According to the World Health Organization's (WHO's) Global tuberculosis report 2017, "TB is the ninth leading cause of death worldwide and the leading cause from a single infectious agent, ranking above HIV/AIDS. In 2016, there were an estimated 1.3 million TB deaths among HIV-negative people . . . and an additional 374,000 deaths among HIV-positive people. An estimated 10.4 million people fell ill with TB in 2016."

Concluding from those numbers that TB is a major scourge is certainly accurate. But another accurate conclusion is that a TB infection most often does not result in illness.

Somewhere between a quarter and a third of the global population, an estimated 1.7 billion and 2.3 billion people, is infected with latent TB. They have no symptoms and are not infectious unless and until their TB becomes reactivated. Even at the high end, that means that less than 1 percent of individuals infected with Mycobacterium tuberculosis will develop TB disease.

The TB vaccine bacille Calmette-Guérin (BCG) has its own paradox. It is "one of the most widely used vaccines with the least amount of data on whether it actually works or not," Louis Picker told BioWorld. Clinical trials have come to widely differing conclusions on whether the vaccine works well, works marginally or doesn't work. There is largely a consensus that "it protects against serious extrapulmonary disease in childhood," Picker said. But that protection wanes by adolescence, and altogether, "there have never been more cases of TB, even though most people are vaccinated."

Picker is the associate director of Oregon Health & Science University's Vaccine and Gene Therapy Institute, where he works on developing better vaccines for chronic diseases. In the Jan. 15, 2018, online issue of Nature Medicine, he and his colleagues have reported that in primate studies, they were able to evoke an immune response to TB that could prevent illness by using a cytomegalovirus (CMV) vector to deliver TB antigens.

Chronic diseases, including TB, but also HIV and malaria, manage to become chronic because they are good at evading the host immune system, and/or manipulating it for their own ends.

For those pathogens that are skilled manipulators, the immune response is composed of components that are helpful in getting rid of the invader, and those that are helpful to the bug.

Picker named the early inflammatory response to TB as an example as being "probably TB making the host do something that walls it off for a bit, but [ultimately creates] an environment that allows it to persist."

The strategy of Picker and his colleagues is to outwit TB's manipulative capacities by adding TB antigens to a CMV vector.

Picker described CMV as "an even cleverer bug than TB – it has been around for 100 million years or longer, lives in our bodies and completely subverts the immune system," he said.

More than half of the CMV genome is dedicated to manipulating the host response, and the immune responses it elicits, he added, are "enormous," and highly effective at preventing illness. But they are ineffective at getting rid of the virus.

In their experiments, Picker and his team used CMV to deliver genes for TB antigens to rhesus monkeys.

Unlike humans, monkeys are normally "extraordinarily sensitive to TB – they get sick 100 percent of the time," Picker said. But 30 percent of monkeys vaccinated with the CMV/TB vaccine showed no signs of infection when they were exposed to Mycobacterium a year after vaccination, and 40 percent of animals showed no signs of illness, while another 30 percent had reduced signs of illness.

Picker's future research will focus on understanding the details of how CMV interacts with the immune system.

Clinically, he said, CMV is a vaccine platform, and "one of the things we have to do is take the platform forward."

That work is being done at Vir Biotechnology Inc., which was co-founded by Picker. Vir is also using the CMV platform to develop an HIV vaccine, which is slated to enter the clinic in 2019. Picker estimated that a TB/CMV vaccine could follow in 2020.

Because the vaccine aims to prevent TB illness as well as infection itself, it could in principle be used both as a preventive and a therapeutic vaccine. Picker said that one possibility is to use it as host-directed therapy in combination with antibiotics. TB treatment is notorious for its complexity and duration, and any approach that could give the immune system a leg up and potentially increase cure rates and/or decrease treatment time would be a valuable addition to the anti-TB arsenal.

"Especially with drug-resistant TB," Picker said, "that could be very useful."