It is a hundred years since the BCG (Bacille Calmette-Guerin) vaccine, the only registered vaccine proven to offer some protection against tuberculosis, was first used in people. A relative shortage of public funding and little interest from pharmaceutical companies to develop new unprofitable TB vaccines has frustrated scientific research in this area for most of the last century.

To add to the problem, much-needed resources are now being diverted to the Covid-19 pandemic setting back the fight against TB by as much as 12 years, according to the Stop TB Partnership. Although Covid-19 overtook TB in 2020 as the most common cause of death from an infectious disease, TB still kills more people than Covid-19 in low- and middle-income countries and its longer-term death toll far exceeds that of other infectious diseases.

South African Tuberculosis Vaccine Initiative (SATVI) director Mark Hatherill is all too familiar with scarce funding for the TB vaccine research field where there also are not many new candidate vaccines to test compared to Covid-19 and HIV.

“Within weeks of Covid being declared a pandemic there were billions of dollars available for vaccine development. TB is also a global pandemic,” he says. 

A world leader

In spite of funding challenges, SATVI, which celebrates its 20th anniversary this week, is at the forefront of TB clinical research globally. For years a deliberate focus on TB vaccines led to it becoming a world leader – then later the focus broadened from vaccines to also include TB diagnostics and treatments.

A total of 28 Phase 1 to 4 trials of the BCG vaccine have been completed and nine new TB vaccines have been tested. The Initiative has grown from three staff members to 108 and more than 30,000 participants have been enrolled in its studies. 

Originally called the “BCG study unit”, it was housed at the Child Health Unit of the School of Child and Adolescent Medicine at the University of Cape Town’s Faculty of Health Sciences. The lead up to SATVI’s launch in 2000 dates back to the mid-1980s and 1990s when the first and former SATVI director Professor Greg Hussey and the late pioneer in paediatrics at UCT Professor Maurice Kibel were doing joint ward rounds at Brewelskloof Hospital in Worcester in the Western Cape.

“One of the things Maurice was quite interested in was why children were still getting TB if they had received the BCG vaccine,” says Hussey. At that stage, a percutaneous (through the skin) injection was used to administer the BCG vaccine to infants. We started looking to see whether other tools  (types of injections) were penetrating the skin,” says Hussey. 

The struggle to find funding for a study took time. Finally, the US-based  Sequella Global TB Foundation, which was interested in new diagnostic tools, new drugs and potentially new vaccines, enabled the launch of SATVI.

Why Worcester?

The team’s decision to settle on Worcester with Brewelskloof Hospital as the field site was crucial to the success of future clinical trial research. The high reported incidence and prevalence of TB  in the Breede Valley area meant clinical trials could be done with reasonable sample sizes. TB prevalence in the Cape Winelands District is 778 per 100,000 people, according to the municipality’s 2020/21 report.

Good transport and telecommunications, access to qualified staff and options for training others made the trials feasible. A relatively stable population was essential, primary health care services were up and running as well as adequate surveillance systems. 

In March 2001, SATVI researchers enrolled 11,680 new-borns in a Phase 4 clinical trial to assess whether the route of administration of BCG to new-borns determined efficacy in protecting against childhood TB. The last clinical trial of a TB vaccine in infants was in the 1930s and 1940s — long before the randomised placebo-controlled trial became the gold standard of clinical research.

The trial found no difference in TB disease rates following BCG vaccination by an intradermal (under the skin) injection compared to the percutaneous injection. A former SATVI director, Professor Willem Hanekom says the study was critical for developing infrastructure to conduct large-scale vaccine TB vaccine trials.

Three large scale epidemiological studies to define the TB epidemic followed from 2004 and 2009. These were the Adolescent Cohort, the Neonatal Cohort and the Adult Prevalence studies.

Hanekom says, “These studies were important preparedness studies for future vaccine trials. To do large, randomised control trials we needed to know infection and disease rates. The adolescent study generated ground-breaking results in describing correlates of risk of TB disease — biomarkers in the blood — that can predict whether a person will get TB or not.”

