Tuberculosis Research Support Increases
In the United States and most other parts of the developed world, both tuberculosis cases and tuberculosis research abated markedly after the introduction of multi-drug therapy during the late 1950s. Then, after decades of decline, tuberculosis made a dramatic comeback. The number of cases in the U.S. increased 14% from 1985 to 1993. The increase is attributed to the association of tuberculosis with the HIV epidemic, immigration from countries with high endemic rates of disease, transmission in congregate settings, and a decline of the health care infrastructure. More challenging for health officials were outbreaks of multidrug-resistant forms of tuberculosis. These events pointed to an urgent need for improved prevention, diagnostic, and treatment interventions to control the disease. In fact, the disease had never left. The increase in cases reported in the U.S. and elsewhere in the developed world reflected a worldwide increase in tuberculosis. The World Health Organization responded and declared tuberculosis a “Global Emergency.” National Institute of Allergy and Infectious Disease (NIAID) responded and dramatically increased support for tuberculosis research.
NIAID Tuberculosis Research Initiatives
In 1994, the NIAID launched a series of research initiatives in tuberculosis. These initiatives comprised a comprehensive program to take advantage of both new technologies and recent developments in tuberculosis basic and applied research. Program activities included research in the areas of microbiology, immunology, epidemiology and clinical studies in both HIV-negative and HIV-positive tuberculosis patients. Together, these multi-disciplinary studies focused three critical needs. These needs were:
- The development of surrogate markers needed to assess the efficacy of new drugs,
- The identification of correlates of protection needed to test the efficacy of new vaccine candidates, and
- An understanding of the microbiologic and immunologic responses to infection by M. tuberculosis.
The centerpiece of these efforts was the phase I and phase II clinical studies. These studies were to be conducted both in the United States and at foreign sites with high endemic rates of tuberculosis.
Yet, these diverse activities still left a serious gap. This gap was described as a missing link in the rapid transfer of new technologies from the research laboratory to the patient. Specifically, any technologies, interventions, and endpoints developed during the various multi-disciplinary studies still needed additional development to evaluate the efficacy of a new vaccine, therapy, diagnostic, or treatment protocol during clinical trials. Such trials also needed support from microbiology, immunology, and epidemiology studies focused on specific outcomes necessary to translate the new development to improved care and prevention to control tuberculosis. The NIAID issued a request for proposals (RFP) to bridge this gap.
Development of the Concept of the TBRU
The purpose of the RFP was to develop, through a multi-disciplinary and focused approach, surrogate markers of disease progression/disease prevention that will aid in the rapid evaluation of new therapies and correlates of protection to assist in the evaluation of candidate vaccines. To accomplish this task, four interactive scientific components were defined. These components were: epidemiological; immunological; microbiological, and clinical trials research. The epidemiologic component provides detailed longitudinal studies in areas of high prevalence of disease. These studies will identify factors associated with disease transmission including primary infection, re-infection, re-activation, and other factors associated with increased spread of infection and expression of disease, including behavioral factors associated with compliance. The immunological component will dissect the immune responses associated with primary infection, re-infection, latency and disease prevention and progression. The microbiological component will identify the microbial factors that are associated with the various stages of clinical illness, drug targets, and potential vaccines as well as factors associated with the emergence of drug resistance. Finally, the clinical component will bring to bear expertise in TB diagnosis and clinical disease as well as the research interest to incorporate the knowledge obtained from the other components in the development and implementation of protocols focused at defining surrogate markers. This RFP defined the Tuberculosis Research Unit (TBRU). The TBRU has the overall responsibility of coordinating these respective activities.
Overview of TBRU
The TBRU originally had five components. Epidemiological studies will be performed to identify the factors to improve our ability to design and implement tuberculosis prevention and treatment regimens. At the same time basic research efforts in immunology and microbiology will address the factors that define the "stages" of disease progression as well as the factors associated with disease prevention. The clinical research component will incorporate this knowledge base in the design and conduct of Phase I/II clinical trials. The fifth component will coordinate all these activities to assure the success of the multi-disciplinary effort.
Contract Awarded to Case Western Reserve University
The “First” Contract Period (1994-2000) - N01-AI-45244
The Tuberculosis Research Unit (TBRU) was awarded to Case Western Reserve University in September 1994. Support under the NIH/NIAID/DMID contract award lasted just over 5 years, through December 1999. The TBRU was organized under the direction of Jerrold Ellner, M.D. as Director with Kathleen Eisenach, Ph.D. of the University of Arkansas for Medical Sciences as Co-Director.
The objectives of the first Contract were similar to the current contract objectives. These objectives worked together to create a multidisciplinary, international team. The work of this team focuses on identifying and validating surrogate markers of human TB disease progression and correlates of the human protective immune response to Mycobacterium tuberculosis infection, and to improve the capability to conduct clinical trials of novel therapeutic, diagnostic and vaccination regimens. TBRU was designed to support translational research in tuberculosis, translating basic research findings into useful tools to improve the treatment and control of tuberculosis.
During the first five years, TBRU forged a team of researchers in the US, India, Uganda, and Brazil that included microbiologists, immunologists, epidemiologists, TB controllers, molecular biologists and clinicians. TBRU activities included developmental research to identify potential surrogate markers and correlates of protective immunity, phase I/II trials of potential immunotherapeutic agents (M. vaccae and rhIL-2), a Household Contact Study to elucidate transmission and natural history of M. tuberculosis infection, and a phase I/II study of a rifamycin-derivative (Rifalazil) to shorten and simplify TB treatment regimens. Completed Research projects are fully described in our research section.
The “Second” Contract Period (2000-2007) - N01-AI-95383
TBRU underwent re-competition for an additional 7-year contract period, which was awarded to CWRU in December 1999 under the direction of W. Henry Boom, M.D. The overarching goal of TBRU was again to integrate four components, epidemiology, immunology, microbiology and clinical trials, for interdisciplinary research to identify surrogate markers of disease, response to therapy and protection in humans, and to use these in clinical trials of therapeutic and prevention strategies. New, additional leaders in the areas of research were added to the previous group of researchers and support components for the scientific areas included a Data and Administrative Coordinating Center based at CWRU in Cleveland as well as a Specimen Repository. Much of the research begun and infrastructure built in the initial contract award continued into the second contract award with expansion to the Philippines and South Africa for clinical studies. Research initiatives in all areas were identified and included intensive immunology and microbiology surrogate marker studies, continuation of the earlier Household Contact Study (re-named Kawempe Community Health Study), BCG vaccine evaluation, a clinical trial for shortened duration of standard TB treatment (4 months compared to 6 months) and a pharmacokinetic study of the early bactericidal activity of linezolid and moxifloxacin to treat TB patients.
The Current Contract Period (2007-2014) - N01-AI-70022
TBRU underwent another competitive cycle and CWRU received a third contract award in May, 2007, again under Dr. Boom's direction. The scope of work although similar, has evolved to address changing TB research needs and will continue to emphasize and address critical gaps in translation TB research and to provide tools needed to advance TB control in TB endemic countries. The team of researchers has been expanded to build upon the existing strengths of the TBRU investigators and capacity. The new award will plan and develop new clinical studies to address the new statement of work and specifically building on human TB immunology, human genetics and vaccine evaluation. The new contract brings together investigators from the U.S., Europe, Uganda, and South Africa.