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One quarter of the global population is infected with Mycobacterium tuberculosis (Mtb), though tuberculosis (TB) is largely eradicated in the global north.
InSight+ spoke with leading Australian researchers who have found that inhaling a more virulent version of the Bacillus Calmette-Guérin (BCG) vaccine activates progenitor cells within the lungs, signalling T cells to differentiate and reside locally. They hope it could lead to a better vaccine.
Associate Professor Andreas Kupz has been an investigator at the Australian Institute of Tropical Health and Medicine, James Cook University, for ten years.
“Tuberculosis is the largest infectious disease in the world, killing 1.5 million people every year,” said Associate Professor Kupz.
“The current vaccine, Bacillus Calmette-Guérin (BCG), is not effective against pulmonary TB in adults,” he said.
The BCG vaccine is administered intradermally and usually given to children after birth.
“In children, TB often presents as a disseminated disease and BCG can prevent this. But for some reason, in adolescents or early adulthood, its effectiveness starts to decline. And we don’t understand why. We need a vaccine that also works in adults and adolescents.”
Approaching a better vaccine
Associate Professor Kupz said that there are a few ways to approach making a better vaccine.
“One is a whole new vaccine essentially replacing BCG with an improved version of BCG, a protein vaccine or mRNA vaccine. The other way is a different route of vaccine delivery. This paper covers both of those approaches.”
“We have developed an mRNA vaccine candidate. We have also developed a peptide-based vaccine candidate. But it’s emerging from the literature that many of those new vaccine types, when they go into human clinical trials, are often not better than BCG.”
“The third approach is to improve BCG itself. That’s what we’re trying.”
“We have previously shown that if you make BCG a little bit more like Mtb, you can induce better protection. But this comes at a cost. You have to balance safety and immunogenicity,” he said.
“Given directly into the lung, these modified BCG strains provide better protection in animal models. This paper provides one explanation as to why mucosal delivery is more protective than intradermal vaccination.”
“It also explains why these more virulent strains of BCG are more protective.”
“Understanding the link between BCG virulence, the induction of protective T cells, and most importantly how you maintain them long term in the lung, will probably be the solution to achieving a much more effective long-term protection [from TB] by vaccination,” he said.
Finding the right path
Associate Professor Kupz believes improving BCG is the correct path to travel, to find the next vaccination that fully eradicates TB.
“Myself and a few others in the field believe BCG improvement is our best shot,’” said Associate Professor Kupz.
“BCG has about 4 000 proteins. Whereas mRNA or protein vaccines are often limited to three or four or sometimes up to ten. It seems to be one of the reasons why it’s hard to beat BCG.”
“For context, about five years ago it was published in Nature that if you deliver BCG intravenously into non-human primates, nine out of ten macaques were completely protected against tuberculosis.”
“Testing different delivery routes is important, but intravenous vaccination is likely not going to be translated into humans. Not many parents would like to have their newborn vaccinated intravenously with a live bacterium,” he said.
“But it opened up the door for understanding why a different delivery route would provide better protection than intradermal.”
“We also know that mucosal delivery in non-human primates, in mice, etc., can produce much better protection. Not sterile, but much, much better. And we’re trying to understand the mechanisms behind this.”
Associate Professor Kupz notes that in the 1920s, the BCG vaccine was first given orally. It was subsequently transitioned to intradermal use after the Lübeck disaster.
“We know that the people who developed BCG intended that giving BCG orally produces similar type of immune cells to intravenous therapy.”
The move to human trials
Associate Professor Kupz and his colleagues were the first to show, around ten years ago, the greater effectiveness of mucosal BCG delivery over intradermal delivery, and how this is linked to those tissue-residing T cells.
There is now a body of work establishing the efficacy and higher level of protection afforded by mucosal vaccination.
“In our studies, we’re using experimental, genetically modified BCG strains. They are more virulent. For now, human trials can only be done with the licensed BCG vaccine created in 1921.”
Associate Professor Kupz notes that clinical trials are being conducted in humans at Oxford University to see how well BCG delivery into human lungs is tolerated.
“These trials are about understanding the safety and immunogenicity, and whether there are side effects associated with BCG delivery into the lung, what dose of BCG can be given to people, and what type of immune responses are induced in the lung. They can do immune assays similar to those we do in animals,” he said.
Associate Professor Kupz noted that the COVID-19 pandemic raised awareness about TB, but there was also a reversal of the slow but steady decline in TB deaths observed in previous years.
“Before COVID, no one in the ‘western’ world seemed to know [about its mortality rates], because it was happening in the lower- and middle-income countries,” he said.
“Diagnosis and treatment for TB takes 6-12 months and requires adherence to protocols and close monitoring. Consequently, deaths from TB grew during lockdowns and clinical trials for new vaccines were also interrupted.”
A responsibility to disadvantaged populations
The World Health Organization describes TB as “a disease of poverty and economic distress, vulnerability, marginalisation, stigma and discrimination”.
Rates of TB infection for First Nations Australians are 5-6 times higher than for the Australian-born, non-Indigenous population.
The intradermal TB vaccine is still given to most newborns in TB endemic areas, including India and Sub-Saharan Africa. In Australia, high-risk populations in the north (mostly Indigenous communities in Cape York and the Torres Strait) are also vaccinated.
Some Indigenous communities have called for better screening for TB.
“One of the challenges of TB is that it is not always an active disease. In COVID-19, you can often tell that a person is ill quite quickly,” said Associate Professor Kupz.
“But about one quarter of the world’s population is infected with Mycobacterium tuberculosis. That’s about 2 billion people.”
“The majority can live relatively well with the latent infection.”
“Over the last few years, the increase in multi-drug resistant (MDR) tuberculosis is now evident all over the world. Papua New Guinea is one of the hotspots for MDR TB. with a high case number and an overall high TB incidence.”
In the north of Australia, the Torres Strait Treaty allows PNG and Torres Strait Islander peoples to freely move between the islands due to social and cultural ties, which creates a biosecurity risk to address.
“It’s obviously our duty of care for our closest neighbour, PNG, and our own communities,” said Associate Professor Kupz.
“And that means that MDR TB cases from PNG need to be treated, often within our health system,” he said.
“TB also has a large individual economic impact. So, if we can find a better solution for TB that is relevant to PNG and disadvantaged populations in the north of Australia, it will also have a large economical and health impact for these affected communities.”
The future of TB research
As the RD1-containing strain of BCG Associate Professor Kupz is studying is not currently safe for human use, the team has developed a modified BCG strain that still induces better immunity compared to BCG, but is not associated with increased virulence as seen with BCG::RD1.
However, Associate Professor Kupz said that developing a better TB vaccine requires a lot more funding.
“We know that mucosal vaccination is better. And we know why it’s better. Now we just need to make it safe enough for it to be a viable option for mass vaccination in humans.”
Becca Whitehead is a freelance journalist and health writer. She lives in Naarm and is a regular contributor to the MJA’s InSight+.
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