The only licensed vaccine for prevention of TB disease is the bacille Calmette-Gurin (BCG) vaccine. The BCG vaccine was developed almost 100 years ago, prevents severe forms of TB in children and is widely used.
However, there is currently no vaccine that is effective in preventing TB disease in adults, either before or after exposure to TB infection: and yet this group makes up around 90% of cases.
M72/AS01E looks to Phase 3 trials
There are several challenges to developing effective TB vaccines. From the scientific side, there is a lack of immune markers for prediction of vaccine-elicited protection, requiring long and expensive efficacy trials, as well as an incomplete understanding of the nature of protective immunity to TB. For vaccine developers, market uncertainties and a long and expensive research timeline can be dissuasive.
There are 14 vaccine candidates in clinical trials: two in Phase I, eight in Phase II and four in Phase III, notes the WHO report.
In particular, the WHO report identifies 'promising' Phase 2 results from candidate M72/AS01E.
The M72/AS01E vaccine candidate contains the M72 recombinant fusion protein, derived from two Mycobacterium tuberculosis antigens (Mtb32A and Mtb39A), combined with the Adjuvant System AS01 (which is also a component of GSK's RTS,S malaria vaccine and vaccine against shingles, Shingrix).
It was developed by GSK in conjunction with IAVI.
The vaccine was developed by GSK, with a Phase 2b trial of a two dose regimen conducted in TB-endemic regions (Kenya, South Africa and Zambia) in individuals aged 18-50 years old. The final analysis of the trial was released in 2019, demonstrating an overall vaccine efficacy of 50% during the three years after vaccination.
In January 2020, the Bill & Melinda Gates Medical Research Institute obtained the license for continued development of M72/AS01E from GSK.
A spokesperson for the Institute told us the development program for the vaccine is ongoing. Researchers are preparing for a Phase 3 efficacy study, with the pre-requisite preliminary studies currently under way.
Meanwhile, a Phase 2 safety and immunogenicity trial in people living with HIV is being conducted.
The Institute will also shortly commence a large epidemiology study across a number of high burden countries.
Global burden
Tuberculosis is caused by bacteria (Mycobacterium tuberculosis) that most often affect the lungs. It can spread when people who are sick with TB expel bacteria into the air (for example, by coughing).
Approximately 90% of those who fall sick with TB each year live in 30 countries. Many new cases are attributable to five risk factors: undernutrition, HIV infection, alcohol use disorders, smoking and diabetes.
Reversals in progress mean that the global TB targets are off track and appear increasingly out of reach, although there have been some regional successes, according to the WHO's report, which was published this month.
Globally, the reduction in the number of TB deaths between 2015 and 2020 was only 9.2% - about one quarter of the way to the 2020 milestone of 35%.
The number of people falling ill with TB each year (relative to population) dropped 11% from 2015 to 2020, just over half-way to the 2020 milestone of 20%
The WHO End TB Strategy aims for a 90% reduction in TB deaths and an 80% reduction in the TB incidence rate by 2030, compared to the 2015 baseline.
“The End TB Strategy targets set for 2030 and 2035 cannot be met without intensified research and innovation," notes its report.
"When these targets were first established, it was highlighted that technological breakthroughs would be needed by 2025, so that the annual decline in the global TB incidence rate could be accelerated to an average of 17% per year between 2025 and 2035.
"Given that reductions in TB incidence achieved between 2015 and 2020 fall far short of the first 2020 milestone of the strategy (11% compared with 20%) and the projected impact of the COVID-19 pandemic on TB incidence in 2021 and 2022, an even faster rate of decline will now be required.
“Priorities include a vaccine to lower the risk of infection, a vaccine or new drug treatment to cut the risk of TB disease in the approximately 2 billion people already infected, rapid diagnostics for use at the point of care, and simpler, shorter treatments for TB disease.
“There is progress in the development of new TB diagnostics, drugs and vaccines, but this is constrained by the overall level of investment, which at US$0.9bn in 2019 falls far short of the global target of $2bn per year.”
Many services were disrupted by the pandemic in 2020: but the impact on TB was particularly severe, says the WHO in its Global tuberculosis report 2021.
Approximately 1.5 million people died from TB in 2020 (including 214,000 among HIV positive people): up from 2019.
The increase in the number of TB deaths occurred mainly in the 30 countries with the highest burden of TB. WHO modelling projections suggest the number of people developing TB and dying from the disease could be much higher in 2021 and 2022.
Challenges with providing and accessing essential TB services have meant that many people with TB were not diagnosed in 2020. The number of people newly diagnosed with TB and those reported to national governments fell from 7.1 million in 2019 to 5.8 million in 2020.
WHO estimates that some 4.1 million people currently suffer from TB but have not been diagnosed with the disease or have not officially reported to national authorities. This figure is up from 2.9 million in 2019.
“This report confirms our fears that the disruption of essential health services due to the pandemic could start to unravel years of progress against tuberculosis,” said Dr Tedros Adhanom Ghebreyesus, WHO Director-General. “This is alarming news that must serve as a global wake-up call to the urgent need for investments and innovation to close the gaps in diagnosis, treatment and care for the millions of people affected by this ancient but preventable and treatable disease.”