AITHM James Cook University

10 March 2020

Tuberculosis (TB) claimed 1.6 million lives globally in 2018. There are 10 million active cases of TB per year and drug-resistant strains are multiplying. The need to develop a new vaccine that provides greater immunity is imperative.

The AITHM TB Immunology group, in collaboration with AITHM bioinformatician, Dr Ashley Waardenberg, has developed a mathematical model to help prioritise new TB vaccine strategies that merit further investigation – a tool which could guide the crucial allocation of limited global resources to find a more effective alternative to the current vaccine, BCG, which has been in use for almost 100 years.

“Given that vaccine development is so expensive – every Phase 3 clinical trial costs at least $500 million dollars – it is really important to make rational decisions; which vaccine should move from one stage to the next. It is essential to rank them,” said group leader, Senior Research Fellow and microbiologist Dr Andreas Kupz. 

The development and trial of the Vaccine Empirical Integrated Model (VEIM) featured this week in the latest edition of the prestigious international journal, Science Advances.

It is a major coup for the three-year-old AITHM research group to achieve publication in the journal. Their findings will now receive worldwide media attention and hopefully attract additional funding for other current major research projects. VEIM was created in parallel with the team’s own recent development and assessment of a promising new strain of the existing TB vaccine.

They believe that safety is currently the lowest priority in traditional pre-clinical evaluation of new TB vaccines, which is heavily skewed towards assessing immunogenicity (ability to stimulate a protective immune response) and/or efficacy, in terms of eliminating Mycobacterium tuberculosis (Mtb), the bacteria which causes TB.

 

“Safety and efficacy are the dominant considerations in human use,” said the first author of the Science Advances paper, JCU medical student Visai Muruganandah, who undertook a research project with the TB Immunology team when the first VEIM trial data was generated.

“Despite this, there remains no gold standard approach to integrating data that covers all three – safety, immunogenicity and efficacy – to rank vaccines based on overall performance and simultaneous comparison in all three categories.”

The VEIM trial assessed 24 vaccine regimens in an animal model of TB, composed of three BCG strains and eight combinations of vaccine delivery, including booster vaccination. An additional control group was also evaluated. (The AITHM vaccine candidate was not included in the trial.)

The team developed a simple empirical model to systematically rank vaccination strategies by integrating multiple measurements of safety, immunogenicity, and efficacy.

“Developing simple models that are readily interpretable is important for understanding what makes an effective vaccination strategy and where we need to focus our efforts,” said Dr Waardenberg.

The trial indicated that vaccination strategies containing BCG::RD1 or a derivative of that strain, ranked most favourably. BCG::RD1 was a previous vaccine candidate that had impressive immunogenic qualities, but too many detrimental side effects to be considered for human use.

“Even though BCG::RD1 was ruled out 20 years ago, because of side effects, with the new knowledge and more sophisticated analysis methods that have been generated since then, it is clear that there are also positives when RD1 is re-introduced into BCG. Research into RD1 immunity should be revitalised,” said Dr Kupz.

The trial results have already excited the interest of the Collaboration for TB Vaccine Discovery (CTVD) Advisory Council, which steers an international TB research network, funded by the Bill and Melinda Gates Foundation.

Dr Kupz joined the council in late 2019, after being elected co-chair of the Live Attenuated Vaccines Research Community, one of seven specialised working groups within the CTVD. In January this year, he attended the annual meeting of the council, held in Santa Fe, New Mexico, where he shared details of the VEIM trial.

“That received a lot of attention, because the council is now planning to invest in data and approaches based on maths and bioinformatics,” he said. “One of the new priorities of the Live Attenuated Vaccines Research Community is to diversify membership to include experts in these fields.”

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