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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.

Pathway to eliminating antibiotic-resistant tuberculosis in the Pacific

Australian researchers, including from the Centenary Institute have been awarded funding for a major project that aims to eliminate both active and latent tuberculosis (TB) found on Kiribati, an island nation in the central Pacific Ocean. The project will also support multidrug-resistant TB control education and management through the Pacific region.

Led by Professor Barend Marais of the University of Sydney, Professor Warwick Britton AO, Head of the Centenary Institute’s Tuberculosis Research Program will be a Chief Investigator (CIB) on the project with colleagues from the NHMRC Centre of Research Excellence in Tuberculosis Control.

“A TB hotspot, Kiribati has extremely high rates of tuberculosis. The capital Tarawa, one of the most densely populated areas in the Pacific, has a TB incidence rate among the highest in the world,” said Professor Britton.

“Our project will ensure that every person over the age of 2 will be screened for TB disease or infection in Tarawa with appropriate treatment strategies then implemented. Our integrated project will also provide a pathway towards drug resistant TB prevention and TB elimination  more broadly within the Pacific, through a program of training and mentoring.”

“Overall, this program will be a catalyst in regional TB elimination efforts, helping save lives and overcoming a disease which has devastating impact on communities,” he said.

The Federal Government’s announcement regarding the project funding can be accessed online.

TB is a leading cause of death globally responsible for approximately 1.5 million deaths annually.

Read more about Professor Britton and his research here.

Image Credit: Vladimir Lysenko. https://commons.wikimedia.org/w/index.php?curid=39278217

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.

Australian trial halves TB

Annual community-wide screening for tuberculosis almost halves the number of cases of the deadly disease, a four-year study by Australian and Vietnamese researchers has found.

Globally significant findings from the Woolcock Institute of Medical Research, in close collaboration with the Centenary Institute in Sydney and the National Lung Hospital in Vietnam, shows a pathway towards the eventual elimination of this global scourge.

The study, involving 100,000 people in Vietnam, found community-wide active case finding was 44 per cent more effective than standard passive case detection alone in reducing the prevalence of tuberculosis in the general population. Importantly, the active case finding intervention halved rates of TB infection among school-aged children.

“Our findings show that, with existing tests and treatments used in innovative ways, we can achieve the sort of impact on TB that makes it possible to consider the elimination of this dreadful disease,” says study leader, Woolcock epidemiologist and respiratory physician Professor Guy Marks. “Community-wide screening can interrupt the cycle of active disease and infection that perpetuates the deadly tuberculosis epidemic.“

Professor Warwick Britton, Centenary Institute’s Head of Tuberculosis Research Program said, “Tuberculosis takes a huge toll in human suffering and economic impact on communities worldwide. The important findings from this study demonstrate the effectiveness of a new approach to tuberculosis control. It highlights the value of collaboration between our Vietnamese colleagues and researchers in the Woolcock and Centenary Institutes.”

Read the full media release from the Woolcock Institute here: https://woolcock.org.au/news-4/australian-trial-halves-tb-study

The paper, ‘Community-wide Screening for Tuberculosis in a High-Prevalence Setting’, can be viewed online at the New England Journal of Medicine: https://www.nejm.org/doi/full/10.1056/NEJMoa1902129

‘The Wire’ radio interview: New tuberculosis vaccine in the works

Dr Anneliese Ashhurst from the Centenary Institute and the University of Sydney has talked about her exciting work on a new tuberculosis vaccine on the radio program ‘The Wire.

“Tuberculosis is a huge world-wide health problem. It’s caused by a bacteria that infects the lungs, is contagious and results in approximately 1.6 million deaths per year globally,” says Dr Ashhurst.

An early-stage synthetic vaccine which has been developed by Dr Ashhurst and a team of scientists has demonstrated its effectiveness in pre-clinical trials. Next steps will be to determine if the vaccine can be developed into a form suitable for use in humans.

Check out the interview here.