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Lire en français It’s hard to imagine that efforts to prevent tuberculosis (TB) infections still rely on a vaccine that some 103 years old. The Bacillus Calmette-Guérin (BCG) vaccine, first

used in humans in 1921, still punches well above its weight. Today, it is administered around the world to some 100 million children every year1 as part of routine newborn immunisation

programmes, as well as adults in high-risk areas. With an efficacy rate of around 70%, it protects small children from most or all severe forms of TB, including TB meningitis, which is a

swelling of the lining of the brain. BCG remains the only TB vaccine approved1 by the World Health Organisation (WHO), but it has limitations. Its protection is known to wane after around 10

to 15 years, after which adolescents and adults, especially those with latent infections, are then vulnerable to severe forms of TB, which includes the development of cavities on the lungs.

Not only is there a higher risk of treatment failure2 among this group, but those with such cavitating pulmonary tuberculosis are also believed to be the main transmitters of the disease.

They become significant drivers of the TB epidemic, says Mark Hatherill, a principal investigator with the South African Tuberculosis Vaccine Initiative (SATVI) at the University of Cape

Town (UCT) in South Africa. DEVELOPING A CENTURY-OLD VACCINE Efforts continue to develop a vaccine that could improve on BCG by either offering lifetime protection, or complementing BCG in

the form of a ‘booster’ vaccine that can be administered in adolescence or early adulthood. There are renewed hopes for a complementary form. Hatherill and his colleagues at SATVI were part

of the international team that conducted phase 2b trials3 of a candidate vaccine known as M72/AS01E, called M72. In March this year, M72 went into phase 3 clinical trials, targeting around

26,000 participants across seven countries that include South Africa, Zambia, Malawi, Mozambique and Kenya. The phase 3 trials will study its efficacy at preventing progression from latent

TB infection to pulmonary TB. But M72 also highlights some of the challenges in developing a suitable vaccine for tuberculosis. The phase 3 trials cost some $550 million, and are sponsored

by charitable organisations Bill & Melinda Gates Foundation and Wellcome Trust. The work is complicated by the fact that only around 10% to 15% of those with dormant infections develop

full-blown TB, so only a fraction of the participants may see those dormant infections become active over the trial period. There are hopes, however, that the trials will shed some light on

the ill-defined immune correlates of protection – markers such as antibody levels and inflammation – that could aid the development of other vaccines should M72 not work. But money isn’t the

only hurdle. _Mycobacterium tuberculosis_, the bacterium that causes tuberculosis has been challenging researchers since its identification as the causative agent of TB 140 years ago.

Relatively little is understood about the early stages of TB infections, for example, or of the workings of the bacterium’s thick, waxy cell wall, which has been described as probably the

most complex membrane of all bacteria4. Its challenges were illustrated by recent studies5 by a team in South Africa that zeroed in on one of the cell wall’s layers known as peptidoglycan,

which plays an important role in the infection process, as it does in the BCG vaccine. Two of the body’s receptors should sense the presence of TB, but the bacteria are able to camouflage

its presence by shrouding their cell walls in other chemical decorations. In the case of the BCG vaccine, only one of these two receptors is activated upon administration “So this entire arm

of the immune system remains dark,” explains one of the co-authors of the new paper, Bavesh Kana of the School of Pathology at the University of the Witwatersrand (Wits), in South Africa.

To offer a full suite of protections, the Wits team cooked up a modified version of the vaccine using CRISPR interference (CRISPi), a gene-modification technique to activate both receptors

and so issuing a stronger immune response. Using mouse models, this modified version of the BCG vaccine has been found to offer “superior protection” against the tuberculosis bacterium, the

team reported in their paper. As promising as these results are, they fall into the category of early, exploratory research conducted by scientists around the world. Many organisations are

trying to bridge the divide between researchers and the pharmaceutical industry. In September 2023, for example, the WHO launched its Tuberculosis Vaccine Accelerator Council, one of its

objectives to “expedite the translation of science into TB vaccines” and work with various international public and private organizations. It is a result of similar initiatives that there

have been some major advances in the TB field over the past 20 years, says Valerie Mizrahi, former director of the Institute of Infectious Disease and Molecular Medicine (IDM) at UCT. “We’ve

seen in the last 25 years the building of a TB drug discovery and development pipeline, which was something that we could only dream of,” she says.