Compositions and methods for treating bacterial infections

Inventors

Shalek, Alexander K. • Hughes, Travis • Wadsworth, Marc H. • SEDER, Robert • Roederer, Mario • Flynn, Joanne L. • Darrah, Patricia

Assignees

Massachusetts Institute of Technology • University of Pittsburgh • US Department of Health and Human Services

Abstract

Provided herein are compositions and methods for therapeutic and/or prophylactic treatment of an intracellular bacterial infection in a subject in need thereof, comprising one or more modulating agents, wherein the one or more modulating agents increase expression of IFNγ, IL-2, TNF, and/or IL-17 in systemic and/or lung T cells. In some embodiments, the increase of expression of IFNγ, IL-2, TNF, and/or IL-17 occurs in lung T cells. The lung T cells can be lung resident T cells or systemic T cells that are recruited to the lung. In some embodiments, the T cells are CD4+ and/or CD8+ T cells. In some embodiments, the intracellular bacterial infection is a Mycobacterium tuberculosis (MTB) infection.

Core Innovation

The invention provides compositions and methods for therapeutic and/or prophylactic treatment of intracellular bacterial infections, particularly Mycobacterium tuberculosis (MTB) infection, in subjects in need thereof. The compositions comprise one or more modulating agents that increase expression of IFNγ, IL-2, TNF, and/or IL-17 in systemic and/or lung T cells. The increase in expression may occur in lung resident T cells or systemic T cells recruited to the lung, and the modulating agents may further increase the abundance of CD3+ T cells, CD11c+ macrophages, dendritic cells, or combinations thereof.

The background of the invention identifies a pressing global health need to develop more efficacious vaccines against pulmonary tuberculosis (TB), since the only licensed TB vaccine, Bacille Calmette-Guerin (BCG), administered intradermally at birth, provides excellent protection against disseminated TB but has variable efficacy against pulmonary disease at other ages. Pulmonary Mtb infection initiates in lung macrophages, with T cell immunity required to control infection and prevent disease. Current vaccine candidates focus on eliciting T cell immunity but face challenges in inducing and sustaining lung-resident T cells with sufficient breadth and durability. Intradermal and intramuscular routes commonly used for vaccines do not induce high frequencies of lung resident T cells, which may be critical for protection. Thus, formulations and delivery routes that induce systemic and tissue resident T cells, particularly in the lung, along with broad antigenic breadth, are critical for efficacious TB vaccines.

The invention addresses the problem of inadequate induction and maintenance of protective lung-resident T cell immunity by providing pharmaceutical formulations comprising modulating agents and/or formulations such as BCG vaccines administered via routes that enhance systemic and lung-resident T cell responses, such as intravenous administration. These formulations increase expression of key immune cytokines (IFNγ, IL-2, TNF, IL-17) and augment the abundance and function of T cells and antigen-presenting cells in lung and systemic compartments, thereby providing enhanced prophylactic and therapeutic efficacy against intracellular bacterial infections such as MTB.

Claims Coverage

The independent claims encompass methods of eliciting enhanced immune responses by intravenous administration of a pharmaceutical formulation comprising one or more modulating agents and BCG, with focus on MTB antigens and T cell cytokine expression.

The claims cover intravenous administration of pharmaceutical formulations including BCG and MTB antigen modulating agents that enhance expression of key immune cytokines in systemic and/or lung T cells, with confirmation by specific T cell subset measurements, and include use of attenuated viral vectors encoding relevant MTB antigens.

Stated Advantages

Documented Applications