Twenty two teams from the Doherty Institute, the University of Melbourne and the Royal Melbourne Hospital received a collective AU$17.4 million in Round One of the Foundation Grants for projects to develop novel therapeutics for pathogens of pandemic potential, in line with the Centre’s mission.
Lead investigators and co-investigators
Adam Wheatley
Accelerating the pipeline of antiviral biologics to strengthen pandemic preparedness
$1,500,000
Co-investigators: Professor Kanta Subbarao, Dr Danielle Anderson, Dr Jennifer Juno, Dr Nick Gheradin, Professor Florian Schmidt, Mr Ben Hughes, Dr Martina Jones, Dr Hyon-Xhi Tan, Professor Stephen Kent and Dr Claire L Gordon.
Pandemic viruses constitute an existential threat to the health and economic well being of communities. Antibodies and nanobodies have unmatched specificity for pathogen targets and a highly favourable safety profile for clinical development. Our project seeks to develop three new platforms to discover, optimise and validate the protective potential of human or humanised biologics as potent antiviral drugs for treatment or prevention of viral infectious diseases. In addition, we will establish a national repository to archive promising biologic agents and accelerate the pathway to clinical manufacture and human trials.
Annabell Bachem
Establishing programmed cell death inhibition as defence against pathogen infections
$600,000
Co-investigators: Dr Marcel Doerflinger, Professor Guillaume Lessene, Professor Marco Herold, Associate Professor Gemma Kelly, Professor Andreas Strasser and Professor Sammy Bedoui
Programmed cell death (PCD) provides the host with an essential mechanism to remove dispensable or unfavourable cells in a coordinated manner. This discovery has been harnessed for the development of FDA-approved inhibitors of PCD molecules for cancer treatments. Importantly, this type of cellular suicide also serves as an effective defence strategy to control intracellular pathogens that aim to repurpose host cells as replicative niche and to evade extracellular immune responses. This project will enhance our scientific knowledge about the different PCD pathways in infection and establish the role for PCD inhibitors for controlling pathogens with pandemic potential.
Ashraful Haque
Mapping the cellular interactome of the lung
$599,151
Co-investigators: Associate Professor Linda Wakim, Professor Scott Mueller, Dr Amanda Oliver and Dr Jan Schroeder
The lung is composed of many different cell-types, which interact with each other to facilitate respiration and protect against infection. Unfortunately, cellular interactions also cause severe symptoms after influenza infection or in COVID-19. To develop new therapies that prevent severe disease, we will map all the molecular and cellular interactions that occur in the lung after severe viral infection, not only amongst immune cells, but also between all other cell-types. To achieve this, we will use a new technique called Spatial Transcriptomics, which permits the study of thousands of genes used by each cell, as well as their specific location.
Ben Howden
Customisable Biotherapeutics Against Pandemic Pathogens
$600,000
Co-investigators: Dr Glen Carter, Dr Vanessa Marcelino, Associate Professor Linda Wakim, Professor Sammy Bedoui, Professor Lachlan Coin, Dr Kathy McCoy, Professor Timothy Stinear, Professor Kim-Ahn Le Cao, Dr Jan Schroeder and Dr Jenny Anderson
The gut microbiome, comprising trillions of microorganisms, controls lung immunity via the gut-lung axis. A robust gut-lung axis is vital for protection against respiratory pathogens, including SARS-CoV-2. Broad-spectrum antibiotics, commonly used during pandemics, disrupt this axis, increasing the risk of severe lung infections. Here, we will establish a biobank of diverse human microbiome species and leverage advanced multi-omics to characterize the isolates. Computational modelling and machine learning will identify microorganisms that modulate lung immunity and prevent infections. These beneficial microorganisms will serve as targeted therapeutics, restoring a healthy gut-lung axis, enhancing immunity, and providing tailored interventions against future pandemic pathogens.
Damian Purcell
Pandemic speed RNA therapeutics
$599,314
Co-investigators: Dr Julie McAuley, Dr Vincent Corbin, Dr Ashley Hirons and Professor Jason Mackenzie
The evolutionary plasticity of pandemic viral RNA genomes typically incorporates RNA-structures and RNA-processing pathways that are common across all strains within a viral family. Next generation mRNA-nanoparticle technologies can target the delivery of mRNA-coded virus-specific protein therapeutics such as antibody, viral-enzyme-activated toxins and cytokines, or direct RNA-disruption of riboswitches that disable the intricate steps of viral RNA-replication and gene-expression. This program will develop rapidly responsive RNA-coded therapeutics for an array of projects by increasing the focus and speed of preparing and testing a wide range of RNA-therapeutics, RNA-diagnostics, RNA-modified cell-substrates and animal models for use in testing relevant PC3 infections.
