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Centenary Institute - Medical Research

New study to investigate lung treatment for COVID-19

Dr Matt Johansen from the Centenary UTS Centre for Inflammation is the successful recipient of the Kenyon Foundation Inflammation Award for 2021. The Award, valued at $20,000, will support Dr Johansen’s study into the development of a potential new treatment for COVID-19 aimed at reducing excessive inflammation in the lungs.

“There’s an urgent need to identify effective therapies that can be used to treat COVID-19 and significantly reduce mortality. Excessive lung inflammation is often the cause of severe disease and death in COVID-19,” said Dr Johansen.

In his study, Dr Johansen will be targeting the NLRP3 inflammasome, a master regulator of inflammation which drives a cascade of downstream inflammatory processes in severely affected COVID-19 patients. A known inhibitor of the NLRP3 inflammasome–a molecule known as MCC950–will be investigated for its efficacy as a potential COVID-19 treatment.

“MCC950 has already been shown to mitigate lung inflammation associated with respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD),” said Dr Johansen.

“It’s also been shown to be highly effective in alleviating virally-driven inflammation in influenza, suggesting it may also be an effective treatment for COVID-19.”

Dr Johansen’s study will be carried out at the Centenary Institute’s high-containment PC3 facility, of which there are only four in Australia that are properly equipped to complete this form of specialised SARS-CoV-2 medical research.

“I am incredibly humbled to have been selected for this Award which will financially assist our efforts to identify the most effective therapies for COVID-19,” said Dr Johansen.

“As governmental funding becomes increasingly difficult to acquire, philanthropic support from organisations such as the Kenyon Foundation are a significant boost that can promote fundamental scientific research that benefits us all.”

David Kenyon, Trustee of the Kenyon Foundation said, “We’re thrilled to be able to support Dr Johansen’s research that could form the basis for new therapies for the treatment of COVID-19 that has the potential to change lives.”

SMH interviews Professor Chris Semsarian AM

Professor Chris Semsarian AM, Head of the Agnes Ginges Centre for Molecular Cardiology at the Centenary Institute and spokesperson for the Cardiac Society of Australia and New Zealand, has been interviewed by the Sydney Morning Herald (SMH) on his response to recent studies linking Pfizer’s COVID-19 vaccine with myocarditis, particularly in young men. In severe cases, myocarditis, inflammation of the heart muscle, can weaken the heart.

“Based on fairly limited studies with small numbers of patients, there is definitely a link between the Pfizer vaccine and myocarditis,” said Professor Semsarian.

“It is an association at this stage,” he said. “Causality needs to be proven with bigger numbers.”

“Regardless, there is a suspicion there is a link there.”

If it is proven the vaccine is causing the increased risk, Professor Semsarian said it was possible authorities would issue advice discouraging young males from receiving this particular vaccine.

“You might do something like avoid the second jab in young males, or use the AstraZeneca vaccine,” Professor Semsarian said.

“But everything in medicine is a balance of benefit and harm. In this situation, it is overwhelming the benefits of the vaccine’s protection from COVID-19 are much higher than the other scenario of not being vaccinated and getting severe life-threatening cardiac complications of COVID-19.”

Click here to view the full SMH news story online.

Further information about Professor Semsarian and the Agnes Ginges Centre for Molecular Cardiology at Centenary can be found here.

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MRFF grant to help fast-track Australian COVID-19 vaccine candidate

A collaborative project involving the University of Sydney, the Centenary Institute, the University of Technology Sydney and the Kirby Institute at UNSW Sydney, has received funding from the Medical Research Future Fund (MRFF) to continue work on the development of a unique, single-shot vaccine against COVID-19 variants of concern.

The MRFF grant, worth $1.6 million, will allow the research team to undertake late-stage pre-clinical assessment of their protein based vaccine candidate. The aim is to be able to fast-track the candidate for testing in human trials.

“We’ve developed a unique, single-shot vaccine that in pre-clinical testing elicits potent SARS-CoV-2 specific immunity,” said lead investigator on the project Professor Jamie Triccas from the Faculty of Medicine and Health and the Charles Perkins Centre at the University of Sydney, and also Centenary Institute affiliate.

“The vaccine is new and built on safe and well-characterised vaccine components that are cost effective to manufacture and don’t require ultra-cold chain storage.”

“In particular, we have partnered with ExcellGene to develop a highly effective form of the SARS-CoV-2 spike antigen in our vaccine, using technology that permits rapid scale up of antigen production. Antigens are the critical triggers that induce the immune response in the body.”

