Managing specific infectious diseases: A to Z

'Gamechanging' TB Vaccine Within Reach After $500m Pledge To Run Final Trials

The first new tuberculosis vaccine in 100 years may be within reach, after the announcement that more than $500m (£395m) has been pledged by philanthropic institutions for final trials involving 26,000 people in Africa and south-east Asia.

The M72/AS01E vaccine, developed by the giant pharmaceutical company GlaxoSmithKline, was shown to be 50% effective in phase 2b trials in 2018, but the company pulled out rather than invest in the large-scale trials needed for a licence, saying it did not see a market.

In 2020, GSK passed the licence to the Bill & Melinda Gates Medical Research Institute, a biotech nonprofit spin-off from the Bill & Melinda Gates Foundation. The foundation, which was already investing in the vaccine, will put up around $400m for the phase 3 trials, while the global charitable organisation Wellcome will provide up to $150m.

"TB remains one of the world's deadliest infectious diseases," said Julia Gillard, the chair of Wellcome. "The development of an affordable, accessible vaccine for adults and adolescents would be gamechanging in turning the tide against TB."

Vaccines for Covid were developed from scratch in less than a year, yet there have been no new vaccines for TB, which kills 1.6 million people a year, since the BCG (Baccilus Calmette-Guérin) was introduced in 1921. All UK schoolchildren were once vaccinated with the BCG, but it is now recognised as effective only in the very young, and lasts only a few years.

Up to a quarter of the world's population is infected with the TB bacteria, which can remain latent but be passed to other people, or cause active disease. TB predominantly affects impoverished populations in Africa and Asia, although there are serious problems in eastern Europe and cases of multi-drug resistant TB across the globe.

Bill Gates, the co-chair of the Gates Foundation, said: "With TB cases and deaths on the rise, the need for new tools has never been more urgent. Greater investment in safe and effective TB vaccines, alongside a suite of new diagnostics and treatments, could transform TB care for millions of people, saving lives and lowering the burden of this devastating and costly disease."

The five-year hiatus between the exciting 2018 results in 3,000 people with latent TB and Wednesday's announcement was spent in negotiating the licence handover and transfer of manufacturing from GSK to Gates, and in investigating the best 50 sites in TB-endemic regions for the final trials.

"When the results were really strong, there was a tremendous interest in the global health community in moving forward to phase 3," said Trevor Mundel, the president of global health at the Gates Foundation. "GSK at that point indicated that this was not going to be a commercial vaccine for them. We negotiated a licence with GSK, which was executed in 2020.

"Then we had the discussions and negotiations with the Wellcome Trust around co-funding the project because it was an enormous enterprise for both our organisations."

Governments need to come onboard such large projects, which are of crucial importance to health worldwide, say the organisations. "We hope that M72 is going to be the first of a number of progressive TB vaccines that will be extremely useful. And for that, I think we need this broader set of funders," said Mundel.

"We would certainly look to governments, and as much as I've said that TB is a disease of poverty, it remains rife in many middle-income countries, even in richer regions of the world. Covid has given us all the sense that there are no national barriers that you can hide behind for a global transmission problem like TB. Not paying attention to it, even if you may have a low incidence in your own geography, opens you up to transmission, with increasing migration and the like," he added.

The phase 3 trial will start early next year, and last between four and six years. Researchers will track the numbers of people with latent TB who convert to active TB. If the vaccine is as successful as it showed itself five years ago in a smaller number, it will prevent half the cases of active disease that would have been expected.

Victory over big pharma opens door to cheaper tuberculosis drugs

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The World Health Organization says that a vaccine with 50% efficacy could prevent up to 76 million cases and 8.5 million deaths over 25 years. It would save billions in costs for families whose wage-earners are hit by the illness and often have to pay to travel for treatment.

The Treatment Action Group (TAG) welcomed the "historic" investment. "We hope this funding commitment sparks governments and other funders to substantially increase investments in the TB vaccine pipeline, which contains a number of promising candidates but faces a dire financial shortfall," said the TAG executive director, Mark Harrington, who urged all involved to improve access to the vaccine should it be approved.

A New TB Vaccine Could Save 8.5m Lives Over The Next Quarter Of A Century

Tuberculosis (TB), which kills one person every 20 seconds, is a forgotten pandemic. About a quarter of the world's population has been infected with the bacterium Mycobacterium tuberculosis. Most will never know, as they are asymptomatic. But these latent infections go on to sicken about one person in ten. And even though TB is treatable, around 1.6m people each year, mostly in poor countries, nonetheless die from it.

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A 100-year-old vaccine, the BCG, has helped, but it is only partially effective. On June 28th two of the world's wealthiest charities, the Bill & Melinda Gates Foundation and Wellcome, said they would fund a late-stage trial of a new TB vaccine known as M72. That will cost $550m, of which the Gates Foundation will contribute $400m, making it the charity's biggest ever investment in a single product.

M72 is a "sub-unit" vaccine. Rather than a dead or weakened form of the bacterium itself, it contains two proteins found on the bug's surface. GSK, a big pharmaceutical firm, acquired it from Corixa, an American company, in 2005. Early trials, the results of which were published in 2019, concluded that it was about 50% effective in preventing TB in the lungs of those with a latent infection—a group in which no other vaccine has worked. But gsk decided developing the vaccine further would not be commercially viable.