Daniel Utzschneider
Development of next-generation humanized mouse model platform to fast-track therapeutic discovery
$1,000,000
Co-investigators: Dr Roberta Mazzieri, Professor Sharon Lewin, Associate Professor Sophie Valkenburg, Professor Damien Purcell, Professor Natalio Garbi, Dr Julie McAuley, Professor Riccardo Dolcetti and Associate Professor Paul Beavis
Preclinical animal models are a powerful tool for the discovery, development and evaluation of effective therapeutics. However, remaining differences to the human immune system critically limit the use of animal models for a wide range of known or emerging human diseases. To close this gap between preclinical models and human studies, we propose to develop a sophisticated humanized mouse model platform to serve as a ‘plug and play’ technology that is widely accessible to foster collaboration. Ultimately, this innovative platform will form the foundation to remove the barriers to long-term innovation and fast-track the development and translation of novel therapeutics.
Danielle Anderson
Building the capacity to assess the efficacy of therapeutics capable of treating viruses with pandemic potential
$596,200
Co-investigators: Dr Julian Druce, Professor Kanta Subbarao, Dr Leon Caly, Dr Glenn Marsh, Professor Sharon Lewin, Dr Mohamed Fareh, Dr Yaw Shin Ooi and Dr Chee Wah Tan
The Cumming Global Centre for Pandemic Therapeutics (CGCPT) will develop new technologies to treat future pathogens of pandemic potential. Our objective is to establish in vitro and in vivo high containment capacity and capability to test therapeutics produced within the Centre. Towards this, we will evaluate two antiviral classes, CRISPR RNA therapeutics and a small molecule modulator. We will achieve this objective with two specific aims: Aim 1: Establish high containment capability to evaluate CRISPR antivirals for high consequence pathogens. Aim 2: Assess a small molecule modulator of proviral host factor Aryl hydrocarbon receptor using the xCELLigence platform.
Debnath Ghosal
A comprehensive structural (-cell) biology platform for rapid characterisation of any pathogen of pandemic potential
$1,500,000
Co-investigators: Professor Michael Parker, Professor Eric Hanssen, Dr Matthew Johnson and Dr Roxanne Smith
This application proposes the establishment of a high throughput structural (-cell) biology platform for rapid characterisation of any pathogen of pandemic potential at (sub) nanometre resolution. The platform will harbour a high throughput end-to-end workflow, including Focused Ion Beam (FIB) milling, Correlative Light and Electron Microscopy (CLEM) and cryo-electron tomography (Cryo-ET) to characterise high-resolution cell biology of any infection. In addition, the platform will also have capabilities to rapidly solve structures of relevant molecular machines at a near-atomic resolution to inform structure-guided drug design.
Frank Caruso
Development of novel nanoparticle platforms for pandemic therapeutics
$596,021
Co-investigators: Dr Robert De Rose, Dr Christina Cortez-Jugo and Dr Jingqu Chen
The COVID-19 pandemic saw an unprecedented response to develop novel drugs and repurpose existing drugs for infection prevention and treatment. Challenges to drug development include degradation, clearance, and limited availability at the target sites. Central to pandemic preparedness is the development of delivery platforms because without a delivery platform, there would be no mRNA vaccines. In this project, we propose to develop highly innovative and biocompatible nanoparticle platforms that can enable the encapsulation of diverse therapeutics, including small drugs, proteins, and nucleic acids and evaluate their capacity to be delivered via various administration routes, including inhalation to appropriate tissues.
Jessica Neil
Development of human and animal in vitro respiratory tract models for risk assessment of viruses with pandemic potential
$587,011
Co-investigators: Professor Kanta Subbarao, Dr Matthew Gartner, Dr Brad Gilbertson, Dr Saira Hussain, Dr Joseph Chen, Professor Jose Polo, Dr Daniel Tan and Professor Alastair Stewart
Respiratory viruses pose a significant risk to global health due to their ability to cause outbreaks on a global scale. To facilitate a rapid response to emerging virus threats, ready-to-deploy models are required to investigate mechanisms of viral entry, replication, host response and antiviral effectiveness. Here, we will establish five in-vitro systems representing the entire respiratory tract and determine their suitability for studying infection with several viruses with pandemic potential. These models will provide insights into the cellular and molecular responses elicited by respiratory viruses, allowing for a deeper understanding of disease mechanisms and the development of targeted therapeutic strategies.
