Scientists develop new weapons in the battle to defeat an ancient disease

Aisha Majid
A TB researcher at GSK's laboratory in Madrid - 8. COPYRIGHT & USAGE LICENCES The entire copyright in the Material and ownership of all physical materials is retained by Photog

It is a disease that has been with us since time immemorial but – despite the fact that is treatable, preventable and curable – tuberculosis is still the world’s biggest infectious killer, taking the lives of 1.6million people in 2017.

Last year, world leaders met at the United Nations and made a series of ambitious pledges to wipe out the disease – including treating 40 million people and preventing 30 million new cases between 2018-2022.

But none of these pledges will be met using existing tools, says Madhukar Pai, director of the International TB Centre at McGill University in Montreal.

“We are using such antiquated tools in TB,” he says. “We are not going to eliminate the disease with a 100-year old microscopy test and vaccine.”

Just two new TB drugs have been discovered in the last 50 years; the only vaccine – the 100-year-old BCG – is only partially effective; and the most widespread test for the disease is only half accurate.

Neglect of the disease is partly down to the complicated nature of the bug. But the fact that it is concentrated in the least wealthy countries also explains why it’s been overlooked, according to Matteo Zignol, coordinator of the World Health Organization’s TB elimination research unit.

“TB is a disease of the poor,” he says.

But after decades of inaction, renewed interest in tackling TB – mostly from a handful of public and philanthropic funders such as the UK government and the Bill & Melinda Gates Foundation – is finally leading to advances in prevention, diagnosis and treatment.

New and old drugs

In a suburb of Madrid a team of 40 scientists in drug giant GSK’s TB laboratory run thousands of tests every month in the search for new treatments.

However, making a breakthrough against one of the world’s most successful pathogens is not easy. Since work started at the site in 2001 just four TB compounds have shown enough promise to move towards clinical trials.

Although much drug discovery focuses on developing new compounds, researchers also comb through the archives to find existing medicines that can be recycled for new uses. Among the drugs currently generating a buzz among the team is an old compound from the 1990s called sanfetrinem, a common antibiotic thought to be ineffective against TB.

“We’ve discovered an improved [antibiotic] that we think has potential for TB,” says Rob Bates, chief scientist in GSK’s TB unit. “It’s resistant to the defence mechanisms of the TB mycobacterium.”

Although clinical trials are two years away, the scientists are hopeful that if tests go well sanfetrinem could be added to the arsenal. “We have a lot of hope on that one,” he says.

David Barros-Aguirre, who heads up the unit, says that TB is concentrated in the most populous countries.

“Brazil, Russia, India, China and South Africa have almost 80 per cent of cases,” he says. “We need to tackle that.”

In the last five years two new TB drugs – bedaquiline and delamanid, the first new treatments in 50 years – entered the market. Further new drugs are also on the horizon.

Currently, patients with the most straightforward form of the disease take a combination of at least three drugs every day for six months. Treatment for multi-drug resistant TB (MDR-TB) takes up to two years and patients have to endure months of painful daily injections and a toxic cocktail of around 14,000 pills.

In a key breakthrough last year WHO recommended that new oral drugs such as bedaquiline should replace injections to treat MDR-TB.

“This is the richest pipeline we have ever had as a global community,” says Mel Spigelman, chief executive of non-profit drug developer the TB Alliance. He cautions however, that without more funding there’s a risk some of this promising work will falter.

Despite the buzz over bedaquiline, Dr Zignol says that single drugs added to existing regimens are insufficient.

“When it comes to drugs, although there are several compounds in the pipeline, the main issue is being able to put them together in a regimen," says Dr Zignol. “What we need is a shorter regimen composed of all new compounds that can be used safely throughout the world.”  

While the prospect of curing all forms of TB with a two-month course of all new pills is at least a decade away, shorter regimens are already in sight with a recent study showing that MDR-TB could be treated in nine to 11 months.

Inhalable vaccines

Last year, GSK and non-profit Aeres unveiled the results of vaccine which showed that it prevents the development of active TB in half the people who receive it.

“It’s the most exciting data I’ve seen in the past 20 years,” says Dr Zignol.

If the vaccine’s efficacy is confirmed in further studies, he believes the vaccine could be available in as little as five years.

“A vaccine with these characteristics is going to be the game changer for sure. There’s solid modelling work that shows that a vaccine will play the largest role in accelerating the fight against TB,” says Dr Zignol.

Although many hopes are pinned on GSK’s vaccine researchers are also looking at more unusual inoculation methods. Professor Helen McShane, director of the NIHR Oxford Biomedical Research Centre, says that early data suggests that inhaled vaccines that target TB right where it hits – in the lungs – could be more effective than injectables.

“There’s some evidence that giving a vaccine by aerosol into the lungs is a better way to protect against TB than an injection,” she says.

The work of Professor McShane’s team, which also includes looking at an inhaled version of the BCG, has attracted the interest of major funders such as the Wellcome Trust.

Although research is at an early stage, aerosol vaccines have several advantages over needles. As well as costing less than injectables, they are easier to give in mass vaccination campaigns such as in schools.  

Diagnostics  the weakest link

According to Professor Pai, diagnostics are however, the weakest link in the TB chain.

Most cases of TB in developing countries are diagnosed just by looking at a patient’s symptoms as accurate culture tests to determine the exact TB strain behind an infection are slow and expensive.

More recent innovations such as GeneXpert, a test that quickly detects TB in sputum and identifies if the strain is resistant to the most common antibiotic, rifampin, are helping move diagnostics forward, says Professor Pai. It’s already being used in many countries.

“GeneXpert has given the whole TB community a first glimpse of what a rapid highly accurate test can do for us,” he says.

However, the machine requires laboratory equipment, which is sometimes beyond the reach of the poorest communities.

“It’s not a simple point-of-care, device-free test,” says Professor Pai. “That’s been elusive for TB.”

Genome sequencing - deciphering the genetic code of TB bacteria to identify mutations that make some strains resistant to certain drugs - is one avenue of hope. And it’s already being used in the UK.

Spending on research needs to be about $2billion a year Credit: Richard Moran Photography

The work, led by a consortium of researchers based at Oxford University, means scientists can now accurately detect resistance to the four first-choice drugs used to treat TB.

“Genome sequencing doesn’t just tell you which drugs to avoid but potentially tells you which drugs to give,” says Tim Walker, a researcher at Oxford.

At the moment, it takes two to three weeks to deliver a result but Dr Walker says that could eventually speed up to a day.

Genome sequencing needs to be simplified before it can be rolled out in poorer countries but Dr Zignol believes it has potential.

“Sequencing is becoming much more available and it’s going to be the gold standard for diagnosing drug-resistant TB in the near future,” he says. “The cost is still high but the field is moving fast and this technology is rapidly becoming more affordable.”

But while science is increasingly generating hope for TB, innovation alone isn’t enough, says Dr Spigelman.

“A vaccine, diagnosis, therapy - they are all within reach in terms of the science,” he says. “But in terms of resources we are only a fraction of what we need.”

In 2017 $772 million was invested in TB research. This is more than ever before, but far short of the $2 billion a year the TB community estimates is needed to end the disease by 2030.

“The progress that has been made in TB for the amount of investment there’s been has been phenomenal,” says Dr Spigelman. “But it’s still the proverbial drop in the bucket.”

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