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26 April 2023

Tuberculosis (TB) claimed 1.6 million lives globally in 2021 and drug-resistant strains are increasing. The current TB vaccine, Bacille Calmette–Guérin (BCG), was introduced over a century ago (in 1921). It is still universally used to prevent TB in children, but protection wanes in adolescence and leaves adults vulnerable to contracting the disease – and transmitting it to others. The need to develop a new vaccine that provides greater immunity is imperative.

A James Cook University (JCU) research team has produced a new tuberculosis (TB) vaccine contender – one of six candidates world-wide shortlisted to take part in the first phase of a US $1.7 million head-to-head vaccine tournament, funded by the Bill and Melinda Gates Foundation.

A mathematical model developed by the JCU TB Immunology Group and JCU bioinformatician, Dr Ashley Waardenberg – to help prioritise global funding for new TB vaccine strategies – will also be utilised to assess which tournament participants show enough promise to proceed to Phase Two of the trial, “Evaluating next generation live attenuated TB vaccine candidates”.

“For our JCU vaccine to qualify as one of the top six global candidates for this tournament is pretty amazing,” said JCU Immunology Group leader, Associate Professor Andreas Kupz, whose pioneering research was recognised in 2019, when he was elected co-chair of the prestigious Live Attenuated Vaccines Research Community, within the Bill and Melinda Gates Foundation-funded Collaboration for TB Vaccine Discovery Advisory Council.

The JCU team has already hit the ground running. It was the first to commence Phase One of the TB vaccine tournament on 20 October 2022.

Five different research institutions produced the six vaccine contenders, which are now being tested on three designated mouse strains in four different laboratories: one in South Korea, two in France and one Australia (JCU). All six vaccines have been blinded and the researchers do not know which vaccine they are administering to each mouse.

“The six vaccines were initially sent to one of the collaborators at the University of Pisa, in Italy, where vaccine stocks were produced, quality controlled and sequenced, then blinded (labelled one to six) and sent to the four laboratories to begin the vaccine challenge,” said A/Professor Kupz.

“This distribution process is essentially mimicking the normal provision of vaccines, where you have one supplier of a vaccine, somewhere in the world, which distributes the vaccine to various other places around the world, where vaccination occurs.

“The advantage of this method is that it eliminates possible bias and accidental manipulation of the bacteria (in the vaccines) at the different tournament test sites, which could lead to variations and additional mutations that jeopardise the results.”

In addition to the six new vaccine candidates, some mice will be vaccinated with the current BCG vaccine (also blinded), while others – the control group – will receive no vaccine.

Sixty days after each mouse has been vaccinated, they will be infected with Mycobacterium tuberculosis. Forty-five days later, they will be assessed to see how far the TB disease has progressed in their lungs.

The two mouse strains used to challenge the efficacy of each vaccine have been selected to provide a range of data. The first, C57BL/6, is a black mouse used in standard laboratory studies. However, they are of limited use in TB research, as they do not develop human-like tuberculosis symptoms in the lung. The second, C3HeB/FeJ, a genetically different brown/grey mouse strain, does produce more similar symptoms to humans.

A third mouse model, known as Severe Combined Immunodeficiency (SCID) mice, is being used to test the safety of the vaccines, in terms of potential impact on vulnerable, immunocompromised recipients.

Two different modes of vaccine delivery – intranasal inhalation and subcutaneous injection – will also be evaluated during the tournament. Two sites, one of which is JCU, will investigate the efficacy of intranasal vaccine delivery in C57BL/6 mice, while another two sites will do the same with C3HeB/FeJ mice.

The JCU TB Immunology Group has already undertaken considerable research into the use of nasal and oral methods (similar to nasal sprays and asthma puffers) to better target vaccine delivery to the main site of TB infection – the lung. A growing number of scientists are now also exploring these options.

While the technology to deliver reliable standard doses of intranasal TB vaccine is still in the pipeline, A/Professor Kupz believes it is the way forward.

“There would definitely be easier uptake; avoiding the pain of vaccinating babies with a needle,” he said.

The Vaccine Empirical Integrated Model (VEIM), an algorithm developed by the JCU team in 2020 to help rank potential TB vaccine candidates, in terms of safety, immunogenicity and efficacy, will play an integral role in deciding if any of the new vaccine candidates have the potential to supersede BCG – the primary qualifier for entry into round two of the tournament.

VEIM has also attracted interest as a potential method to evaluate vaccine candidates for other infectious diseases, such as COVID-19 and influenza, in light of the massive expense involved in trialling new vaccines – which can cost up to $1 billion.

A maximum of three TB vaccines will be short-listed for Phase Two of the tournament, in which they will be tested against each other, in the same laboratories as round one. However, this time, all the vaccines will be evaluated for efficacy via both intranasal and subcutaneous delivery at all sites.

The first round of the TB vaccine tournament will conclude in September 2023.  Whatever the results, A/Professor Kupz is still focussed on the main game – saving lives.

“It would be nice if our JCU vaccine outperformed others from around the world,” he said. “

But at the end of the day, if this tournament leads to one potential vaccine that could replace BCG in the future, that would be a great achievement.”

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