infective challenge. In other words, this is not a delayed-type hypersensitivity mechanism, and while HSP-60 may still play a role, it is not responsible for the persistence of inflammation.

• While there may be 15 serovariants, typically 1 or 2 serotypes will be dominant in any given population. Researchers don’t understand why, and indeed they can’t always differentiate among strains. Nevertheless, in terms of vaccine development, this makes for a much simpler “cocktail”, rather than trying to include all 15.

• Studies of antibody passive-immune therapy were conducted before a neu-tralizing assay was available and produced ambiguous results. These studies need to be repeated in light of new understanding of antibody response at mucosal sites.

• Most researchers would agree that the route of administration should be mucosal. It is unclear whether intranasal, rectal, etc., would elicit the best response.

• MOMP is down-regulated by interferon (IFN) gamma, but only in 3 of the 15 serotypes.

Incidence and Burden. A third of the world’s population is thought to be infected with tuberculosis, and 10 million die from TB each year. In the United States there are an estimated 10 million people infected with TB, and the numbers of infections and deaths has been rising rather than falling—there were more than 50,000 excess deaths between 1985 and 1992. And while a number of effective chemical therapies are available, clinicians are seeing increasing numbers of multiple-drug-resistant strains of TB. The massive epidemiology of this disease demands an effective preventative vaccine.

Problems with Existing Vaccine. Unlike many other infectious diseases, there is already a vaccine for tuberculosis (TB) —the Bacillus Calmette-GuJrin (BCG) vaccine, developed over 70 years ago in France. But while BCG is one of the oldest vaccines, it is also one of the most controversial. Its effectiveness varies considerably, and there is concern over the potential variability among the various strains of the vaccine that have developed over the years. Consequently, there is growing interest in finding a possible replacement for BCG as a vaccine against TB.

BCG is made with attenuated Mycobacterium bovis, the other species that, like M. tuberculosis, can cause TB. It was developed in the 1920s, but was never cloned and, as it passed through different laboratories throughout the world, a lot