A new candidate vaccine for tuberculosis (TB) was shown to be effective and safe in animal studies. Researchers from Albert Einstein College of Medicine of Yeshiva University in New York report in the 4 September online issue of Nature Medicine how they developed and tested the vaccine in mice. They say while this is a significant step towards developing a TB vaccine, they don’t know yet if it will work on humans, and they need to do more work to improve its effectiveness since in this study it only worked for one in five of the mice.

According to the World Health Organization, TB infects about one in every three humans walking on this planet and kills about 1.7 million every year. As if this is not bad enough, the spread of drug-resistant strains threatens to increase these numbers significantly unless we develop an efffective vaccine soon.

Senior author of the study, Dr William Jacobs Jr, professor of microbiology & immunology and of genetics at Einstein and a Howard Hughes Medical Institute investigator, told the media that the only currently used vaccine, the Bacille Calmette-Guérin (BCG) vaccine, does not have a consistent track record of protecting against TB.

Jacobs and colleagues decided that the best way to find a new vaccine was to understand the way the bacterium that causes TB, Mycobacterium tuberculosis, manages to evade the body’s immune system.

They started with a relative of M. tuberculosis, a bacterium called Mycobacterium smegmatis that is lethal to mice at high doses but harmless to humans.

They focused on a group of genes in the bacterium called ESX-3; these are known to be key to its ability to outwit the host immune system.

The researchers removed the ESX-3 genes from M. smegmatis bacteria and infused high doses of them into mice. The mice’s immune system mounted a robust T-cell response that cleared the infection; the same type of response that a successful TB vaccine would elicit. T cells are white blood cells that among other things, kill virally or bacterially infected cells in the body.

But, just when they thought they had solved the problem, as often happens in research, they hit a snag: when they tried to remove the ESX-3 genes from M. tuberculosis to take away its ability to evade the host immune system, they found this killed the bacterium. So while this was a neat trick that worked for M. smegmatis, it wasn’t going to work for M. tuberculosis. They had to find a way around this: and they did.

Jacobs and colleagues went back to M. smegmatis and took out its ESX-3 genes and replaced them with the equivalent ESX-3 genes from M. tuberculosis. They infused this “recombinant” bacterium into mice and found their immune systems successfully fought off the infection, as before.

Then, eight weeks later, they gave these mice high doses of M. tuberculosis, which kills mice as well as humans. The “vaccinated” mice survived much longer than control mice that had not been vaccinated: the average survival times were 135 versus 54 days respectively.

But the researchers found even more reason to be impressed: there was a markedly reduced level of TB bacteria in the animals’ bodies.

“Most notably,” said Jacobs, “those vaccinated animals that survived for more than 200 days had livers that were completely clear of TB bacteria, and nobody has ever seen that before.”

However, the researchers cautioned there is still work to be done: only about one in five of the mice showed the robust response, which means the vaccine needs further development before it can be said to be sufficiently effective, and they don’t know if it will work in humans.

“… but it’s certainly a significant step in efforts to create a better TB vaccine,” said Jacobs.

Funds from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and the Howard Hughes Medical Institute, helped pay for the study.

Aeras, a non-profit development partnership based in Rockville, Maryland, has already licensed the technology developed by Jacobs that was used in the study and is using it to develop a new TB vaccine.

The technology could also be used to develop vaccines for leprosy and other virulent mycobacteria.

Written by Catharine Paddock PhD