Project Summary
Tuberculosis (TB), caused by pathogenic bacteria Mycobacterium tuberculosis (Mtb), is causing significant
morbidity and mortality to humans across the world. Live, attenuated M. bovis Bacillus Calmette-Guérin (BCG),
is the only TB vaccine currently licensed by the World Health Organization for use in humans. Although BCG
prevents severe disease in children with variable efficacy, it fails to protect against pulmonary TB in adults, who
are the primary source of transmission of Mtb in the community. Moreover, BCG may cause disease in immune-
compromised individuals, such as those co-infected with HIV. To control the development of active disease and
to break the chain of Mtb transmission, a new, safer and more effective vaccination approach is urgently
required. The development of “paradigm-shifting” protective measures against TB will significantly be aided by
the optimization of safe and effective combinatorial platforms, such as integrating novel vaccines with adjunct
host-directed therapy (HDT) and/or antimycobacterial drugs. This strategy is aimed at inducing appropriate
innate immunity along with potent and durable T cell responses, both of which are necessary for effective control
of TB. Such an integrated approach is urgently needed to control the pathology of active, cavitary TB cases and
transmission of Mtb, as well as to prevent reactivation of latently infected individuals, estimated to be about a
quarter of the world population, who are Mtb-infected and mostly asymptomatic but can reactivate the disease
upon immune suppression. Selection and usage of a relevant animal model that recapitulates the
pathophysiology of cavitary TB, as seen in humans is vital to screen novel and better intervention strategies to
combat the disease, including potent vaccine and drug candidates. We have established a rabbit model of
aerosol Mtb infection that mimics the range of human manifestations of pulmonary TB, from cavitary
(transmissible) disease to latent infection. Dr. Subbian has established a rabbit model of cavitary TB and the
sub-award PI, Dr. Kupz has developed a tractable and reproducible mouse model to study the reactivation
dynamics of latent Mtb infection following the loss of CD4+ T cells as it occurs in HIV co-infected individuals.
Using these two models, we propose to determine the ability of a novel recombinant BCG strain (BCG::ESAT-
6-PE25SS developed in Dr. Kupz lab), in combination with mTOR inhibitor (everolimus) and/or two first-line
antibiotics, isoniazid and rifampicin, to protect against progression to cavitary TB (rabbit) and/or induce
sterilizing immunity in latency (mice). To compare our approach, we will test individual components in these
model animals. We will also define mucosal (lung) and systemic (blood) immune parameters that predict
protection against Mtb challenge in our model system. The results of these studies can contribute towards the
development of new generation vaccine platforms for targeting other intracellular pathogens, in addition to Mtb.