Later in 2016, another study on biomarkers called the Correlate of Risk Targeted Intervention Study (Cortis) began. The results, published in The Lancet medical journal this year found that a specific set of biomarkers could predict whether people will develop active TB. Disappointingly, the results showed preventive therapy for those at risk remains elusive. (Spotlight reported on the Cortis trial here.)

Making history

On 15 July 2009 four-month-old Janenique Pienaar made history when she became the first infant to be enrolled and vaccinated with a TB vaccine called MVA85A — the first new experimental infant TB vaccine since BCG almost a century earlier.

The viral vector vaccine was developed as a booster to enhance the protective efficacy of the BCG vaccine. The Phase 2b efficacy trial catapulted SATVI onto the global stage of clinical TB research, securing its position as a preferred clinical trial partner to test the safety, immunogenicity (ability to stimulate an immune response), and efficacy of new TB vaccines in the development pipeline.

Although the trial did not show efficacy against TB it was considered a scientific success, according to Hatherill. 

“We showed we could do large trials with sophisticated immunology in a TB endemic setting in Africa,” he says. “However the lack of efficacy had a ‘negative impact’ on the TB research field. For two years the atmosphere at academic meetings was depressed. There was also a backlash in the funding space, Funders became risk-averse and looked to data from pre-clinical or animal studies to provide a signal before they were prepared to invest money in efficacy trials.” 

It was only years later that investors’ appetite for funding returned but even then it was slow.

In 2014 SATVI researchers began the first Phase 2 study to find out whether a second dose of BCG in 990 healthy adolescents could prevent TB infection. BCG was shown to have 45% protection against infection. Hatherill says the value of the prevention of infection trial design is that it can be used to inform clinical development of new TB vaccine candidates before entry into large-scale prevention-of-TB efficacy trials.  Hatherill says “Because latent infection with Mycobacterium TB is very common (it accounts for two-thirds of South Africans) whereas TB disease is much less common, you can do a prevention of infection trial with a few hundred people but to do a prevention of disease trial you need a few thousand people.”

Landmark success

SATVI ’s landmark success came with a Phase 2b trial to test the safety and efficacy of a new vaccine called M72/AS01E in adults. The study, conducted at 11 sites in Kenya, South Africa and Zambia, began in August 2014. The findings, published in 2018, showed that three years after vaccination there were 50% fewer cases of TB among study participants who received the vaccine, as opposed to a placebo (those who did not get the vaccine). It was the first robust TB vaccine trial since BCG to show efficacy.

The good news is that the M72 vaccine is going into a multi-country Phase 3 efficacy trial for adults next year. The trial is funded by the Bill & Melinda Gates Medical Research Institute. “Nothing is signed yet but we are hoping to take part in the trial,” says Hatherill.

Another large-scale Phase 3 efficacy trial in infants is scheduled for next year. The vaccine called MTBVAC uses a live attenuated (weakened) mycobacterium which has been tested in adults and recently in infants. It is safe and induces an immune response. The vaccine has been funded by the European and Developing Countries Partnership but the team is looking for co-funding. “It’s going to be a big year for SATVI,” says Hatherill.

Like driving a very old car

Hatherill says it’s scandalous that “we have been using the same vaccine for 100 years. It’s like we are driving the Model T Ford of vaccines when other infectious diseases are driving Ferraris… If there is 1% of funding left over from Covid-19, it would make a massive difference to TB vaccine development.” 

He says SATVI’s research is dependent on a high rate of TB in the Breede Valley. “So, the challenge is keeping the trust of the community and working in partnership. Although we work hard to benefit our participants — through access to health care, education about TB care and TB diagnostics — the reality is that we can do very little about the fundamental social and economic determinants of the burden of TB in that community.

“Until we can get to that prize — a world without TB — only then can we do something for the community. It’s only when we find a vaccine that is effective that we can eliminate TB. It’s a long-term slog and it’s not happening anytime in the immediate future.” DM/MC

Note: The Bill and Melinda Gates Medical Research Institute is mentioned in this article. Spotlight receives funding from the Bill and Melinda Gates Foundation.