The COVID-19 pandemic initiated an unprecedented global research effort. At Garvan, we responded immediately: by driving or collaborating on projects locally and globally to develop new ways to treat and prevent infection. And to learn more about virus strains, and inform global treatment strategies.
As there are no guarantees on which treatment or vaccine will prove most effective, researchers must take as many approaches as possible.
Garvan’s excellence in antibody research, immunology, cellular genomics and whole genome sequencing is well positioned to contribute valuably to the global research effort. We use cutting-edge technology and genomics research to drive innovative projects, with a focus on improving outcomes for patients.
Key areas of investigation
Tracing coronavirus evolution
Thanks to cutting-edge ‘Nanopore’ genome sequencing technology, researchers at the Garvan Institute of Medical Research and the Kirby Institute at UNSW Sydney have developed the most rapid coronavirus genome sequencing strategy in Australia to date. The technological advance has the potential to provide critical, timely clues on how cases of SARS-CoV-2 infection are linked.
“When a new ‘mystery’ coronavirus case is identified, every minute counts. At Garvan, we have repurposed our genomic sequencing capabilities to enable a rapid analysis of a coronavirus genome in just a few hours,” says senior author Dr Ira Deveson, Head of the Genomic Technologies Group at Garvan’s Kinghorn Centre for Clinical Genomics.
The coronavirus may be microscopic, but it consists of approximately 30,000 genetic ‘letters’, otherwise known as nucleotides. These accumulate mistakes over time as the virus continues to replicate, resulting in genetic variation. By constructing a ‘family tree’ for coronavirus, which shows how different variants of the virus are related, our researchers aim to help pinpoint the origin of new infections and study how the virus spreads through the community.
In collaboration with researchers at the UNSW Kirby Institute, the Garvan team has already begun analysing the genetic material of virus samples from patients with COVID-19. The researchers have fine-tuned the protocols for cutting-edge Oxford Nanopore Technologies to sequence SARS-CoV-2 in less than four hours. Garvan’s Kinghorn Centre for Clinical Genomics is the first facility in Australia to establish and apply this Nanopore technology for genomic surveillance of SARS-CoV-2.
The researchers’ work will contribute to an international network of COVID-19 surveillance.
In addition, the researchers are developing an assay to agnostically detect other known human respiratory viruses, including influenza, which could provide invaluable co-infection data for individual patients – critical for the healthcare system in the lead-up to Australia’s flu season.
Genome sequencing of coronavirus may also allow researchers to identify any emerging coronavirus sub-strains that could be more or less infectious than current strains. There is also the potential to reveal patients with abnormally high transmission rates, and uncover how the virus responds to new treatments or vaccines.
Engineering antibodies for COVID-19 protection and therapy
A research team led by Professor Daniel Christ is developing antibodies designed to target surface proteins of SARS-CoV-2, the novel coronavirus that causes COVID-19, which the virus needs to infect human cells. The potential antiviral therapy could be particularly suited to at-risk individuals, including the elderly and chronically ill patients, and could be administered as a preventative therapy to health workers on the frontline.
“Our expertise and track record in antibody therapeutics position us perfectly to develop therapeutic antibodies for COVID-19. Through Garvan’s Centre for Targeted Therapy, we are mobilising the institute’s capability to move on an urgent therapy for at-risk individuals,” says Professor Christ, who heads the Centre for Targeted Therapy at the Garvan Institute.
Antibodies are part of a healthy human immune system – we naturally produce them in response to a vaccine or an infection, to recognise and neutralise pathogens such as viruses in our body. However, those with compromised immune systems, older individuals and chronically ill patients, may not produce enough antibodies to the virus in time to recover. They are also at risk of failing to mount robust immune responses after vaccination, even after a vaccine becomes available.
The Garvan-led team is working to develop monoclonal antibodies to COVID-19, which could be produced in laboratories and injected monthly as an antiviral treatment to provide patients with ‘passive immunity’. Such antibodies would achieve the end-result of the body’s natural defences and target the coronavirus, preventing it from infecting cells.
Professor Christ, together with Garvan’s Executive Director Professor Chris Goodnow and the UNSW Kirby Institute’s Director Professor Tony Kelleher, has assembled a research team to rapidly develop monoclonal antibodies for COVID-19 and to test if these are safe and effective in people.
The researchers will leverage research on antibodies developed for SARS, following the 2003 outbreak. These antibodies target the spike protein, the part of the virus that acts as a first point of contact with human cells, and which is necessary to infect individuals.
The Garvan-led researchers have already identified a lead antibody that targets the spike protein of COVID-19 and aim to develop this and others for use in therapy. The team will employ in-house expertise at Garvan to engineer antibodies, and will work with collaborators at the UNSW Kirby Institute to validate leads and progress these antibodies into clinical trials. The engineered antibodies, once validated in clinical trials, will be administered to patients with an acute infection, or as a preventative treatment to at-risk individuals.
Searching for genes key to COVID-19 protection
Researchers led by Professor Stuart Tangye are undertaking crucial research to determine the genetic basis of severe COVID-19.
Professor Tangye and his colleagues are using whole genome sequencing to identify variants that could predispose healthy individuals to severe COVID-19.
The team is also assessing the immune responses of individuals with inborn immune conditions who were infected with SARS-CoV-2, and will test how well they respond to the different coronavirus vaccines, to determine whether they may be at risk of future infection.
“Every person’s immune system is unique, just like their DNA. We already know of hundreds of gene variants that can change how individuals respond to different pathogens – whether they are highly susceptible or even resistant to infection. Through our research, we hope to seek out such variants in those patients who develop severe COVID-19,” says Professor Stuart Tangye.