“Ensuring a diverse, rapid and global vaccine supply to combat emerging variants will be necessary to end the global COVID-19 pandemic,” said Professor Triccas.

Dr Claudio Counoupas, research scientist at the Centenary Institute and Chief Investigator on the project said that they had rapidly updated their vaccine candidate to incorporate the spike antigen from the B.1.351 (South African) variant of COVID-19.

“We’re hopeful that our vaccine may offer broader protection than first generation vaccines against emerging, highly transmissible SARS-CoV-2 variants. This is key as we’re already aware that the B.1.351 variant of COVID-19 is able to avoid both natural and vaccine-induced immunity,” said Dr Counoupas.

Professor Phil Hansbro, Director of the Centenary UTS Centre for Inflammation and also a Chief Investigator on the project noted that a key research focus would be to determine both efficacy and safety of the vaccine candidate.

“We will be determining the optimal formulation of the vaccine candidate for maximal immunity as well as assessing vaccine tolerability and safety levels.”

“We will also be looking at developing a suite of vaccines specifically targeting other emergent SARS-CoV-2 variants as they arise,” said Professor Hansbro.

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Pictured: Dr Claudio Counoupas (left) and Professor Jamie Triccas (right).

Enzyme may be reason why older people and men are more susceptible to COVID-19

A team of Australian researchers, including from the Centenary Institute, has shown in a new study that older people and men tend to have higher levels of the enzyme ACE2 on the cells of their lower lungs–and that this may be the reason for their increased risk from COVID-19.

“The ACE2 enzyme is the entry receptor for the SARS-CoV-2 virus. The spike of the virus binds to ACE2 on the surface of the cell which is a crucial step to the cell being infected,” said Professor Phil Hansbro, Director of the Centenary UTS Centre for Inflammation and co-author on the study.

“We found increased ACE2 expression occurring in older people and males which may explain their higher risk profiles for COVID-19,” he said.

“We also discovered lower ACE2 levels in people with asthma which may indicate why this population group appear to suffer less from severe coronavirus complications.”

The study was led by Professor Peter Wark from the Hunter Medical Research Institute and the University of Newcastle and was published in the journal ‘Respirology’.

Research paper: ACE2 expression is elevated in airway epithelial cells from older and male healthy individuals but reduced in asthma.

COMMENT: DPP9 enzyme deficit could be key to severe COVID-19 infection

The first study of human gene associations with severe COVID-19 has just been accepted for publication in the highly prestigious journal ‘Nature’.

In the study, led by Dr Kenneth Baillie at the University of Edinburgh, five genetic sequences associated with severe COVID-19 illness were found. The sequences are known to be involved with inflammation and the body’s defence mechanisms.

Professor Mark Gorrell, Head of the Centenary Institute’s Liver Enzymes in Metabolism and Inflammation Program, comments, “I’m particularly interested in this study because one of the proteins identified by this large UK consortium as being associated with severe COVID is an enzyme that we discovered and which we are continuing to investigate at the Centenary Institute, called dipeptidyl peptidase 9 or DPP9.”

“DPP9, an enzyme encoded by the DPP9 gene, has many functions including several related to immune responses and cell growth and cell movement. Potentially most significant to COVID-19, in which inflammation can get out of control, is that DPP9 restrains inflammation. So, we think that possibly a deficit in DPP9 may be exacerbating inflammation.”

Professor Gorrell says that his ongoing work with DPP9 and this Nature paper show that few people have a deficit in DPP9.

“This may be one of the reasons as to why many people experience no symptoms from the illness, while a small minority of others become critically ill.”

Professor Gorrell and his group first discovered the enzyme DPP9 in 1999.  

Human enzyme DPP4 does not enable COVID-19 infection

Research from the Centenary Institute has found that the human enzyme dipeptidyl peptidase (DPP4) does not bind to the spike protein of the SARS-CoV-2 virus and so cannot enable COVID-19 infection in our bodies.

DPP4, which is known to be the key receptor for the MERS-coronavirus (Middle East respiratory syndrome), had been identified as a potential binding target of the SARS-CoV-2 spike protein. The spike protein forms the spikes of the ‘crown’ after which coronaviruses are named. If DPP4 had been able to bind, it would have suggested an alternate port of entry for SARS-CoV-2 into human cells, thus exacerbating COVID-19.

“We already know that SARS-CoV-2 cell entry depends on the interaction between the virus’ spike and the human enzyme ACE2. We needed to find out if DPP4 was also acting as a gateway for COVID-19,” said senior author on the paper, Professor Mark Gorrell, Head of the Liver Enzymes in Metabolism and Inflammation Program at the Centenary Institute.

