even lower in the more immunogenic conjugate vaccines currently being developed; these will also be very expensive, thereby limiting their use in developing countries, where the need for effective paediatric vaccines is greatest. Pneumococci produce a variety of proteins which are important in causing disease, but the relative contribution of these factors at each stage of the infection process remain to be determined. Moreover, virtually nothing is known of the mechanism whereby these virulence factors are regulated in response to the external environment of the bacterium. In view of this, we are conducting a comprehensive examination of the mechanisms of pathogenesis of pneumococcal disease, with particular reference to the role of putative virulence proteins. This information is being used to develop cheap and effective vaccines based on pneumococcal protein antigens common to all serotypes.Read moreRead less
Pathogenesis And Prevention Of Shiga Toxigenic Escherichia Coli Infections
Funder
National Health and Medical Research Council
Funding Amount
$341,320.00
Summary
Shiga toxin (Stx)-producing strains of Escherichia coli (STEC) are known to cause diarrhoea and haemorrhagic colitis in humans. In a proportion of cases, this leads to potentially fatal systemic complications, such as haemolytic uraemic syndrome (HUS), which is the commonest cause of acute renal failure in children. HUS has a high mortality rate in spite of intensive supportive therapy. Morbidity is also substantial, as permanent renal damage and neurological sequelae occur in a significant prop ....Shiga toxin (Stx)-producing strains of Escherichia coli (STEC) are known to cause diarrhoea and haemorrhagic colitis in humans. In a proportion of cases, this leads to potentially fatal systemic complications, such as haemolytic uraemic syndrome (HUS), which is the commonest cause of acute renal failure in children. HUS has a high mortality rate in spite of intensive supportive therapy. Morbidity is also substantial, as permanent renal damage and neurological sequelae occur in a significant proportion of survivors. Large outbreaks of STEC infection are becoming increasingly common, and highlight the threat to public health posed by these bacteria. The serious systemic complications of STEC disease, as well as much of the intestinal pathology, are directly attributable to Stx. However, pathogenesis is multifactorial and capacity of the bacteria to colonize the gut is a crucial virulence trait. STEC infections can now be diagnosed very early in the course of disease, but currently no effective therapeutic intervention is possible. We are addressing this deficiency by developing a novel therapy for STEC infections based on a genetically modified harmless bacterium capable of binding toxin in the gut. Vaccines capable of preventing transmission of STEC disease in the community are also needed, but development of these demands a full understanding of the mechanisms whereby diverse STEC strains adhere to intestinal epithelium and colonize the human gut. We are therefore also examining the interaction between STEC and gut epithelial cells at the cellular and molecular level, with a view to identifying and assessing the vaccine potential of key determinants of adherence.Read moreRead less