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Examples of how research funded by ACH4 has promoted the
translation of research outcomes.
Descriptions of translated research have been
provided by selected researchers and are shown below.
mRNA VACCINES FOR HCV
CI Heidi Drummer
Burnet Institute, 2022
Burnet Institute’s has recently been awarded a grant of over AUD$3 million from the Victorian Government’s mRNA Victoria Activation Program to accelerate the development of next generation mRNA vaccines. The Burnet is a targeting its lead vaccine candidates for viruses such as hepatitis C through pre-clinical validation to first trials in humans in collaboration with mRNA vaccine pioneers, Moderna.The new funding allows the expansion of the program in collaboration with the Monash Institute for Pharmaceutical Sciences (MIPS). Professors Heidi Drummer and Dr Andy Poumbourios, have been able to advance their HCV mRNA vaccine through the support of ACH2, this year and in the past.
Evaluation of Enfuvirtide-loaded Nanoparticles for Oral Administration – New Treatment Option for HIV/AIDS
CI Felicity Han
University of Queensland, 2022
CI Felicity Han, Enfuvirtide (also known as T-20) is an U.S. Food and Drug Administration (FDA) approved inhibitor of HIV-1 fusion that blocks infection. However so far, no oral T-20 formulation is available, which hinders its wider application. To address this, the research team has developed several types of biodegradable oral formulations. Relatively high T20 loading efficiency of 67.4% and 99.9% were achieved with particle sizes 100 to 800 nm. Two formulations of poly(lactic-co-glycolic acid) (PLGA) nanoparticles & alginate microcapsules show promising release profile.The promising in vitro results from the current project and success in the upcoming ACH4 project will lead to a preclinical study for treatment of HIV. To enable this, we would approach NHMRC development, or MRFF Accelerator Grants for further funding.
Utility of a rapid point of care ALT1 test to monitor disease progression and treatment eligibility in people living with hepatitis B
CI Jessica Howell
Burnet Institute, 2020
Antiviral therapy for chronic hepatitis B virus is highly effective, but treatment is only recommended for patients with indications of active liver damage and/or very high levels of virus replication, and David Anderson and colleagues at the Burnet Institute and Burnet spinoff company, Nanjing BioPoint Diagnostics, China, had recently developed a point-of care (POC) test for alanine aminotransferase (ALT1) to address this need. Validation studies on archival samples from Australian patients, supported by ACH4, showed that the ALT1 POC test has exciting potential to expand access to affordable liver disease screening and monitoring in low resource and remote settings.Development of dual specific CAR T cell therapy after Interferon alpha pretreatment to eliminate the latent HIV-CD4 T cell reservoir
CI Tony Cunningham
The University of Sydney, 2022
This project focusses on developing a combination therapy using IFNa pre-treatment with immunotherapy using CD8 + CAR T cells, as a novel “Shock and Kill” approach, to markedly reduce the size of the latent HIV T cell reservoir, the barrier to complete cure of HIV infected patients. The researchers have engineered CD8+ single CAR T cells with two different broad neutralising monoclonal antibodies (bNabs), recognizing different epitopes of HIV gp120, to effectively target these HIV infected, IFN-pre-treated memory CD4 T cells. Currently they are completing their development as ‘dual’ CAR T cells, containing both bNabs in the one CAR, by two comparative methods, Tandem (Tan) and dual CAR T cells.To expedite the transfer of this strategy to an in vivo model system of HIV latency with AI Pellegrini we are currently determining the optimal type, dose and kinetics of IFNa treatment for HIV reactivation. Then they will combine optimized interferon alpha pre-treatment with the optimised CAR T cells for killing of the reactivated HIV expressing memory T cells in this model. To test whether specific targeting of these cells to the main site of HIV latency, the Lymph Node, enhances this activity, we will introduce the lymph node homing protein CXCR5 into the CAR T cells.
Ultimately, after further grant funding or investment the researchers will then adapt all processes to GMP compliance and plan for phase 1 trials to demonstrate efficacy.
