The Frothingham lab studies the role of antibodies in protection from tuberculosis (TB). The current TB vaccine reduces disease severity, but it does not prevent the spread of TB in human populations. We hope to develop a better vaccine that will produce protective antibodies against Mycobacterium tuberculosis, the bacterial cause of human TB.
Frothingham and colleagues have identified a novel class of protective antibodies, namely those that bind to the surface of live virulent M. tuberculosis in the ELISA assay. These antibodies reduce the severity of pulmonary TB when they are administered in advance of an aerosol exposure. Humans with TB infection produce low levels of these surface-binding antibodies and their quality is poor (weak binding avidity and low IgG/ IgM ratio). We hope to develop a vaccine that improves on the natural human immune response to TB infection.
We have identified several monoclonal antibodies (mAbs) to the M. tuberculosis surface, and have used them to determine some of the mechanisms for protection against TB by this class of antibodies. Surface-binding mAbs block the uptake of M. tuberculosis bacteria by alveolar macrophages, and divert them to other cell populations in the lung (dendritic cells and neutrophils) that are better at killing the bacteria. Protection by surface-binding mAbs is independent from their ability to bind to the Fc-receptor, an antibody receptor found on immune cells in the lung.
We have identified several M. tuberculosis targets for protective mAbs, and are conducting studies to define these targets more precisely. We hope to develop human vaccines to generate M. tuberculosis surface-binding antibodies with high avidity and high titer. We will evaluate these vaccines based on two protective effects, preventing pulmonary M. tuberculosis infection and reducing disease after infection.