In this era of multi-drug resistant TB and growing numbers of people with active TB due to coinfection with HIV, the advance could herald a needed breakthrough against one of the world's leading killers. Their study appears in the August issue of the Journal of Clinical Investigation.
TB is caused by Mycobacterium tuberculosis, a bacterial species that infects one third of the world's population (up to 10% of whom will develop active TB) and causes up to three million deaths annually. The only available vaccine--known as Bacille Calmette-Guérin (BCG)—is a live, attenuated (weakened) strain of M. bovis, which causes TB in cattle. Despite being the world's most widely used vaccine, BCG fails to protect adults from TB infection and doesn't reliably stem the reactivation of pulmonary TB (the most common form of the disease) in adults.
"Virtually all efforts to develop a better TB vaccine have focused on 'boosting' BCG—modifying it to elicit a stronger immune response in people," says Dr. William Jacobs, Jr., co-senior author of the paper and a Howard Hughes Medical Institute investigator at Einstein as well as professor of microbiology & immunology and molecular genetics.
"But we feel that tweaking the marginally useful BCG vaccine is the wrong strategy. So we've started with virulent M. tuberculosis—the organism that actually causes TB in humans—and are knocking out certain genes to yield a live, attenuated M. tuberculosis strain that still produces a strong immunological response that protects people."
TB bacteria invade human cells and then--successfully evading a person's immune response--lurk inside cells and multiply. A key evasion strategy involves preventing their host cells from undergoing apoptosis—the "cell suicide" often triggered when microbes invade cells.
For intracellular TB bacteria, avoiding apoptosis is an understandable aim: Apoptosis flushes them into the open, activating immune cells known as CD8+ T cells. These T cells make important contributions to the immune response by mopping up the bacteria and then becoming "memory" cells that can respond swiftly if the same bacterial species infects the person later on.
In designing their TB vaccine, the Einstein researchers discovered a gene in M. tuberculosis, known as secA2, that the TB bacteria rely on to prevent apoptosis of the mammalian cells they infect. The researchers then knocked that gene out of the TB chromosome, creating a weakened mutant strain of the bacterium.
When the mutant TB strain was injected into laboratory animals, infected cells underwent apoptosis, eliciting a strong and long-lasting T-cell response against the bacteria—just what is needed from an effective TB vaccine.
"Our secA2 mutant TB vaccine elicited protective immunity that was measurably superior to the standard BCG vaccine," says Dr. Steven Porcelli, professor of medicine (rheumatology) and microbiology & immunology at Einstein and the paper's other senior author.
"Two months after vaccination, significantly fewer bacteria persisted in the tissues of secA2 mutant-vaccinated animals than in the tissues of animals vaccinated with BCG. And compared with BCG, animals vaccinated with the mutant vaccine had much larger populations of the vital CD8+ memory T cells that a vaccine must elicit to optimally protect against infection."
Since the completion of this study, the Einstein researchers have knocked out an additional gene that has made the vaccine safer for human use without reducing the protective immunity it provides. The researchers now plan to knock out yet another gene to make the vaccine safer still. "We're hopeful that initial human trials of the secA2 mutant TB vaccine could begin within two to three years," says Dr. Porcelli.