Performance of the pre-diagnostic pilot ELISA assay for capsid-antibody-complex in HBV mono-infection and HIV/HBV co-infection
CI Xiaonan Zhang
University of Canberra, 2022
The current project aims at establishing a novel assay for detection of Capsid-Antibody Complexes (CACs) and characterise its general feature in chronic HBV infection. Development of novel biomarkers for chronic hepatitis B has always been an area of intensive clinical and commercial interest. For example, serum HBV RNA and HBcrAg have been proposed to be surrogate markers for cccDNA and predictors for functional cure. Nevertheless, their clinical benefits are still under debate. On the other hand, assessment of intrahepatic inflammation and fibrosis in chronic hepatitis B is also a central issue in the decision to initiate antiviral therapy.Serum alanine aminotransferase is the most widely used surrogate marker in evaluating liver damage, however multiple studies indicated its limited value in revealing intrahepatic inflammation. Our preliminary data showed promise in utilizing CACs as a complementary marker particularly when ALT level is within upper-limit-of-normal. If further evidence supported this claim, the CACs assay would be an attractive alternative for non-invasive analysis of liver injury in CHB. The translational potential of this assay has become evident as the data collected so far showed a sensitivity superior to the commonly used serum alanine aminotransferase in revealing intrahepatic inflammation. We are doing preparation work for application of intellectual property on this assay. Meanwhile, we are actively looking for partnerships who can provide further support for development of commercial assay which will be translated it into clinical practice.
Plasma collection/drying device to facilitate HIV viral load testing for patients in remote settings
CI David Anderson
Burnet Institute, 2013
Almost all countries now have a policy of “treat all” for HIV, with provision of antiviral treatment for all patients. However proper management of HIV requires regular (at least annual) testing of viral load (HIV-VL) to ensure the treatment is working to suppress the virus. In remote and regional settings where fresh blood cannot be sent to the lab for HIV-VL testing, dried blood spots (DBS) are commonly used for this purpose, but DBS gives false results indicating treatment failure in around 50% of patients using some lab tests. David Anderson and Berhan Haile at the Burnet Institute (in collaboration with Bill Heath at Axxin Ltd, Melbourne) developed a novel device for separation of whole blood and drying of the plasma at point of care. The device was subsequently manufactured under license by Burnet spinoff company Nanjing BioPoint Diagnostics, China as “VL-Plasma”, and achieved CE Mark for use in HIV VL testing in 2020Pre-clinical validation of CRISPR-Cas13 as a new therapeutic approach targeting hepatitis B virus RNA
CI Margaret Littlejohn
Doherty Institute, 2022
The research team are developing a new potential treatment for chronic hepatitis B disease using CRISPR-Cas13 technology, which they have shown is highly effective at reducing hepatitis B virus (HBV) replication in laboratory cell culture models. In this study they are evaluating this therapy using a validated pre-clinical mouse model. This proposal will pave the way for clinical studies that may lead to CRISPR-Cas13’s use as a new HBV therapy, benefiting all who currently live with chronic HBV infection.The team are the leading group worldwide in developing this technology as a novel HBV therapeutic and the first to use LNP technology to deliver our technology directly to the liver. Provisional patent protection has been filed.
