An Inside-out Approach To Muscosal Vaccination: MAdCAM Targeting
Funder
National Health and Medical Research Council
Funding Amount
$174,250.00
Summary
The mucosal surfaces are the entry site for many pathogens (eg. cholera, rotaviruses, helicobacter, SARS and sexually transmitted diseases including HIV infections). The ideal vaccine would elicit both systemic and mucosal immune response, enhancing immunity at this first line of defence. The oral route has formidable barriers to antigen uptake such as digestive enzymes, commensal microbes, mucous layers and gastric acid. Our strategy targets the vascular addressin found in immune tissues of the ....The mucosal surfaces are the entry site for many pathogens (eg. cholera, rotaviruses, helicobacter, SARS and sexually transmitted diseases including HIV infections). The ideal vaccine would elicit both systemic and mucosal immune response, enhancing immunity at this first line of defence. The oral route has formidable barriers to antigen uptake such as digestive enzymes, commensal microbes, mucous layers and gastric acid. Our strategy targets the vascular addressin found in immune tissues of the gut (called MAdCAM) so that the vaccine is linked to an antibody against MAdCAM. Thus for the first time we believe that a parenteral vaccine ie. injected im or iv (bypassing the oral barriers) can induce mucosal immunity.Read moreRead less
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
Development Of Chimeric Hepatitis B Virus Like Particles As A Vaccine Delivery Platform For Multiple HIV-1 Epitopes
Funder
National Health and Medical Research Council
Funding Amount
$139,500.00
Summary
The small envelope protein of hepatitis B virus (HBsAg) can self-assemble into highly organised viruslike particles with about 150 HBsAg-proteins forming a virus-like particle (VLP). VLPs induce an effective immune response, mainly against the exposed major antigenic site, the hydrophilic ‘a’- determinant region. To create a novel HBsAg-specific vaccine vector, foreign epitopes were inserted into the major antigenic site allowing surface orientation of the inserted sequence. Pilot studies involv ....The small envelope protein of hepatitis B virus (HBsAg) can self-assemble into highly organised viruslike particles with about 150 HBsAg-proteins forming a virus-like particle (VLP). VLPs induce an effective immune response, mainly against the exposed major antigenic site, the hydrophilic ‘a’- determinant region. To create a novel HBsAg-specific vaccine vector, foreign epitopes were inserted into the major antigenic site allowing surface orientation of the inserted sequence. Pilot studies involving the vaccination of mice with VLPs containing an epitope derived from the AIDS-virus (human immunodeficiency virus 1, HIV-1) or various hepatitis C virus-specific epitopes resulted in high titre antibody responses. This project aims for the development of a multi-component vaccine targeting a non-structural HIV-1 protein and therefore, avoiding the selective pressure directed against the structural proteins. The non-structural HIV-1 tat-protein is a multi-functional protein with an extracellular mode to sensitise uninfected cells for HIV-1 infection and to reactivate HIV-1 from quiescently infected cells. The use of eight tat-sequences is sufficient to provide coverage against 99% of HIV-1 sequences. We will develop hybrid particles that are composed of different sets of chimeric HBsAg proteins each containing a distinct tat-epitope. With this application, we aim to develop hybrid particles for the delivery of the complete set of tat-epitopes. The hybrid particles will be used for vaccination studies in mice, and the antibodies assessed by an in-vitro assay. This will lead to the development of a therapeutic and-or prophylactic HIV-1 vaccine, which could be used either for mass immunisation or in support of combination drug therapy and would have all the cost and production advantages of the widely used hepatitis B vaccine.Read moreRead less
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.
