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
Development Of Novel Vaccine Strategies To Prevent Genital Tract Chlamydial Infections
Funder
National Health and Medical Research Council
Funding Amount
$33,626.00
Summary
Chlamydia trachomatis is one of the most common sexually transmitted diseases in the developed world. Because an infection can remain undetected it can cause severe long term problems such as infertility. The aim of this project is to develop a successful vaccine using novel immunization regimes that not only protects from infection but also prevents the development of any long term problems.
Oxidised Mannan As A Novel Adjuvant To Vaccinate Against Mucosal Infections
Funder
National Health and Medical Research Council
Funding Amount
$150,000.00
Summary
Most pathogens invade via the mucosal surfaces. However, current vaccines, which are delivered by injection, are poor at inducing mucosal immunity. An ideal vaccine would comprise a defined protein antigen combined with a suitable adjuvant which could be administered intranasally or orally. Protective antigens have been defined for a number of infections but suitable adjuvants have been elusive. We showed that mannan, a complex carbohydrate from yeast, oxidatively linked to protein antigens can ....Most pathogens invade via the mucosal surfaces. However, current vaccines, which are delivered by injection, are poor at inducing mucosal immunity. An ideal vaccine would comprise a defined protein antigen combined with a suitable adjuvant which could be administered intranasally or orally. Protective antigens have been defined for a number of infections but suitable adjuvants have been elusive. We showed that mannan, a complex carbohydrate from yeast, oxidatively linked to protein antigens can be used as an adjuvant for mucosal IgA and other classes of antibody. Given to mice intranasally, antigen coupled to mannan markedly enhanced production of IgA, IgG1 and IgG2a in serum, and IgA in lung, tears, vaginal secretions, saliva and gut. We have confirmed this for a number of known or putative protective antigens. In addition, both the Th1 and Th2 arms of the lymphocyte response were activated. We have demonstrated protection against P. gingivalis (cause of periodontitis and associated with premature birth and cardiovascular disease) in a mouse lesion model. However, before commercial interests will commit themselves, we need to demonstrate protection against viral infections and in other sites like lungs and gut. Three infection models where IgA has been shown to protect are already set up and can realistically produce results in 1 year. 1. Rotavirus is the major cause of severe infantile gastroenteritis in humans and animals world wide. The latest (live) vaccine was withdrawn because of side effects. We have established a model with Simian rotavirus causing an acute self-limiting disease in infant mice. Adult females will be immunised with mannan linked to killed virus preparations, mated and passive protection of their offspring will be assessed. Preliminary evidence links rotavirus infection with the onset of type 1 diabetes. If this is confirmed, there will be an opportunity to test the vaccine against diabetes. 2. Influenza: IN infection of mice with flu virus is a well established model. Mice will be immunised IN with mannan coupled to haemagglutinin-neuraminidase purified from egg-grown virus. They will be challenged IN with influenza virus and virus titrated in lung homogenates. Neutralising antibody in serum and lung washings will essayed. 3. Respiratory syncytial virus: RSV is the commonest cause of bronchiolitis and pneumonia in infants for which there have been unsuccessful attempts to produce a vaccine. F and G membrane glycoproteins have been shown to protect mice against IN infection, and they will be used coupled to mannan to vaccinate mice against intranasal challenge.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
Antigens, Allergens And Immune Responses In Normal And Crusted Scabies
Funder
National Health and Medical Research Council
Funding Amount
$302,036.00
Summary
Scabies (itch mite), a parasitic skin infestation of the mite Sarcoptes scabiei, is a major problem among most children in many Aboriginal communities in Australia, often accompanied by streptococcal infections which cause serious diseases. Our world-first molecular studies utilised variable microsatellite markers to demonstrate that scabies mites on people are genetically distinct from those on dogs. This has important implications in control programs in Aboriginal communities. In our current N ....Scabies (itch mite), a parasitic skin infestation of the mite Sarcoptes scabiei, is a major problem among most children in many Aboriginal communities in Australia, often accompanied by streptococcal infections which cause serious diseases. Our world-first molecular studies utilised variable microsatellite markers to demonstrate that scabies mites on people are genetically distinct from those on dogs. This has important implications in control programs in Aboriginal communities. In our current NHMRC program we have cloned scabies antigens, with the aim of understanding more about immunity, which normally limits infestation from developing to the extreme levels seen in the debilitating disease crusted scabies. Our hypothesis is that crusted scabies is the consequence of an immune deficit in these patients. The first such cloned antigen is the equivalent of a known asthma-inducing allergen from a closely related housedust mite. We seek support to continue this successful program and to extend it to search for candidate vaccine antigens.The development of a vaccine would be a step of major importance in prevention. Recent reports estimate up to 300 million scabies cases worldwide, commonly associated with overcrowding and poverty. We are the first laboratory worldwide to have successfully initiated molecular studies on scabies. We have formed close collaborations with the only laboratory with an animal model (Arlian, USA), and the best group working on epidemiology and control of human scabies (Taplin, USA) and co-published with these groups. It is imperative that our NHMRC support be continued and increased to a level compatible with the importance, potential and achievements so far of this unique program.Read moreRead less
I am an immunologist with a background in virology and peptide chemistry and my work is therefore inter-disciplinary but focused on the design of synthetic, epitope-based vaccines against infectious agents particularly influenza and hepatitis C viruses an
Development Of A Vaccine For Genital Chlamydial Infection
Funder
National Health and Medical Research Council
Funding Amount
$207,551.00
Summary
Genital Chlamydia infections are the most common sexually transmitted infection in Australia with annual health costs of 90-160 million dollars. Infection rates in 15-29 olds are increasing at 15-20% per year. Antibiotics are currently the treatment of choice, however antibiotic resistance is increasing and most infections are asymptomatic and not treated in the absence of screening programs. This project aims to develop a genital Chlamydia vaccine using a combination of novel antigens.