That is where the charities come in. The Foundation will not only pay for most of the bigger trial that is required before the vaccine can be approved by regulators, it will also sort out the logistics. It has identified a dozen sites in Africa and Asia where rates of latent tb infection are unusually high, between 40% and 60%. Testing here will allow scientists to see more quickly whether the vaccine prevents the emergence of active TB. But the trials will still take four to six years, says Trevor Mundel, president of global health at the Foundation. That is one reason for the high cost; others include the number of participants required—around 26,000—and the expense of setting up laboratories.

If the new jab really is 50% effective, it could save 8.5m lives, and prevent 76m cases of TB, over the next 25 years. It could also avert 42m courses of antibiotic treatment, which might slow the rate at which TB is evolving resistance to such drugs.

Academic and charitable support for vaccines is not new. But such organisations can only do so much. The vaccine will ultimately need a commercial partner to put it through regulatory assessments and organise sales and distribution. Pharmaceutical firms also conduct post-marketing surveillance, which helps regulators spot side-effects that might have gone unseen during the trials themselves. Despite their financial firepower, "there is no way Wellcome and the Gates Foundation can…become a vaccine company," says Mr Mundel. Other vaccines, such as one for Lassa fever being developed by the non-profit group IAVI, remain in commercial limbo for such reasons.

Wellcome and the Foundation hope to secure a commercial partner for their new vaccine within 12 months. Indian vaccine-makers, which are more used to investing in developing medicines for low and middle-income countries, seem interested. An earlier GSK vaccine for malaria was licensed to Bharat Biotech, an Indian firm, in 2021. As for all the new trial sites built for testing M72, Mr Mundel is hoping the investment may also be of use to others wanting to test other vaccines in future. BioNTech, a German firm, is developing an mRNA vaccine to target TB, for example. With a growing pipeline of drugs and vaccines for TB, optimism over better treatments is growing—even if getting them to market needs a helping hand. ■

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Experts Say Herbalists Complicating TB Treatment Efforts

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Health experts have said herbalists are complicating the treatment of tuberculosis in Uganda by mixing wrong quantities of Western medicine for sale to patients.

Dr Mary Nabukenya, the director of the USAID TB Flagship project in the Ministry of Health, told journalists in Kampala that herbalists buy regular Western TB drugs from pharmacies and use them to make concoctions that they sell to unsuspecting victims.

"Those herbalists move around with jerrycans, claiming they can cure tuberculosis," she said.

"Some popular ones that claim to treat TB buy antibiotics from pharmacies crush them to mix and sell to patients, claiming the concoction cures tuberculosis whereas not. If you take such concoctions, the disease may subside but will come back worse than it was initially."

Dr Akello Susan Adakun, a multi-drug resistant TB specialist and physician at Mulago Hospital in Kampala, said the intake of drugs in wrong quantities is one of the factors driving up the number of multi-drug resistant tuberculosis cases in Uganda.

'Permanent damage'

Multi-drug-resistant TB is caused by a strain of TB bacteria that is resistant to at least isoniazid and rifampicin, which are the two commonly used anti-TB drugs.

"The challenge is most patients take herbals when they get a cough, but the problem is that we do not know what is in the herbals, unlike the Western medicine that has ingredients properly written on them," said Adakun.

She added that people who take these herbals in the early stages of tuberculosis end up damaging their kidneys and lungs.

"Such people usually come to us late when and at this stage, we can't give them TB drugs because they can end up worsening the problem.

"The delay to diagnose tuberculosis early will leave permanent damage on the lungs in that even when tuberculosis cures, the scars in the lungs do not go away. Tuberculosis can be treated as an out-patient condition but if there is damage on an organ, you must be admitted because we have to keep monitoring you.

Let's go for early diagnosis and avoid using herbs. For us in TB, we advise you to please keep away from herbs," said Adakun.

Latent TB

Meanwhile, Nabukenya revealed that to prevent tuberculosis cases from rising, they are stepping up latent TB management among adults under new guidelines.

Latent TB is when the bacteria is present in the body but has not progressed to a disease.

To suppress the multi-drug-resistant tuberculosis numbers, Nabukenya said that initially, their preventive therapy targetted children under five and people living with HIV because they are more at risk.

But now, as long as anyone gets in contact with a patient who has tuberculosis, they are given treatment.

"We test and find that you have latent TB in your body, we start you on preventive therapy," said Nabukenya.

She also revealed that previously, people were taking drugs for six months, but now, new drugs that people take for three months have been introduced.

"It is called isoniazid and rifapentine which is taken every week for three months. This preventive therapy just helps you not to progress into TB disease. They are not yet on the market in Uganda," she said.

It is hoped the shift from the nine-month isoniazid regimen to the three-month drug will reduce the pill burden for people under treatment.

"When we were starting the Multi-Drug Resistant TB management, we used to do drugs for 24 months," said Adakun, going on to advise people with a cough for two weeks, sweating at night, fevers, weight loss and other symptoms to visit the health centres for diagnosis.

She said once one starts treatment, one should take medicine on time to avoid progression to multidrug-resistant TB, which is expensive to treat.

Statistics

According to the World Heath Orgainsation and the Ministry of Health, at 199 cases per 100,000 people, Uganda remains one of the countries with one of the high tuberculosis burden countries in the world.

Globally, the number of tuberculosis cases stands at about 1.7 billion, according to the Centres for Disease Control and Prevention.

In its National TB and Leprosy Strategic Plan 2020/21-2024/25, Uganda aims to achieve more than 90% TB treatment.

The overall goal of this National TB and Leprosy Strategic Plan 2020/21-2024/25 is to reduce the incidence of TB by 20% from 200/100,000 population in 2019/20 to 160/100,000 population by 2024/25.

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