Tuberculosis (TB) : Preventing

by National Institute of Health

(Page 10 of 13)

Improving a Tried and True Vaccine-BCG for the 21st Century

A jab with bacillus Calmette-Guérin (BCG) vaccine is one of the first experiences of life for most newborns around the world, says Marcus Horwitz, M.D., a tuberculosis vaccine researcher at the University of California, Los Angeles. Although not given routinely in the United States, BCG is the mostly widely administered vaccine in the world-some four billion people have been inoculated with the safe and easy-to-produce vaccine. Developed in the early 1900s by Frenchmen Albert Calmette and Camille Guérin, BCG is made from live, weakened Mycobacterium bovis, a close relative of the bacterium that causes TB in humans.

BCG does a good job of protecting infants from a form of TB that attacks the brain, but the vaccine's effects wear off over time and it probably prevents the common pulmonary form of TB only about half the time, notes Dr. Horwitz. Research in his lab centers on using genetic engineering to make a better BCG-what Dr. Horwitz calls "BCG-plus." Dr. Horwitz and his colleagues designed a vaccine that uses recombinant DNA technology to add a specific protein from Mycobacterium tuberculosis (M. tb), the bacterium that causes TB, to the basic BCG vaccine. The result, rBCG30, does a better job at protecting guinea pigs from TB than BCG, Dr. Horwitz found.

Guinea pigs are a good stand-in for humans in TB vaccine experiments for several reasons, says Dr. Horwitz. Unlike mice, another frequently used experimental animal, guinea pigs are naturally susceptible to infection by M. tb and readily develop disease in their lungs that resembles the disease in humans. Whereas mice used experimentally are typically highly inbred, guinea pigs used experimentally are generally outbred and thus possess a genetic diversity among individuals that mirrors that of humans. Dr. Horwitz published his findings about the effectiveness of rBCG30 in guinea pigs in 2000. The recombinant vaccine entered early stage human clinical trials in 2004.

While a vaccine like rBCG30 might one day replace BCG as a vaccine given to infants, Dr. Horwitz and his colleagues are also working on a vaccine "booster" that could be used by the billions of people who have already received the standard BCG. In this strategy, the body's ability to detect and fight off invasion by M. tb is primed by BCG at birth, and then boosted by a later inoculation. Using the same M. tb protein as in the rBCG30 vaccine, the booster vaccine being designed by Dr. Horwitz is aimed at a subset of immune system cells called memory lymphocytes. Theoretically, a person who received a BCG prime and a boost with M. tb protein would be able to fight off infection by the TB bacterium by quickly producing large numbers of lymphocytes able to attack cells harboring the TB bacterium.

A third vaccine under development in Dr. Horwitz's lab is genetically engineered to be even safer than the time-tested BCG. The live, weakened strain of M. bovis in standard BCG is readily controlled by a healthy immune system, but can be dangerous for someone with a weakened immune system such as people infected with HIV. Dr. Horwitz has developed versions of BCG and rBCG30 in which the bacterium's ability to divide has been severely curtailed, which should make the vaccine safe even for people with a compromised immune system.

How Microarrays May Lead to Better Vaccines

Peter Small, M.D., of Stanford University, is a molecular epidemiologist-a still-young field that combines genome studies with traditional epidemiological techniques in efforts to control diseases such as TB.

With colleagues at Stanford University's Center for Tuberculosis Research and other institutions, Dr. Small employs DNA microarray technology to detect genetic variations among strains of Mycobacterium tuberculosis (M. tb), the bacterium responsible for TB. What they are learning may lead to better treatments and vaccines for TB.

In the Chips

DNA microarrays (also called gene chips) caused a sensation in science when they were introduced in the mid-1990s. The chips-tiny squares of glass containing hundreds of thousands of "spots" of DNA arrayed in a checkerboard pattern-give researchers a bird's-eye view of gene activity. Every spot in the grid is a short strand of DNA representing part of a known or suspected gene. Chopped up DNA pieces ("probes") taken from a cell are first attached to molecules that will make them fluoresce under a laser, then poured onto the chip. If a probe matches the DNA sequence of a spot, the two will stick to each other. Under a laser, the intensity of the glow reflects the numbers of copies of the DNA sequence. By analyzing the pattern of glowing spots, researchers see which genes are actively producing instructions for proteins. This, in turn, tells them something about the gene's function.

Along with collaborators including Thomas Gingeras, Ph.D., of the biotech company Affymetrix, Dr. Small used gene chips to see how various strains of M. tb differ at the genetic level.

TB does not affect every person equally. In most cases, an infected person's immune system successfully contains the organism within the lung. Sometimes, however, M. tb escapes containment and creates rampant, often deadly, TB. The Stanford team hypothesized that genetic characteristics of different strains of M. tb could explain some of the variation. Ultimately, Dr. Small hopes, it may be possible to "fingerprint" the particular strain of bacteria that a person has and tailor treatments precisely to that strain's weaknesses.

About the Author

NIH is the nation's medical research agency - making important medical discoveries that improve health and save lives. The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the primary Federal agency for conducting and supporting medical research.