The National Institutes of Health (NIH) has awarded researchers at Albert Einstein College of Medicine at Yeshiva University a five-year, $5.9 million grant to develop a new vaccine against tuberculosis (TB), including the toughest-to-treat forms of the disease known as multidrug-resistant and extensively drug-resistant. The grant will build on a new approach to TB vaccine design that is based on genetically altered Mycobacterium smegmatis, which is closely related to the bacterial species (Mycobacterium tuberculosis) that causes TB in humans.
In a study published last September in Nature Medicine, Einstein researchers demonstrated that some animals inoculated with the altered M. smegmatis are able to generate a robust immune response when challenged with M. tuberculosis.
Despite widespread use of the 90-year-old Bacille Calmette-Guérin (BCG) vaccine and the availability of several anti-TB drugs, TB remains a major global health problem. In 2010, 8.8 million people fell ill with TB and 1.4 million died of the disease, according to the World Health Organization. The situation has worsened in recent years with the rise of multi drug-resistant TB (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), which are especially common in Africa and Asia.
“Novel therapies for TB are urgently needed, particularly a new and effective vaccine,” says William Jacobs, Jr., PhD, professor of microbiology and immunology and of genetics at Einstein and a Howard Hughes Medical Institute investigator, who led the development of the new vaccine approach and is principal investigator of the NIH grant.
Einstein’s vaccine approach emerged from basic studies of how TB bacteria outwit the immune system. Jacobs and his colleagues worked with M. smegmatis, which in high doses is lethal in mice but does not harm humans. The researchers created a version of M. smegmatis lacking a set of genes, known as ESX-3, considered crucial for evading host immunity. When high doses of the altered bacteria were infused into mice, it became clear that bacteria lacking the ESX-3 genes could no longer evade their hosts' immune system: the mice controlled and cleared the infection through a robust T-cell response – the same response a successful TB vaccine would elicit.
Unfortunately, Jacobs found that removing the same set of genes from M. tuberculosis killed the bacterium – which meant M. tuberculosis could not be manipulated in this way to make a vaccine. But Jacobs and his colleagues found a way around this stumbling block. They took the M. smegmatis bacteria lacking ESX-3 and inserted the analogous set of M. tuberculosis ESX-3 genes. These M. smegmatis bacteria were then infused into mice, which once again fought off the infection. And eight weeks later, when the mice were challenged with high doses of M. tuberculosis – which kills mice as well as people – these “vaccinated” mice lived much longer than control mice: an average survival time of 135 days vs. 54 days.
Of particular note was the markedly reduced level of TB bacteria found in the animals’ tissues. “Most notably,” says 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.”
Only about 1 in 5 mice showed this robust response – indicating that the vaccine must be improved before it can be considered sufficiently effective.
With funds from the NIH grant, the researchers will try to make the vaccine more effective by further genetically modifying the bacteria that it uses. They will also develop a manufacturing process for making batches of the vaccine for human use and develop assays for identifying the most potent batches.
The grant “Vaccines for Extensively Drug Resistant Tuberculosis” (1R01AI098925-01) was awarded by National Institute of Allergy And Infectious Diseases, a division of the NIH.