Tuberculosis: An Ancient Disease in Need of Modern Scientific Tools
Posted on by Anthony S. Fauci, M.D., National Institute of Allergy and Infectious Diseases
Although COVID-19 has dominated our attention for the past two years, tuberculosis (TB), an ancient scourge, remains a dominating infectious disease globally, with an estimated 10 million new cases and more than 1.3 million deaths in 2020. TB disproportionately afflicts the poor and has long been the leading cause of death in people living with HIV.
Unfortunately, during the global COVID-19 pandemic, recent gains in TB control have been stalled or reversed. We’ve seen a massive drop in new TB diagnoses, reflecting poor access to care and an uptick in deaths in 2020 .
We are fighting TB with an armory of old weapons inferior to those we have for COVID-19. The Bacillus Calmette–Guérin (BCG) vaccine, the world’s only licensed TB vaccine, has been in use for more than 100 years. While BCG is somewhat effective at preventing TB meningitis in children, it provides more limited durable protection against pulmonary TB in children and adults. More effective vaccination strategies to prevent infection and disease, decrease relapse rates, and shorten durations of treatment are desperately needed to reduce the terrible global burden of TB.
In this regard, over the past five years, several exciting research advances have generated new optimism in the field of TB vaccinology. Non-human primate studies conducted at my National Institute of Allergy and Infectious Diseases’ (NIAID) Vaccine Research Center and other NIAID-funded laboratories have demonstrated that effective immunity against infection is achievable and that administering BCG intravenously, rather than under the skin as it currently is given, is highly protective .
Results from a phase 2 trial testing BCG revaccination in adolescents at high risk of TB infection suggested this approach could help prevent TB . In addition, a phase 2 trial of an experimental TB vaccine based on the recombinant protein M72 and an immune-priming adjuvant, AS01, also showed promise in preventing active TB disease in latently infected adults .
Both candidates are now moving on to phase 3 efficacy trials. The encouraging results of these trials, combined with nine other candidates currently in phase 2 or 3 studies , offer new hope that improved vaccines may be on the horizon. The NIAID is working with a team of other funders and investigators to analyze the correlates of protection from these studies to inform future TB vaccine development.
Even with these exciting developments, it is critical to accelerate our efforts to enhance and diversify the TB vaccine pipeline by addressing persistent basic and translational research gaps. To this end, NIAID has several new programs. The Immune Protection Against Mtb Centers are taking a multidisciplinary approach to integrate animal and human data to gain a comprehensive understanding of the immune responses required to prevent TB infection and disease.
This spring, NIAID will fund awards under the Innovation for TB Vaccine Discovery program that will focus on the discovery and early evaluation of novel TB vaccine candidates with the goal of diversifying the TB vaccine pipeline. Later this year, the Advancing Vaccine Adjuvant Research for TB program will systematically assess combinations of TB immunogens and adjuvants. Finally, NIAID’s well-established clinical trials networks are planning two new clinical trials of TB vaccine candidates.
As we look to the future, we must apply the lessons learned in the development of the COVID-19 vaccines to longstanding public health challenges such as TB. COVID-19 vaccine development was hugely successful due to the use of novel vaccine platforms, structure-based vaccine design, community engagement for rapid clinical trial enrollment, real-time data sharing with key stakeholders, and innovative trial designs.
However, critical gaps remain in our armamentarium. These include the harnessing the immunology of the tissues that line the respiratory tract to design vaccines more adept at blocking initial infection and transmission, employing thermostable formulations and novel delivery systems for resource-limited settings, and crafting effective messaging around vaccines for different populations.
As we work to develop better ways to prevent, diagnose, and treat TB, we will do well to remember the great public health icon, Paul Farmer, who tragically passed away earlier this year at a much too young age. Paul witnessed firsthand the devastating consequences of TB and its drug resistant forms in Haiti, Peru, and other parts of the world.
In addition to leading efforts to improve how TB is treated, Paul provided direct patient care in underserved communities and demanded that the world do more to meet their needs. As we honor Paul’s legacy, let us accelerate our efforts to find better tools to fight TB and other diseases of global health importance that exact a disproportionate toll among the poor and underserved.
