November 2007
Closing In: The Long Road to a TB Vaccine
National Institute of Allergy and Infectious Diseases (NIAID)
To cure TB worldwide would be a marvelous feat, to prevent it altogether would be even better. Currently only one TB vaccine exists. First administered in 1921, the BCG vaccine is safe, inexpensive and the most widely used vaccine in the world, according to the World Health Organization. There's only one thing wrong with BCG -- it doesn't work very well. For children, BCG probably does prevent TB that infects the lining of the brain, but its ability to prevent adult pulmonary TB, the most common form of the disease, is doubtful.
Steven Reed, Ph.D., of the Infectious Disease Research Institute in Seattle, Washington, is trying to make a better TB vaccine. Vaccines work by showing the immune system a "preview" of certain parts (called antigens) of a microbe. The immune system learns what to expect, and if the actual disease-causing organism ever invades, the system is primed to respond quickly.
Stimulating Memory
Mycobacterium tuberculosis (M. tb), the microbe that causes TB, lives inside immune system cells called macrophages and thwarts their infection-fighting ability. Because M. tb is so good at hiding inside the macrophages, some scientists think it may be impossible to prevent TB infection completely. A good vaccine, however, could keep infected cells to a minimum and thus prevent TB disease.
Between 1995 and 2002, Dr. Reed and collaborators at the Seattle biotech company Corixa, in collaboration with the pharmaceutical company GlaxoSmithKline (GSK), identified specific M. tb proteins that trigger a strong reaction in immune system "memory" cells. When properly activated, memory cells confer long-lasting immunity. Using genetic engineering and recombinant DNA technology, Dr. Reed's group first created a single, artificial gene encoding the instructions for two proteins, and then produced sizable quantities of this so-called fused protein.
Adding Adjuvant
To create the immune-stimulating effect of a vaccine, proteins must be combined with an adjuvant. The only FDA-approved adjuvant now used in human vaccines, alum, boosts antibody production -- one of two arms of the immune system. Alum does not, however, boost the second, non-antibody, arm of the immune system, called cellular immunity. Cellular immunity, which includes memory T cells, is what TB vaccine developers care about most. Creating adjuvants that can precisely drive the immune response is an area of intense research.
With their fused protein and a new kind of adjuvant developed by GSK, and previously shown to be safe and effective in clinical trials, Dr. Reed and his colleagues built various vaccine constructs in an effort to find one that best stimulates the immune system. One, named Mtb 72f, entered the first stage of safety testing in healthy human volunteers in 2004.
Closing In
"As recently as three years ago, no one thought we could improve on BGC enough to make a vaccine effort worthwhile," says Dr. Reed. "Now, we are closing in, and I really believe a new kind of vaccine -- perhaps given as a booster to BCG -- will be capable of preventing TB."