Pre-clinical Development Of A Chemically Synthetic Anti-toxic Vaccine Against Malaria
Funder
National Health and Medical Research Council
Funding Amount
$165,000.00
Summary
Plasmodium falciparum malaria infects 5-10% of the global population (400 million clinical cases) and kills two million people annually1. As such it ranks along with HIV and TB as the most serious infectious disease of humanity. It is widely accepted that an efficacious vaccine is required to afford protection against malarial fatalities. The induction of broad-ranging sterilizing immunity is not considered a likely objective for anti-malarial vaccines. Instead, reduction in morbidity and mortal ....Plasmodium falciparum malaria infects 5-10% of the global population (400 million clinical cases) and kills two million people annually1. As such it ranks along with HIV and TB as the most serious infectious disease of humanity. It is widely accepted that an efficacious vaccine is required to afford protection against malarial fatalities. The induction of broad-ranging sterilizing immunity is not considered a likely objective for anti-malarial vaccines. Instead, reduction in morbidity and mortality is the realistic aim of malaria vaccine strategies. Traditional approaches seek to provide this clinical protection indirectly, by killing the parasite or by reducing parasite multiplication. To this end, current anti-malarial vaccines candidates seek to confer on the host parasiticidal immune mechanisms, which have as their target antigenic proteins expressed on the surface of the different stages of the parasite. No malaria vaccine is yet on the market. There exist several potentially competitive leads in late-stage pre-clinical-early stage clinical development, particularly recombinant proteins. The US Navy MUSTDO-25 DNA vaccines are not living up to their promise. Most leading “vaccine candidates” are polymorphic alleles. There are significant prospects for vaccine-induced selection of breakthrough variants. Multiple alleles may also prove cost-prohibitive for vaccine development. The novelty and uniqueness of this approach have contributed to the acceptance of this study for publication by Nature. The aims of this proposal are four-fold: i) to further rationalize the target through chemical synthesis of intermediates and partial structures; (ii) to examine antigenicity and immunogenicity in large experimental mammals, and undertake epitope mapping of human anti-GPI IgG responses; (iii) to obtain preliminary safety data in these animals; and (iv) to undertake a vaccine trial in a simian malaria model. We envisage objectives (i)-(iii) will take 12 months. Objective (iv) will proceed in the six months thereafter.Read moreRead less
A Novel Vaccine Platform For Trimeric Envelope Proteins: HIV-1 Envelope
Funder
National Health and Medical Research Council
Funding Amount
$139,250.00
Summary
Vaccines are urgently needed for the prevention of HIV/AIDS. The design of this vaccine candidate is based on the display of HIV-1 envelope spikes using a related primate retrovirus envelope with a more stable assembly to anchor the the spikes in a particle.
Phase 1 Clinical Trial Of Autologous Dendritic Cells To Induce Antigen-specific Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$165,125.00
Summary
We have previously generated modified dendritic cells in mice with the ability to suppress immune responses once they have started. This project will develop the dendritic cell vaccine as a platform technology for human clinical use. We aim to demonstrate, in a phase I clinical trial, the capacity of modified human autologous dendritic cells to suppress the immune response to a model antigen in a group of healthy volunteers and a group of patients with rheumatoid arthritis taking drugs for their ....We have previously generated modified dendritic cells in mice with the ability to suppress immune responses once they have started. This project will develop the dendritic cell vaccine as a platform technology for human clinical use. We aim to demonstrate, in a phase I clinical trial, the capacity of modified human autologous dendritic cells to suppress the immune response to a model antigen in a group of healthy volunteers and a group of patients with rheumatoid arthritis taking drugs for their diseaseRead moreRead less
Preclinical Studies Of Group A Streptococcal Vaccine Candidates
Funder
National Health and Medical Research Council
Funding Amount
$532,492.00
Summary
Group A streptococcus causes 520,000 deaths each year. A safe and effective vaccine is not commercially available. We have identified 2 new protective candidate antigens, and we seek to undertake critical preclinical studies to provide further proof-of-concept data. This work will underpin commercial decisions by our industry partner (Wyeth) leading to human trials and the development of a safe group A streptococcal vaccine for human use.
Development Of A Novel Mannan-based Avian Influenza Vaccine
Funder
National Health and Medical Research Council
Funding Amount
$195,566.00
Summary
We have a sugar (mannan) that can be used to increase immune responses. We have found that mannan decreases the dose of inactivated virus needed for intranasal immunization. We will investigate if dose sparing is seen when given intramuscularly. This method will be first tried with the human flu virus and if successful will be tried with the bird flu virus. If the preparation can protect mice and ferrets from human or bird flu infection it could develop into a human vaccine against bird flu.
RV3 Rotavirus Vaccine: Developing A Neonatal Rotavirus Vaccine Formulation For The Global Community
Funder
National Health and Medical Research Council
Funding Amount
$135,075.00
Summary
Rotavirus infection is the leading cause of severe dehydrating gastroenteritis responsible for approximately 600,000 deaths per year in children under 5 years of age worldwide. There is a commercial and public health opportunity to develop a new rotavirus vaccine that can be given at birth. By modifying the way the vaccine is made we hope that it will be more acceptable and easily delivered to children in remote communities and developing countries without the need for refrigeration.