 Global tuberculosis report 2021. WHO. October 14, 2021.
 Prevention of tuberculosis in macaques after intravenous BCG immunization. Darrah PA, Zeppa JJ, Maiello P, Hackney JA, Wadsworth MH,. Hughes TK, Pokkali S, Swanson PA, Grant NL, Rodgers MA, Kamath M, Causgrove CM, Laddy DJ, Bonavia A, Casimiro D, Lin PL, Klein E, White AG, Scanga CA, Shalek AK, Roederer M, Flynn JL, and Seder RA. Nature. 2020 Jan 1; 577: 95–102.
 Prevention of M. tuberculosis Infection with H4:IC31 vaccine or BCG revaccination. Nemes E, Geldenhuys H, Rozot V, Rutkowski KT, Ratangee F,Bilek N., Mabwe S, Makhethe L, Erasmus M, Toefy A, Mulenga H, Hanekom WA, et al. N Engl J Med 2018; 379:138-149.
 Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis. Tait DR, Hatherill M, Van Der Meeren O, Ginsberg AM, Van Brakel E, Salaun B, Scriba TJ, Akite EJ, Ayles HM, et al.
 Pipeline Report 2021: Tuberculosis Vaccines. TAG. October 2021.
Tuberculosis (National Institute of Allergy and Infectious Diseases/NIH)
NIAID Strategic Plan for Tuberculosis Research
Immune Mechanisms of Protection Against Mycobacterium tuberculosis Centers (IMPAc-TB) (NIAID)
Partners in Health (Boston, MA)
[Note: Acting NIH Director Lawrence Tabak has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the seventh in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.]
Speeding COVID-19 Drug Discovery with Quantum Dots
Posted on by Dr. Francis Collins
These round, multi-colored orbs in the illustration above may resemble SARS-CoV-2, the coronavirus responsible for COVID-19. But they’re actually lab-made nanocrystals called quantum dots. They have been specially engineered to look and, in some ways, act like the coronavirus while helping to solve a real challenge for many labs that would like to study SARS-CoV-2.
Quantum dots, which have been around since the mid-1980s, are designed with special optical properties that allow them to fluoresce when exposed to ultraviolet light. The two pictured here are about 10 nanometers in diameter, about 3,000 times smaller than the width of a human hair. The quantum dot consists of a semi-conductive cadmium selenide inner core (orange) surrounded by a zinc sulfide outer shell (teal). Molecules on its surface (yellow) allow researchers to attach the viral spike protein (purple), which SARS-CoV-2 depends on to infect human cells.
To the left is a human cell (gray) studded with the ACE2 receptors (blue) that those viral spike proteins bind to before SARS-CoV-2 enters and infects our cells. In the background, you see another spike protein-studded quantum dot. But human neutralizing antibodies (pink) are preventing that one from reaching the human cell.
Because SARS-CoV-2 is so highly infectious, basic researchers without access to specially designed biosafety facilities may be limited in their ability to study the virus. But these harmless quantum dots offer a safe workaround. While the quantum dots may bind and enter human cells just like the virus, they can’t cause an infection. They offer a quick, informative way to assess the potential of antibodies or other compounds to prevent the coronavirus from binding to our cells.
In work published in the journal ACS Nano, a team that included Kirill Gorshkov, NIH’s National Center for Advancing Translational Sciences (NCATS), Rockville, MD, along with Eunkeu Oh and Mason Wolak, Naval Research Laboratory, Washington, D.C., demonstrated how these quantum dots may serve as a useful new tool to speed the search for new COVID-19 treatments. The dots’ fluorescent glow enabled the researchers to use a microscope to observe how these viral mimics bind to ACE2 in real time, showing how SARS-CoV-2 might attach to and enter our cells, and suggesting ways to intervene.
Indeed, imagine thousands of tiny wells in which human cells are growing. Imagine adding a different candidate drug to each well; then imagine adding the loaded quantum dots to each well and using machine vision to identify the wells where the dots could not enter the cell. That’s not science fiction. That’s now.
