Prevention: Vaccine Developoment
Beating the World’s Most Successful Bug
William Jacobs, Ph.D.
TB researcher William R. Jacobs, Jr., Ph.D., calls his foe, Mycobacterium tuberculosis (Mtb), the planet’s most successful pathogen. The bacterium infects one-third of the world’s population and can survive for decades inside immune system cells, called macrophages, that kill many other disease-causing organisms. But Dr. Jacobs, of Albert Einstein College of Medicine in New York City, says a detailed understanding of Mtb’s genetics is emerging from work in his and other labs and may lead researchers to new and more effective ways to prevent TB.
Dr. Jacobs has devised ways to find which genes Mtb must have to effectively invade and persist inside macrophages as well as the genes needed for robust growth inside the human host. Dr. Jacobs selectively mutates specific Mtb genes to create strains that cannot grow or persist well inside mouse models of TB. He and his colleagues are testing these mutants for their suitability as the basis of new kinds of TB vaccines.
With colleagues from the research labs at the Food and Drug Administration in Rockville, Maryland, Dr. Jacobs published findings that a vaccine they made with mutant Mtb conferred long-term protection against TB in mice, including mice lacking CD4 cells, a key component of the immune system. The severely attenuated mutant Mtb strain lacked two specific genes that wild-type Mtb must have to successfully infect animal cells. The mutant strain is very safe to use in the mouse model infection and yet can confer long-term protection against TB infection.
The apparent effectiveness of this kind of severely attenuated live vaccine in immune-deficient mice is significant, say the scientists. Live, attenuated vaccines against such diseases as polio and measles have certain advantages over vaccines made with killed disease-causing organisms—they can generate immune responses that confer long-term protection against the disease after a single inoculation, for example. But vaccines containing live, weakened pathogens may not be safe for people whose immune systems are damaged, including those with HIV. The only existing vaccine against TB, Bacille Calmette-Guérin (BCG), is a live, attenuated vaccine that is not recommended for people with HIV.
Vaccines being developed by Dr. Jacobs and his colleagues are more severely weakened than the strain of TB in BCG and are weakened through the deliberate and specific deletions of critical Mtb genes. The hope is that this will make these new vaccines safe enough for people with HIV or other conditions that impair immune health to use.
References
Sambandamurthy VK. Long-term protection against tuberculosis following vaccination with a severely attenuated double lysine and pantothenate auxotroph of Mycobacterium tuberculosis. Infect Immun. 73(2):1196-203 (2005).
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