Jose Villadangos
Host-Centric Therapeutics for the Prevention of Secondary Infections in Pandemic Patients
$1,000,000
Co-investigators: Dr Laura Cook, Associate Professor Adam Deane, Dr Julie McAuley and Professor Antoine Roquilly
The impact of pandemics depends on the number of patients requiring hospitalisation, the duration of hospitalisation, and disease severity (mortality and morbidity). If these factors remain low, the healthcare system can avoid collapse, which reduces requirements for quarantine measures and mobility restrictions. Pneumonia caused by secondary bacterial infections of the lungs is a major contributor to mortality and morbidity during Influenza and Coronavirus pandemics. Patients succumb to secondary pneumonia because the viral infection induces immune paralysis, resulting in reduced ability to fight bacteria. This project will develop therapeutics to prevent, reduce and shorten paralysis and secondary pneumonia in future pandemics.
Kanta Subbarao
Broad Spectrum Antiviral Drugs Targeting Coronavirus Replication in Human Lung Cells
$596,796
Co-investigators: Professor Jose Polo, Dr Sean Humphrey, Dr Jessica Neil and Dr Sarah Londrigan
There is a critical need for new drugs to treat coronavirus infections that are effective against COVID-19 as well as other coronaviruses that may emerge in the future. We have established an innovative drug discovery pipeline, where we identified new pathways and targets for COVID-19 that we will extend to include four other coronaviruses that infect humans and animals. The outcome of this research is the development of antiviral drugs that target critical interactions between coronaviruses and human lung cells. The innovation lies in the intersection of tissue engineering using stem cells, virology and molecular analysis for drug discovery.
Katherine Kedzierska
Defining key mediators of life-threatening disease across emerging and re-emerging viral infections, age groups and vulnerable populations.
$600,000
Co-investigators: Dr Oanh Nguyen, Dr Brendon Chua, Dr Louise Rowntree, Dr Carolien van de Sandt, Dr Lukasz Kedzierski, Dr Jan Schroeder and Dr Nichollas Scott
Although viral infections cause profound morbidity and mortality, it is still unclear why some individuals die while others recover. Over the last decade, we have been researching mechanisms underpinning severe and fatal disease following infection with newly-emerging and re-emerging viruses. Our proposal is based on strong novel data linking life-threatening disease with expression of host enzyme mediating free fatty acid production (oleoyl-ACP-hydrolase), and excessive immune hyperactivation in COVID-19, influenza, RSV and MVE. Here, we will define in-depth key druggable targets mediating life-threatening disease across viral infections, age groups and vulnerable populations to inform rational therapy designs against severe viral disease.
Kevin John Selva
Harnessing IgA as a therapeutic against respiratory viral infections
$600,000
Co-investigators: Associate Professor Amy Chung, Professor Stephen Kent, Dr Adam Wheatley and Dr Ryan Thwaites
The COVID-19 pandemic highlighted how immunoglobulin G (IgG) antibody-based therapies are susceptible to loss of activity against emerging viral variants and may even worsen clinical outcomes in severe patients. In contrast, immunoglobulin A (IgA) binds broadly to viral variants from both SARS-CoV-2 and influenza respectively and regulates immune responses during severe infection. Furthermore, unlike IgG, IgA dimers are transported to the mucosa providing localized protection. Here, we will identify the best viral targets for broad IgA activity against both SARS-CoV-2 and influenza, modify IgA’s structure to improve its stability and function, and finally develop delivery systems to boost mucosal protection.
Liz Vincan
Human Organoids: innovative, authentic models of infection
$600,000
Co-investigators: Associate Professor Kaylene Simpson, Dr Claire L Gordon, Dr Danielle E Anderson and Professor Lachlan Coin
Organoids are mini replicas of organs grown in a dish. They retain key characteristics and function of their tissue of origin and are consequently proving to be very accurate models of infection. The host cells are in a physiological state and the pathogen genome is preserved. Importantly, findings in authentic human organoid infection models translate directly to infection of humans. All the pathogens with pandemic potential listed by WHO are viruses. To respond to the next pandemic, we establish organoid models of the main organs targeted by viruses, ready to deploy to grow and identify the pathogen and develop therapeutics.
Marios Koutsakos
Evaluation of therapeutic Y against pathogen X using a deep mutational scanning platform
$599,994
Co-investigators: Dr Rubaiyea Farrukee, Dr Sebastian Duchene Garzon and Dr Sasha Pidot
Pathogens accumulate mutations that cause escape or resistance from therapeutics, limiting the clinical benefit of such treatments. Deep mutational scanning is a versatile platform technology that determines the impact of every possible mutation in a protein. This enables exploration and prediction of immune escape/resistance mutations from any therapeutic against any pathogen. We will integrate this platform technology in the preclinical assessment of various classes of therapeutics in order to predict the likelihood of a therapeutic being rendered ineffective as the target pathogen evolves. Theraupitcs, or variants of, with greater tolerance to pathogen evolution can then be selected for further development.
