Tuberculosis: An Ancient Disease in Need of Modern Scientific Tools

Caption: Here I am with Paul Farmer, who was a strong voice for improving TB prevention and treatments in resource-scarce settings, when he came to NIH in 2007 to deliver my institute’s James C. Hill Memorial Lecture. Credit: NIH

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 [1].

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 [2].

Results from a phase 2 trial testing BCG revaccination in adolescents at high risk of TB infection suggested this approach could help prevent TB [3]. 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 [4].

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 [5], 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.

References:

[1] Global tuberculosis report 2021. WHO. October 14, 2021.

[2] 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.

[3] 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.

[4] 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.

[5] Pipeline Report 2021: Tuberculosis Vaccines. TAG. October 2021.

Links:

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.]