A Phase 2a, Double-Blind, Placebo-Controlled, Randomized Clinical Trial to Evaluate the Safety and Immunogenicity of ID93 + GLA-SE Vaccine Administered to HIV-Negative Patients at 3 Time Points During Multidrug Therapy for Drug Susceptible Pulmonary TB

This study was terminated in April 2020. Vidya Mave was PI of this HIV vaccine trial.

BACKGOUND:

Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis (Mtb). TB is one of the leading causes of morbidity and mortality around the world with an estimated 10 million cases of active TB each year and 1.6 million deaths annually. Though TB is often curable, treatment requires prolonged multidrug therapy (6 or more months). Compliance is difficult in all patient populations, but it is particularly difficult in resource-limited countries where the majority of cases of active TB are identified. Therapy has become more complex since it is increasingly common to find strains of Mtb that have developed resistance to many of the standard antimycobacterial drugs. Extensively drug resistant strains that are resistant to first and second line antitubercular agents have been identified around the world.

Given the widespread prevalence of TB, the high rates of morbidity and mortality, and the complexities of treatment, effective TB vaccines could have profound impacts on global health. However, it is critical to realize that the nature of protective immunity for Mtb is complex and immune correlates of protection remain unknown. Animal and human studies have demonstrated that a robust T cell-mediated immune response with active engagement of Th1 CD4 and CD8 cells is critical for control of Mtb. In particular, interferon gamma (IFNγ) and tumor necrosis factor (TNF) producing CD4 T cells are critical. The only licensed TB vaccine is Bacille Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis. BCG has been extensively studied around the world. It is effective in preventing TB meningitis and disseminated TB in children living in high prevalence areas of the world, but has had little effect on preventing reinfection and active pulmonary disease. Today, BCG is often administered to infants and young children residing in many TB endemic countries, but as TB remains the leading infectious disease killer in the word, there is a clear need for more effective vaccines that better prevent infection, reactivation and reinfection.

A number of Mtb vaccine candidates are under development and have entered clinical trials. Vaccines can be grouped based on their target population as therapeutic or preventative and preventative vaccines can be used either pre-exposure or post-exposure. Post-exposure vaccines are intended to prevent development of active disease in already exposed and/or latently infected individuals. Though some of the vaccine candidates are being designed to replace BCG, others incorporate BCG into their proposed vaccine schema and would serve as a booster vaccine to be administered either soon after BCG administration in infants or later in life to boost waning BCG responses. ID93 is a recombinant subunit vaccine antigen that combines four antigens comprised of Mtb proteins that are associated with virulence and latency into a single recombinant protein. The antigenicity of ID93 was tested by ex vivo stimulation of human leukocytes isolated from humans who were reactive to Mtb purified protein derivative (PPD+). 

ID93 stimulation elicited CD4 and CD8 T cells expressing one or more of the cytokines, IFNγ, TNF, or IL-2. Various adjuvants and adjuvant formulations were explored to enhance the Th1 response. Mice, guinea pigs, and cynomolgus monkeys immunized with ID93 + GLA-SE showed reduced pathology and/or fewer bacilli after challenge with virulent Mtb. ID93 + GLA-SE was also demonstrated to reduce the duration of antibiotic treatment of TB in mice and improve responses to TB therapy (as determined by chest x-ray) in non-human primates. IDRI Protocol TBVTC-204 Version 1.0 ID93 + GLA-SE 09 May 2019 16 of 69 This document is proprietary and is to be used only as authorized. No part is to be reproduced, disclosed to others, or quoted without prior written authorization from IDRI. In this clinical trial, we plan to extend on these investigations to assess the safety, immunogenicity and efficacy of ID93 + GLA-SE in individuals with pulmonary TB disease undergoing standard TB treatment. 

Primary Objective:
To evaluate the safety and tolerability of ID93 + GLA-SE vaccine compared to saline placebo in adult TB patients receiving  standard multidrug therapy (MDT), initiated at 3 different time points over the course of MDT.

Secondary Objective:
To evaluate immunogenicity to ID93 + GLA-SE vaccine compared to saline placebo in adult TB patients receiving standard  multidrug therapy (MDT), initiated at 3 different time points over the course of MDT.