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Centenary Institute - Medical Research
Centenary Institute - Medical Research

New method to assist fast-tracking of vaccines for pre-clinical tests

Scientists in Australia have developed a method for the rapid synthesis of safe vaccines, an approach that can be used to test vaccine strategies against novel pandemic pathogens such as SARS-CoV-2, the virus that causes COVID-19. 

Led by Professor Richard Payne at the University of Sydney and Professor Warwick Britton (pictured) at the Centenary Institute, the team has demonstrated application of the method with a new vaccine for use against tuberculosis (TB), which has generated a powerful protective immune response in mice. 

Researchers are keen to develop the vaccine strategy further to assist in the rapid pre-clinical testing of new vaccines, particularly for respiratory illnesses. 

“Tuberculosis infects 10 million and kills more than 1.4 million people every year,” said joint first author Dr Anneliese Ashhurst from the University of Sydney. “Historically, it is the leading cause of death worldwide from a single infectious agent. So far, a TB vaccine that is highly effective and safe to use in all populations has eluded medical science.” 

The only current vaccine for tuberculosis, the Bacille Calmette-Guerin vaccine, uses an injected live bacterium. It is effective in infants but has reduced effectiveness in adolescents and adults and poses significant health risks for immunocompromised patients, particularly for people living with HIV/AIDS. 

Protein-based vaccines have been shown to be very safe, but they must be mixed with enhancers, or adjuvants, to make them effective, which is not straightforward. 

Dr Ashhurst said: “The challenge is to ensure that our immune cells see both the protein and adjuvant simultaneously. To overcome this difficulty, for the first time we have developed a method that synthesises the protein with an attached adjuvant as a single molecule.” 

The vaccine strategy and synthetic technology could be deployed to rapidly generate new vaccines for pre-clinical testing for a range of diseases, the researchers say, including the respiratory pathogen that causes COVID-19. 

Their results are published today in the Proceedings of the National Academy of Sciences of the United States of America

HOW IT WORKS 

In order for vaccines to be effective, they need to stimulate behaviour in protective T-cells that allows them to recognise the pathogen as an antigen, or foreign body. In the case of tuberculosis, our immune system needs to respond quickly to the bacteria that causes TB – Mycobacterium tuberculosis – to reduce infection in lungs. 

Using the method developed by the Sydney scientists, an inhaled vaccine provides a low-dose immune-stimulating molecule – containing a synthesised bacterial protein attached directly to an adjuvant – to the immune cells in the lungs. 

A major hurdle overcome by the scientists was the difficulty in fusing hydrophobic (water-repellent) adjuvants with a water-soluble protein antigen. 

“We got around this problem of keeping hydrophobic and hydrophilic molecules together in a vaccine by developing a way to permanently bind the protein and adjuvant together as a single molecule using synthetic chemistry. Our approach overcomes the solubility problems faced by other methods,” said Professor Payne from the School of Chemistry and Deputy Director of the ARC Centre for Innovations in Peptide & Protein Science (CIPPS). 

The team says that synthesising an entire bacterial protein with attached adjuvant has not been achieved before. 

Professor Britton from the Tuberculosis Research Program at the Centenary Institute said: “As well as providing a rapid method to develop a range of vaccines for pre-clinical testing, we expect that this pulmonary vaccination approach will be particularly beneficial for protecting against respiratory diseases.” 

He said: “We hope that an inhaled vaccine for tuberculosis using a protein-based immunisation will allow us to develop a universal and safe approach to combatting this deadly disease.” 

The other major advantage with this method is that vaccines for a range of diseases can be developed rapidly and safely in the laboratory. 

“We don’t need to grow the actual pathogen in the lab to make the vaccine,” said Dr Ashhurst, who holds a joint position in the School of Chemistry and the School of Medical Sciences. “Using this new method, we can rapidly and safely synthesise highly pure vaccines in the lab and take them straight into animal models for pre-clinical testing.” 

Research paper: Synthetic protein conjugate vaccines provide protection against Mycobacterium tuberculosis in mice.

Read more about the Centenary Institute’s TB related medical research here.

Biomarker signature found for TB infection

A group of leading Australian researchers have uncovered a unique blood-based biomarker signature in individuals infected by tuberculosis (TB).