Grants through ACH2 have funded a project titled Phase II of Laboratory-Based Platforms To Manage Patients Who Develop Antiviral Drug-Resistance To Direct-Acting Antiviral Agents (DAAs)
CI Michael Beard
University of Adelaide
Direct acting antiviral agents (DAAs) targeted against the HCV NS3/4A, NS5A and NS5B viral proteins are emerging to combat chronic hepatitis C. The first to the clinic will be the NS3/4A protease inhibitors however the ability of HCV to mutate to high levels means that resistant will rapidly emerge. We have developed laboratory based assays that allows for tracking of the emergence of these resistance mutations during therapy, to determine their effect on viral replication develop a clinically useful data-base-derived clinical management algorithm in order to predict the next and appropriate therapeutic option. The ultimate outcome of this platform will be optimised patient care for persons with chronic hepatitis C.Refinement of HTLV-1 POC for Remote Settings
CI Belinda de Villiers
Griffith University, 2022
In order to address the need for easy to use, rapid HTLV-1 point-of-care testing suitable for use in the remote Australian outback regions, we are developing diagnostic assays that utilize CRISPR cas technology. Our optimised assays will be IP protectable and will see a translation of bench-based research into a utlisable, portable diagnostic tool. Future collaboration with research engineers will see the development of upstream sample processing technologies as well as mobile handheld electronic readers. Both of these future directions are contingent to sourcing of funding.We use ACH2 funding to develop a reliable vaccination regimen of dairy cows with HIV-1 Env oligomers that produces high titers of anti-HIV neutralising antibodies (NAb) in bovine colostrum
CI Damian Purcell
The University of Melbourne
We have performed an early proof-of-principle study that shows that the colostrum NAb from these vaccinated cows is able to prevent infection by diverse strains of HIV-1 in vitro. Bovine colostrum Ab product is considered safe when taken orally, and has favourable properties for use when formulated into a topical microbicide for vaginal or rectal use. Hyperimmune colostrum represents an inexpensive source of very large quantities of HIV-NAbs, and uses established dairy manufacturing protocols that are potentially transferrable to developing countries. Vaccinating cows with HIV Env gp140 avoids the problem of HIV mimicry of human self-antigens and therefore viral avoidance of Ab responses due to self-tolerance mechanisms. This process is a commercially viable production process yielding a polyclonal NAb product that can inactivate HIV. Partners, Immuron Ltd, and The University of Melbourne patented the intellectual property for this technology. The intellectual property was vested in a new start up company, Reef Pharmaceuticals, that has taken the patent protection to the national phase. Reef Pharma has strong links to the technology, production and processing partnerships required to move this product to a human marketQuantitative determination of CD4+ T-cells at point of care
CI David Anderson
Burnet Institute, 2010
Measurement of CD4+ T-cell levels continues to be an essential tool in management of HIV infection, especially in newly diagnosed HIV. ACH2 provided critical funding in Burnet’s development of a prototype lateral-flow, point-of-care (POC) test to measure CD4+ T-cells, subsequently manufactured under license by Omega Diagnostics, UK as “VisitectTM CD4” and “VisitectTM CD4 Advanced Disease”, with both tests achieving CE Mark and the Advanced Disease test now recognised with WHO Prequalification and included in the WHO Essential Diagnostics List. The VisitectTM CD4 POC test is now available in more than 70 countries worldwide, with major implementation programmes in 7 countries supported by UNITAID and the Clinton Health Access InitiativeA novel gel for targeting vaginal inflammation to prevent HIV transmission
CI Gilda Tachedjian
Burnet Institute, 2022
A major biological mechanism increasing the risk of women acquiring HIV from their male partners issubclinical genital inflammation due to the presence of diverse ‘harmful’ (dysbiotic) vaginal microbiota depleted of beneficial lactobacillus species.Bacterial vaginosis is the most clinical manifestation of a dysbiotic vaginal microbiome affecting 30% of women of reproductive age globally. Prof Tachedjian and colleagues have discovered that lactic acid (LA), a metabolite produced by protective vaginal lactobacilli, has direct anti-inflammatory properties on cervicovaginal epithelial cells that could protect against HIV (US patent granted).
LA also kills harmful vaginal bacteria but not lactobacilli indicating that it could shift a harmful vaginal microbiota towards being dominated by bacteria that protect against HIV. In 2023 Prof Tachedjian and colleagues were awarded a Victorian Medical Research Acceleration Fund Tier 2 grant to accelerate the preclinical evaluation of custom-made lactic acid containing vaginal gels in an animal and human 3D vaginal tissue models to advance optimal gels to test the activity of lactic acid in women with bacterial vaginosis.
This work is critical for advancing LA as a drug for preventing HIV and other STIs. This program of work has been supported by ACH2/ACH4 as well as NHMRC and has attracted translational funding from the MRFF and the Campbell Foundation for HIV/AIDS research (USA).
Grants through ACH2 have funded a high throughput screening (HTS) campaign against the Hepatitis C Virus (HCV) RNA polymerase
CI Peter White
University of New South Wales
The HCV RNA dependent RNA polymerase (RdRp) plays a key role in HCV replication and humans harbor non analogue; it is therefore an ideal drug target. There is an extremely active hunt for new polymerase inhibitors as none have yet reached phase III clinical trials. Our HTS has revealed four compounds with potent anti-viral activity, further work continues as we currently test derivatives of these primary hits a potential antivirals for HCV