“Our findings however put to rest the suggestion that DPP4 could be a co-receptor or alternate receptor for SARS-CoV-2 entry. There was no binding detected between the two molecules in our study and so we can be reassured that ACE2 is the sole method for SARS infection.”

The publication, which is in pre-print, is accessible online: A Novel Purification Procedure for Active Recombinant Human DPP4 and the Inability of DPP4 to Bind SARS-CoV-2.

Further Information on the Centenary Institute’s coronavirus activity can be found here.

COVID-19 reinfection case raises questions

The first case of COVID-19 reinfection has been documented by scientists from Hong Kong  who report that a 33 year old man has been infected by two different strains of the virus. The second infection occurred more than four months after recovery from the first episode of the disease. The finding raises questions as to the duration of human immunity to the virus and may have implications for COVID-19 vaccines if immunity to the virus is short-lived.

Dr Mainthan Palendira, Head of the Human Viral and Cancer Immunology Laboratory at the Centenary Institute comments, “We should be careful in interpreting too much out of a single case of reinfection, however, it is the first lab-confirmed case of reinfection that we know of.”

“This case is interesting because the person had a mild infection the first time and remained asymptomatic the second time. The virus that caused the infection the second time appears to be different from the original virus. Interestingly there were no detectable antibody responses after the first infection, however, a boosting of antibody response was seen after the second infection.”

“I would look at the positive side of the story. He was asymptomatic and there was a boosting of his antibody responses. This tells us that immunity can be enhanced by reinfection and that could potentially mitigate the severity of the disease when we get it the second time. This is good news for vaccine development and this is what we would expect vaccines to do.”

Information on Dr Palendira and his research can be found here.

Further Information on the Centenary Institute’s coronavirus activity can be found here.

Pre-clinical models crucial for effective COVID-19 treatments

Centenary Institute researchers have outlined the crucial importance of diverse animal, cell and tissue model usage in the development of effective COVID-19 treatments and medications.

In a review publication published in the prestigious journal ‘Mucosal Immunology’, the paper authors noted that the scientific and clinical community was racing to define and develop effective preventions and treatments. However, that these efforts were being hampered by  competing interests, small scale programs and a lack of defined patient cohorts and defined readouts.

“What is needed now is head-to-head comparison of existing drugs, testing of safety including in the background of predisposing chronic diseases, and the development of new and targeted preventions and treatments,” said Professor Phil Hansbro, Director of the Centenary UTS Centre for Inflammation and senior author of the publication.

“This is most efficiently achieved using representative animal models of primary infection including in the background of chronic disease with validation of findings in primary human cells and tissues,” he said.

“Interrogation of representative models lets us define cause and effect and to explain mechanisms of pathogenesis that are then able to be confirmed and translated in human studies,” said Centenary Institute researcher Dr Matt Johansen, the review paper’s lead author.

The paper can be accessed here.

More information on the Centenary UTS Centre for Inflammation can be found here.

ABC News article features Professor Mathew Vadas

The Centenary Institute’s Executive Director, Professor Mathew Vadas, together with other leading Australian researchers, have featured in a recent ABC News article, explaining that COVID-19 appears to be far more than just a respiratory disease.

The article notes that the SARS-CoV-2 virus, in severe cases, has been shown to invade blood vessels both in the lungs, and in other parts of the body as well as to cause cardiovascular complications.

“At this stage of knowledge I think we can say that [COVID-19] is also a vascular disease because the virus has been demonstrated to be in these linings of blood vessel cells, and has been demonstrated to cause damage there,” Professor Vadas says.

Fully understanding the properties of the SARS-CoV-2 virus is critical to developing new treatments as well as for potentially repurposing existing therapeutics.

Read the full ABC News story here.

Find out more about the COVID-19 research projects being undertaken at the Centenary Institute here.

10 News features COVID-19 vaccine project

A collaborative project between the University of Sydney and the Centenary Institute to find a COVID-19 vaccine has been featured on 10 News.

The innovative research, focused on using the tuberculosis vaccine Bacille Calmette-Guérin (BCG) together with major components of the SARS-CoV-2 virus has seen promising early results in pre-clinical testing.

Lead investigator of the project Professor Jamie Triccas from the University of Sydney was interviewed for the story as was project co-lead Dr Claudio Counoupas, research scientist at the Centenary Institute.

View the 10 News story here.

Read more about the COVID-19 vaccine project here.