The presence of the biomarker signature, found through a simple blood test, allows individuals with infectious TB–including those with non-symptomatic early-stage disease–to be easily identified and treated.

The finding, reported in the Journal of Infection, could be key in supporting health efforts to control and eventually eliminate the TB epidemic which is responsible for approximately 1.5 million deaths each year globally.

“A major issue in controlling the spread of tuberculosis is the difficulty of detecting the disease quickly and effectively, particularly in developing countries and in remote areas where technology and testing facilities may be limited,” says lead author of the study, Dr Jennifer Ho from the Centenary Institute and the Woolcock Institute of Medical Research

“Sputum smear microscopy is the test used to diagnose TB in the majority of endemic settings but it is unable to pick-up TB in its early stages which prevents timely diagnosis and treatment.”

“Also problematical are individuals with latent TB who possess no physical sickness or symptoms,” she says. “Unaware they are infected, these individuals can become TB spreaders if their disease progresses at some point to an active state.”

Dr Ho notes that it is estimated that over 3.3 million cases of active TB are undetected annually, contributing to the uncontrolled spread of TB.

“Our biomarker discovery could be used as the basis for a highly effective and simple diagnostic blood test to help detect these prevalent cases of TB in the community,” she says.

Professor Warwick Britton, Head of the Centenary Institute’s Tuberculosis Research

Program and senior researcher on the project says that active TB case finding, including systematic screening of high risk groups, will be required to dramatically reduce TB incidence worldwide.

“Early case detection and appropriate treatment is absolutely critical to getting on top of this highly infectious disease,” he says. “Our research offers up an exciting new approach to help realise the ambition of global TB elimination.”

The research was a collaboration between scientists at the Centenary Institute, the Woolcock Institute of Medical Research, University of Sydney, UNSW Sydney and University of Technology Sydney.

Read the full media release here.

Influenza susceptibility linked to variable responses to interferons in the lung

Researchers at the Centenary Institute and the University of Sydney have discovered a key reason as to why the influenza virus is so effective at establishing infection and causing damage in the lungs.

They found that a group of lung-cells, following influenza infection, responded only poorly to interferons (the signalling proteins that help defend the body against viral attack). The research could pave the way for the development of new and improved anti-influenza drugs and vaccines, to both improve health and to save lives.

“Interferons are critically essential to our defence against pathogens including the influenza virus,” said Associate Professor Carl Feng (pictured), senior study author from the Centenary Institute and the University of Sydney. “The proteins are so named because they ‘interfere’ with the ability of viruses to multiply in the body.”

“It’s been known for a long time that during influenza, lung cells and immune cells in the lungs secrete interferons causing virus-infected cells to initiate anti-viral defences,” said Associate Professor Feng.

“However, how interferons actually undertake this protective activity is still not understood because the signalling proteins can act on hundreds of different types of cells in our body,” he said.

In their study, Associate Professor Feng and colleagues have generated a new tool to identify which cells respond to interferons in influenza infected mice. The goal was to work out whether the outcome of infection and interferon signalling differed between different cell types. What the researchers have demonstrated in the study is that not every cell type reacts equally to the interferons, even when they are in close proximity to each other.

“We were able to show that cells in influenza-infected mice reacted to interferons in dissimilar ways. Most notably, we found that one type of lung cell, the major target of the influenza virus, responded extremely poorly to interferons and were highly vulnerable to viral infection. This was particularly noticeable at the early-stage of the influenza infection cycle,” said Associate Professor Feng.

The research has the potential to lead to the development of new vaccination strategies and therapeutics that are more effective than the currently available anti-influenza drugs.

“Influenza remains among the most significant global infectious diseases owing to its high infectivity, the variable usefulness of current vaccines and the limitations of anti-viral therapy. It’s also a major health burden in Australia and globally,” said the Centenary Institute and University of Sydney’s Professor Warwick Britton, also an author of the study.

“A better understanding of how this virus infection is controlled by lung cells can help us to find medical solutions against influenza which results in millions of cases of severe illness and which is responsible for killing up to half a million people each and every year,” he says.

The investigators plan to study human lung-cells and their response to interferons and the influenza virus as a next-step of the research program.

Read the full media release here.

Read the publication in Cell Reports here.