William Bishai, M.D., Ph.D.
Johns Hopkins School of Public Health

Transmission Blocking Vaccines for Tuberculosis.

Mycobacterium tuberculosis is an obligate human pathogen whose only significant reservoir is the human host. Of the 6 billion world inhabitants, 2 billion are infected with latentM. tb. and approximately 8 million have active, transmissible tuberculosis. A strategy to block transmission from the 8 million active cases to the 4 billion susceptible individuals would, over time, lead to the elimination of TB.

The ultimate goal of this research is to develop transmission-blocking vaccines against TB. Such vaccines would prevent the evolution of transmissible TB among vaccinees. It is estimated that an average active case of TB leads to 8 - 10 new infections. Even if the vaccine did not block disease, but kept recipients non-infectious, the ability to interrupt TB spread would be of significant public health value.

The full cycle of TB transmission requires bronchial rupture of virulent M. tb and exhalation of the microbe into the environment for subsequent inhalation by a susceptible host. While patients who lack cavitary TB are capable of transmitting the disease, it has been well documented that patients with large cavitary lesions or with laryngeal TB are the most productive disease transmitters. The goal of this project is to illuminate the poorly understood phenomenon of cavity formation, to identify both bacterial and human determinants of cavitation, and to develop rational vaccines to inhibit transmission by preventing cavitary disease.

The project will rely heavily upon the rabbit TB model. In contrast to in vitro models and other animal models of TB, the rabbit is unique in forming both liquefied and cavitary TB granulomas and in exhaling infectious aerosols (Table 1). These features closely mimic human TB.

Table 1
Site of Bacteria or Stage In vitro Macrophage Model Mouse Model Guinea Pig Model Rabbit Model
Inhalation   + + +
Alveolar granuloma + + + +
Immature granuloma *   + + +
Solid caseous granuloma   + + +
Liquefied granuloma       +
Cavitary granuloma       +
Bronchial rupture       +
Exhalation / Transmission       +

*multinucleated giant cells, foamy macrophages, peripheral mononuclear cells

Using the rabbit model of tuberculosis we will correlate infectivity with pulmonary disease stage, identify bacterial and host factors which control and modulate cavity formation, and evaluate interventions to block cavitation and disease transmission.

Contact Dr. Bishai.