Ruby Farrukee
Harnessing the power of innate immunity using mRNA
$599,744
Co-investigators: Dr Stanislav Kan, Professor Patrick Reading, Dr Sarah Londrigan, Professor Peter Revill, Professor Jason Mackenzie and Professor Kanta Subbarao
As evidenced by the recent COVID-19 pandemic, there are limited treatment options following the emergence of a novel virus in the human population. Many antiviral drugs are currently being researched, but their use is often limited to targeting a specific virus or virus family. The goal of this project is to target host proteins which inhibit replication of multiple viruses using mRNA technology and therefore advance the development of novel broad-spectrum antivirals to combat the global health impact of respiratory viral infections.
Stanislav Kan
Development of potent lipid nanoparticles for mRNA delivery to the lung
$597,292
Co-investigators: Dr Mohamed Fareh, Professor Colin Pouton, Dr Robert De Rose and Professor Sharon Lewin
This project aims to develop powerful lipid nanoparticles (LNPs) for delivering messenger RNA (mRNA) to the lungs. LNPs are tiny protective shells that deliver a therapeutic mRNA to cells, and they played a crucial role in the success of COVID-19 vaccines. However, there is currently no effective LNP designed specifically for delivering mRNA to the lungs, where respiratory infections occur. These potent LNPs will be a versatile tool to deliver different types of mRNA to the lung offering a promising solution to enhance our preparedness and response to future outbreaks.
Thomas Fulford
Harnessing the antiviral properties of γδ T cells
$596,277
Co-investigators: Dr Brendon Chua, Dr Adam Uldrich, Professor Katherine Kedzierska and Professor Mike Rogers
The immune system has evolved many strategies to detect and eradicate disease causing agents such as viruses, however, many viruses counter this by evading detection. We have recently described the mechanism that one immune cell type, called gamma-delta T cells, use to identify cells infected with a broad range of diseases. We will leverage this knowledge to enhance the detection and removal of virally infected cells, using pandemic causing agents, influenza- and corona- viruses, as model diseases to investigate this anti-viral potential.
Vincent Corbin
Viral riboswitch structures as therapeutic targets
$300,000
Co-investigators: Professor Damien Purcell and Dr Ashley Hirons
RNA structure and natural chemical modification is a current field of significant scientific focus. New technology and recent advances in computational biology have for the first time recently allowed characterization of the RNA structurome in its cellular habitat, as well as the role played by structural heterogeneity. Identifying regions of viral RNA whose secondary structure is associated with pathogenicity can lead to exciting new RNA therapeutic.
Wei Zhao
Developing CRISPR Cas 13 antiviral therapeutics for respiratory pathogens of pandemic potential
$2,500,000
Co-investigators: Professor Sharon Lewin, Dr Mohamed Fareh, Dr Stanislav Kan, Dr Matthew McKay, Dr Robert De Rose, Professor Kanta Subbarao, Dr Bang Tran, Dr Rhiannon Werder, Dr Zhiwei Chen and Dr Danielle Anderson
We will develop a novel treatment targeting the genetic code of the virus, rather than targeting viral protein, for viruses of pandemic potential that can be transmitted by the respiratory route. We will use a gene editing tool called Cas13 that can be designed to only target viral genes and will deliver Cas13 using mRNA wrapped in a unique fat bubble that is selective for lung tissue. We will mainly focus on COVID-19 using both laboratory and animal models but will investigate if this approach can be used for viruses such as MERS, Measles and the deadly Nipah virus.
Wen Shi Lee
Optimisation of antibody Fc backbones for pathogen-agnostic pandemic therapeutics
$599,996
Co-investigators: Associate Professor Amy Chung, Dr Bruce Wines, Dr Adam Wheatley, Dr Danielle Anderson and Dr Glenn Marsh
An unprecedented number of antibody therapeutics were developed as antiviral drugs to prevent and treat COVID-19. However, viral escape has limited their clinical utility. Virus receptor decoys attached to antibody backbones are a potential antiviral therapeutic that could circumvent drug resistance. It is currently not known which antibody backbone is the most optimal for these therapeutics to prevent or treat infection. We propose a rational selection pipeline to define the most optimal antibody backbone for the prevention or treatment of a diverse range of viruses with pandemic potential, providing a blueprint for rapid antiviral development to combat future outbreaks.