March 24, 2022
Statement of Lakshmi Ramachandra, Ph.D., Peter Kim, M.D., and Anthony S. Fauci, M.D.
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Today marks the 140th anniversary of the announcement by Dr. Robert Koch that tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis. World TB Day is a reminder that this ancient disease remains a relentless killer. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, affirms its commitment to the 2022 World TB Day theme, Invest to End TB. Save Lives, by supporting and conducting wide-ranging research aimed at reducing the health and economic impacts of TB.
The global burden of TB is profound. The World Health Organization estimates that, in 2020, approximately 10 million new TB cases were diagnosed globally, including as many as 500,000 cases of multidrug-resistant (MDR) or extensively drug-resistant (XDR) TB. That year, at least 1.5 million people died of TB, and it remains the leading cause of death among people living with HIV. The COVID-19 pandemic has hampered the fight against TB in many ways, such as by making it difficult for many people to get timely access to accurate diagnoses and drug treatments. As one result, recent progress in declining TB deaths was reversed; in 2020, annual deaths rose for the first time since 2005.
TB is treatable with antibiotics, but drug regimens for drug-susceptible disease require months of treatment and come with toxic side effects, while regimens for MDR-TB and XDR-TB require even longer duration and are complex, costly, and prone to failure. Improving TB treatment has long been a key goal of NIAID research. For example, through its AIDS Clinical Trials Group (ACTG), NIAID recently supported a trial in collaboration with the CDC that found a 4-month drug regimen was as effective as the standard 6-month regimen in treating drug-susceptible TB. The ACTG is currently supporting a trial that will determine if a shorter, 3-month regimen of a new combination of TB drugs is better than the standard 6-month regimen. NIAID also supported early research leading to the TB drug pretomanid (Pa824). When used in combination with other TB drugs, pretomanid can offer people with XDR-TB a relapse-free cure lasting at least two years, as demonstrated in the NixTB trial. A follow-up trial, ZeNix, reported results this year showing further refinement to the regimen and shortening of the duration of treatment. As a further example, NIAID supports an innovative Phase 2 trial to estimate the optimal duration of treatment for MDR-TB in the Philippines and Vietnam using new and established oral drugs. In addition, scientists in NIAID’s Division of Intramural Research and their collaborators developed a new TB-selective oxazolidinone drug that is expected to be free of the side effects caused by the TB drug linezolid. The drug candidate is a once-daily, oral formulation scheduled to enter early-stage clinical evaluation next year.
The world’s only licensed TB vaccine, the Bacille Calmette-Guerin (BCG) vaccine, has been in use since 1921. While it does provide protection against disseminated TB disease in infants and children, BCG vaccine cannot be given to infants who have HIV and does not offer lasting protection against lung disease in adults. Thus, safe and effective TB vaccines for all manifestations of the disease are urgently needed. There are numerous challenges to overcome, including gaps in the fundamental understanding of TB pathogenesis and host immune responses to TB bacteria. In addition, it is not known precisely which immune responses correlate with protection from TB infection or disease, making it difficult to assess the effectiveness of candidate TB vaccines, a problem compounded by the absence of robust assays to measure biological responses to vaccine.
These challenges notwithstanding, NIAID investments in conducting and supporting TB vaccine-related research provide reasons for optimism. For example, NIAID will work with other stakeholders to integrate information gathered in two recently completed TB vaccine clinical trials with information from small animal and non-human primate studies to help answer pressing questions about correlates of protection following vaccination. Also, NIAID’s Immune Mechanisms of Protection against Mtb (IMPAc-TB) program is developing a comprehensive understanding of the immune responses required to prevent initial infection with TB bacteria, the establishment of latent infections, or the transition from latent to active TB disease. Better understanding of these processes will inform TB vaccine development.
This year, NIAID plans to fund two new initiatives: Advancing Vaccine Adjuvant Research for TB (AVAR-T) and the Innovation for TB Vaccine Discovery (ITVD) program. The objective of AVAR-T is to further the development of preventive TB vaccines through side-by-side comparison of adjuvants—substances that boost the immune response to vaccine—in combination with various Mtb immunogens with the goal of identifying promising adjuvant-immunogen candidates for further clinical development. The ITVD program will help expand the pipeline of early-stage vaccine candidates, including those that use such new platform technologies as nanoparticles and mRNA to deliver vaccine, into preclinical testing in animal models.
Looking ahead, we may be able to apply lessons learned during the COVID-19 pandemic response to improve and accelerate TB vaccine design and testing. For example, the novel mRNA technologies that were so successful in the rapid development of COVID-19 vaccines could potentially be used in novel TB vaccine design. The use of innovative clinical trial design, real-time data sharing, and community engagement tools to rapidly enroll volunteers in clinical trials all might find applications in the cause of TB vaccine advancement.
NIAID supports the development of new TB diagnostics, including tests to distinguish drug-resistant and drug-susceptible strains of TB. Since 2020, NIAID has supported three clinical research centers to evaluate early-stage diagnostics in TB-endemic counties. The centers provide clinical site capacity in 12 countries and will evaluate 36 different assays and biomarkers, including diagnostics for triage testing, rapid point-of-care diagnosis, and drug susceptibility. The diagnostics are designed to be useful in a variety of settings and in different patient populations, including children and people living with HIV. This month, NIAID issued a new funding opportunity announcement to support the development of improved drug susceptibility diagnostic tests, including ones that can be used at the point of care. Knowing drug susceptibility helps clinicians provide optimal treatment regimens at the time of diagnosis. Another recently announced funding opportunity, with awards expected next year, will support research to discover and validate TB biomarkers in very young children with and without HIV infection. Biomarkers are substances in blood or other tissue that reliably indicate the presence or progression of disease. Identification of TB biomarkers could help reveal which children are more liable to develop serious disease.
NIAID also conducts and supports basic research to understand the biology of replicating and non-replicating TB bacteria during infection and disease as well as investigations of interactions between TB bacteria and the human host cells they infect. For example, this year NIAID made four grant awards to scientists seeking to better understand tuberculous granulomas. Granulomas are clusters of inflammatory cells that can contain and ‘wall-off’ TB bacteria in the lung, but that also allow bacteria sequestered there to avoid elimination. Improved understanding of granulomas promises to provide a much-needed knowledge base for the development of therapeutic approaches suited to their specific features.
NIAID invests in TB research through numerous global collaborations, including ones that operate in virtual, rather than physical, space. A prime example of this is the NIAID TB Portals Program, a multi-national collaboration for TB data sharing and analysis. Collaborators from 16 countries across four continents bring expertise in medicine, information technology, genomics, and data visualization to the online, open-access platform. Today, to complement the TB Portals TB in 3D feature, the site adds TB in VR, an immersive learning experience about tuberculosis pathology and antibiotic resistance that can be accessed from a web browser with or without a virtual reality headset. NIAID also partners with governments of countries with high burden of TB to fund collaborative, independent observational research networks known as RePORT.
As one of the world’s largest funders of biomedical research on TB, NIAID has prioritized investing in TB to save lives. Today, we stand with our global health partners in firm resolve to overcome the challenges posed by TB and recommit ourselves to putting an end to the devastation it causes.
Anthony S. Fauci, M.D., is Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Lakshmi Ramachandra, Ph.D., is Chief, Tuberculosis and Other Mycobacterial Diseases Section, Division of Microbiology and Infectious Diseases, NIAID. Peter Kim, M.D., is Director, Therapeutics Research Program, Division of AIDS, NIAID.
Media inquiries can be directed to the NIAID Office of Communications at 301-402-1663, email@example.com.
NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.
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