With slightly different versions of their quantum dots, the NCATS researchers and their colleagues at the Naval Research Laboratory will now explore how other viral proteins are important for the coronavirus to infect our cells. They also can test how slight variations in the spike protein may influence SARS-CoV-2’s behavior. This work provides yet another stunning example of how scientists with widely varying expertise have banded together—using all the tools at their disposal—to forge ahead to find solutions to COVID-19.
 Quantum dot-conjugated SARS-CoV-2 spike pseudo-virions enable tracking of angiotensin converting enzyme 2 binding and endocytosis. Gorshkov K, Susumu K, Chen J, Xu M, Pradhan M, Zhu W, Hu X, Breger JC, Wolak M, Oh E. ACS Nano. 2020 Sep 22;14(9):12234-12247.
What are Quantum Dots? (National Institute of Biomedical Imaging and Bioengineering/NIH)
Coronavirus (COVID-19) (NIH)
I Am Translational Science: Kirill Gorshkov (National Center for Advancing Translational Sciences/NIH)
U. S. Naval Research Laboratory (Washington, D.C.)
NIH Support: National Center for Advancing Translational Sciences
Wearable mHealth Device Detects Abnormal Heart Rhythms Earlier
Posted on by Dr. Francis Collins
As many as 6 million Americans experience a common type of irregular heartbeat, called atrial fibrillation (AFib), that can greatly increase their risk of stroke and heart failure . There are several things that can be done to lower that risk, but the problem is that a lot of folks have no clue that their heart’s rhythm is out of whack!
So, what can we do to detect AFib and get people into treatment before it’s too late? New results from an NIH-funded study lend additional support to the idea that one answer may lie in wearable health technology: a wireless electrocardiogram (EKG) patch that can be used to monitor a person’s heart rate at home.
Basic Research: Building a Firm Foundation for Biomedicine
Posted on by Dr. Francis Collins
A major part of NIH’s mission is to support basic research that generates fundamental knowledge about the nature and behavior of living systems. Such knowledge serves as the foundation for the biomedical advances needed to protect and improve our health—and the health of generations to come.
Of course, it’s often hard to predict how this kind of basic research might benefit human populations, and the lag time between discovery and medical application (if that happens at all) can be quite long. Some might argue, therefore, that basic research is not a good use of funds, and all of NIH’s support should go to specific disease targets.
To counter that perception, I’m pleased to share some new findings that underscore the importance of publicly supported basic research. In an analysis of more than 28 million papers in the PubMed.gov database, researchers found NIH contributed to published research that was associated with every single one of the 210 new drugs approved by the Food and Drug Administration from 2010 through 2016 . More than 90 percent of that contributory research was basic—that is, related to the discovery of fundamental biological mechanisms, rather than actual development of the drugs themselves.
Clinical Trials Bring Hope to Kids with Spinal Muscular Atrophy
Posted on by Dr. Francis Collins
More than a decade ago, the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) launched a special project to accelerate the translation of basic scientific discoveries into new treatments for a rare and often fatal disease. Five-year-old Faith Fortenberry whom you see above is among the kids who may benefit from the success of this pioneering endeavor.
Faith was born with spinal muscular atrophy (SMA), a hereditary neurodegenerative disease that can affect movement, breathing, and swallowing. When the NIH project began, there was no treatment for SMA, but researchers had discovered that mutations in the SMN1 gene were responsible for the disorder. Such mutations cause a deficiency of SMN protein, leading to degeneration of neurons in the brain and spinal cord, and progressive muscle weakness throughout the body. The NIH effort supported research to discover ways of raising SMN levels in cells grown in lab dishes, and then worked closely with patient advocates and pharmaceutical companies to move the most promising leads into drug development and clinical testing.
Given the desperate need for SMA treatments and all of the scientific energy that’s been devoted to pursuing them, I’ve been following this field closely. So, I was very encouraged to learn recently about the promising results of human tests of not just one—but two—new treatments for SMA [1, 2].