In collaboration with major Sydney hospitals and the UNSW Kirby Institute, the researchers are analysing the DNA of children and adults who were diagnosed with SARS-CoV-2 infection and developed severe symptoms, despite not having any pre-existing health conditions. In experimental models, the team is then further investigating candidate gene variants and their impact on immune cell function.
While these gene variants may only explain a fraction of the severe symptoms, the researchers hope they will uncover genes and immune pathways that are critical for a good immune response to prevent COVID-19.
The approach may point to new therapeutic targets for COVID-19 or could uncover existing medication that may help protect individuals against coronavirus infection.
The project is part of the COVID Human Genetic Effort, a global research consortium working to discover genetic variants that impact the host response following exposure to and infection with SARS-CoV-2, and of which Professor Tangye heads the Oceania node.
Professor Tangye has over 25 years’ experience in immune and inflammatory diseases. As part of his work leading the Clinical Immunogenomics Research Consortium Australasia (CIRCA) program, his team has established robust protocols to investigate how gene variants impact immune cell function. The work of this program has already substantially improved outcomes of patients with rare immune diseases.
Generous seed funding from UNSW Sydney has enabled this project to commence. Additional funding will enable scaling up of the project and protect more people from coronavirus infection.
Other Garvan researchers involved in this project are Professor Chris Goodnow, Associate Professor Joseph Powell, Associate Professor Elissa Deenick, Associate Professor Daniel MacArthur, Associate Tri Phan, Associate Professor Sarah Kummerfeld, Associate Professor Alex Swarbrick and Ms Mary-Anne Young.
Visualising the 3D shape of SARS-CoV-2 viral proteins
Developing new precision treatments for COVID-19 requires a detailed understanding of the SARS-CoV-2 virus.
An international team led by Professor Sean O’Donoghue from the Garvan Institute and CSIRO’s Data61 has developed a computational resource that allows scientists to visualise the 3D shape of the viral proteins of SARS-CoV-2 and could help identify how the virus might best be targeted.
By systematically comparing the SARS-CoV-2 viral genome with existing databases, the team constructed an online COVID-19 resource that consists of almost one thousand detailed, 3D models, and which captures many different states of the proteins that make up the SARS-CoV-2 virus. The researchers added the protein models to their online platform Aquaria, where they can be visualised with tens of thousands of different protein features. Integrating SARS-CoV-2 protein models through this method can help scientists rapidly gain insights into the molecular mechanisms underlying COVID-19 infection.
The new resource pieces together the most detailed picture of SARS-CoV-2 proteins to date. It will be used by researchers to help investigate how the virus interacts with human proteins, inform lab experiments and aid in the development of treatments.
“We think this resource will be a useful contribution to COVID-19 research, and has already revealed some novel insights into potential infection mechanisms,” says Professor O’Donoghue. “These insights may help identify new targets for therapeutic interventions, including vaccines.”
Professor O’Donoghue launched the online resource at the International Society for Computational Biology’s annual conference on 17 July 2020.
Investigating genes linked to severe COVID-19 in immune cells
A team led by Associate Professor Joseph Powell is leading a global effort to uncover how the genetics of different immune cells determines susceptibility, severity and outcomes of COVID-19.
The researchers are analysing the data generated by the COVID-19 Host Genetics Initiative – a worldwide collaboration aimed at identifying the genetic basis for the immune system’s response to COVID-19. With worldwide cases of COVID-19 on the rise, the number of patient samples is growing daily.
The Garvan researchers are using sophisticated statistical methods at the Garvan-Weizmann Centre for Cellular Genomics to analyse the genetic variation associated with severity of COVID-19 symptoms, through data made available by the Host Genetics Initiative.
The researchers have identified a list of candidate genes that are likely to have an effect on how an individual’s immune system responds to SARS-CoV-2 infection. They are now investigating how the genetic variation changes immune cell function in the lab.
For their research, Associate Professor Powell’s team is leveraging existing genomic data available through OneK1K, a pioneering study investigating the genetic data of single cells from 1000 healthy individuals, which has provided a ‘snapshot’ of a healthy immune system, and how our genetics control the immune system.
“We’re hoping to identify different copies of genes that can predict how the immune system responds to COVID-19,” says Associate Professor Powell. “If we can predict whether an individual is likely to have mild or severe symptoms, we can possibly stratify patients to the best therapeutic strategies.”
The team’s approach may guide the targeting of existing or new therapeutic targets to prevent people with COVID-19 infections from progressing to severe disease requiring intensive care.
COVID-19 symptoms and links with genetics and chronic disease
A team led by Associate Professor Sarah Kummerfeld are developing a method for investigating COVID-19 in Australians currently enrolled in genomic studies.
The research aims to identify groups of people with mild COVID-19 symptoms, and genetic variation linked to COVID-19 severity, which may provide crucial insights into the underlying causes behind severe symptoms. A further goal of the research is to determine impacts of chronic disease co-morbidities on COVID-19 patients.
This opt-in study aims to recruit individuals that are part of existing research programs, such as the Sax Institute’s 45 and Up study, which has enrolled over 80,000 older Australians, more than one thousand of whom have had their genome sequenced as part of the Medical Genome Reference Bank program. Through an online questionnaire, the researchers will collect basic information on symptoms, potential exposure, and whether they have been diagnosed with COVID-19.
The Garvan team are collaborating with researchers in the US and UK to enable international comparisons of COVID19 presentation and spread.