Senior Scholar Award in Global Infectious Disease
Carl Nathan, M.D.
Weill Medical College of Cornell University

Genomic Approach to Improved Immunogenicity of M. tuberculosis

Mycobacterium tuberculosis (Mtb) infects about one-third of the people in the world. About 8 million people a year develop tuberculosis as a result and about 2 million a year die from it. The future for this global infectious disease (pandemic) looks even more ominous, for several reasons. First, the Mtb pandemic and the HIV pandemic extensively overlap, and each infection exacerbates the other. Second, Mtb infection is spread simply by sharing air, so that extensive international travel and migration put people in all nations at risk. Third, Mtb is increasingly resistant to antibiotics. Multi-drug resistant tuberculosis can kill about 50% of those who have it even if they are otherwise healthy and get excellent medical care.

Clearly we need a highly effective vaccine. Because people are the only known hosts for Mtb, it might even be possible to eliminate tuberculosis entirely by a combination of high-efficiency vaccination and antibiotic regimens that work faster and more broadly than those presently in hand. However, putting aside the technical, fiscal and social challenges, there are enormous biological challenges in trying to improve on the marginally effective Mtb vaccine currently in use or the experimental vaccines now in development. First, infection by Mtb, or even full-blown tuberculosis that is treated and cured, do not protect a person against getting infected with Mtb again. Second, antibodies offer no protection in experimental animals; only cell-mediated immunity appears to protect, and much less is known about how to induce strong cell-mediated immunity. Third, no adjuvants (vaccine-augmenting agents) are available for clinical use that induce cell-mediated immunity as well as Mtb, and yet, as noted, Mtb does not induce clinically effective cell-mediated immunity against itself. Fourth, among those most in need of a vaccine are HIV positive people whose capacity for cell-mediated immunity is particularly weak. In sum, Mtb itself should be the best Mtb vaccine because it offers all its antigens and is a strong adjuvant, and yet Mtb is both a poor vaccine and a dangerous one. Thus it is hardly surprising that protection is limited following vaccination with BCG (the current standard), a mycobacterium that is safer than Mtb because it has lost many genes; or with Mtb that has been crippled to make it safer than BCG by deleting genes needed for growth in people; or by small numbers of individual Mtb antigens administered as DNA preparations, as pure proteins, or as proteins expressed artificially in other types of bacteria that can be administered safely.

The present project is based on the view that Mtb is an extremely complex collection of antigens. Some Mtb antigens induce protective immune responses. But other Mtb antigens interfere with induction of protective immune responses, or even induce counter-protective responses. The goal of this project is to query each of the 4000 genes of Mtb and systematically identify those genes whose products elicit counterproductive host responses. In the future, such genes can be deleted in Mtb, along with genes identified by others as necessary for growth in people. The resulting variants of Mtb may be both safer and more effective as a vaccine than Mtb itself.

Contact Dr. Nathan.