2019: A Banner Year for Tuberculosis Research

Abstract

This article outlines the significant scientific progress reported in 2019 that has led to the development of new drugs and therapeutic regimens, vaccine candidates, and diagnostics for the prevention and treatment of tuberculosis. In 2020, it will be important to build on this momentum and continue to advance basic and clinical research to develop improved tools and interventions, simultaneously optimizing their implementation in national control programs. To successfully achieve the goal to end tuberculosis within a generation, a concerted, collective, and collaborative effort is required, involving government, academia, industry and civil society at all levels.

The year 2019 marked a period of significant progress in the biomedical research arena supporting the global effort to successfully achieve an end to tuberculosis. Advances in the development of tuberculosis vaccines, therapeutics, and diagnostics have resulted from an intensified research effort characterized by increased investment in research resources and collaborations stimulated by both the political declaration of the United Nations General Assembly high-level meeting on tuberculosis [1] and the recent Lancet Commission on Tuberculosis report [2]. In addition, the National Institute of Allergy and Infectious Diseases (NIAID), which supports 38.9% of the global biomedical research effort on tuberculosis, issued in late 2018 its strategic plan for tuberculosis research [3], which has laser-focused the efforts of the scientific community on the highest research priorities needed to develop new tuberculosis treatment and prevention tools that are essential to end tuberculosis within a generation.

Although tuberculosis continues to be the leading infectious disease cause of death, steady progress in translating and implementing these tools continues to be seen in the decreasing numbers of deaths associated with tuberculosis, as well as decreases in the number of new, multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis cases reported in many geographic and demographic regions, according to the 2019 global tuberculosis report from the World Health Organization (WHO) [4]. In addition, WHO reported that a record number of individuals, 7 million, had tuberculosis diagnosed and treated in 2018 and that approximately 58 million lives have been saved by tuberculosis care and prevention between 2000 and 2018 [4].

VACCINES

The pathway to a safe and effective tuberculosis vaccine accelerated during 2019 with exciting preclinical and clinical results. An innovative preclinical study demonstrating that intravenous administration of BCG in rhesus macaques significantly prevented the acquisition of infection after aerosol challenge with Mycobacterium tuberculosis. Antigen-responsive CD4⁺ and CD8⁺ T cells were increased systemically and across all lung parenchymal tissues after immunization. Of the 10 macaques that received intravenous BCG vaccination in this study, 9 were highly protected from disease after challenge with virulent M. tuberculosis, with 6 demonstrating no detectable infection. These findings indicated that intravenous BCG vaccination can prevent or substantially limit M. tuberculosis infection in highly susceptible macaques. This study has important implications for vaccinology in general by providing potentially highly effective alternative delivery strategies for other vaccines, as well as insight into the mechanisms of protection and immune correlates specifically against M. tuberculosis [5].

A groundbreaking advance toward the development of a safe and effective tuberculosis vaccine resulted from the phase 2b clinical trial of the M72/AS01_E recombinant fusion protein vaccine candidate (GlaxoSmithKline). This large-scale clinical study, including 3575 participants with latent tuberculosis in Kenya, South Africa, and Zambia, demonstrated 49.7% efficacy for this vaccine candidate in preventing the development of active pulmonary tuberculosis for ≥3 years after the second dose of the vaccine, compared with the placebo group [6]. Efforts to identify correlates of protection will be critical to developing next-generation vaccine candidates that improve on the efficacy observed in this trial. In addition, in 2019, a phase 2b clinical trial (NCT04152161) was launched to confirm earlier results suggesting that BCG revaccination may prevent sustained infection with M. tuberculosis [7].

To further advance the development of potential tuberculosis vaccines, the NIAID in 2019 established 3 Immune Mechanisms of Protection Against Mycobacterium tuberculosis (IMPAc-TB) Centers. Multidisciplinary research teams in these centers will elucidate the immune responses needed to prevent initial tuberculosis infection, the mechanisms of establishment for latent tuberculosis infection, and the factors involved in the transition from latent infection to active tuberculosis disease. Findings from animal and human studies conducted at these centers also will inform the development of novel tuberculosis vaccine candidates and elucidate the effects of human immunodeficiency virus (HIV) and other coinfections on immune responses to tuberculosis infection or vaccination [8]. Several additional novel and promising tuberculosis vaccine candidates were progressing through the pipeline in 2019, including VPM1002, MTBVAC, H56:IC31, and a thermostable version of the ID93:GLA-SE vaccine candidate [4].

THERAPEUTICS

The treatment tools reported in 2019 included several novel and improved strategies and regimens for the treatment and prevention of tuberculosis. The Brief Rifapentine-Isoniazid Efficacy for TB (Tuberculosis) Prevention/A5279 (BRIEF TB/A5279) randomized, open-label phase 3 clinical trial (NCT01404312) demonstrated that a 1-month regimen of rifapentine plus isoniazid was noninferior to 9 months of isoniazid for preventing tuberculosis in adults and adolescents with HIV. There also were fewer adverse events and increased completion rates among study participants in the 1-month regimen group, compared with those in the 9-month group [9]. This treatment regimen represented an important new intervention for persons with tuberculosis and HIV coinfection.

In 2019, important information was gained regarding timing of chemoprevention in pregnant women. The TB APPRISE study (IMPAACT P1078) compared the safety and efficacy of initiating isoniazid preventive therapy during pregnancy versus 3 months post partum, in women living with HIV in countries with high tuberculosis prevalence. Although there were no significant differences in maternal safety outcomes between the groups, the study did observe a higher incidence of adverse pregnancy outcomes in the group treated during pregnancy. This finding is concerning and merits research into alternative approaches to tuberculosis preventive therapy in pregnant women [10].

Another significant treatment tool was demonstrated with the final results from the Transmission Investiguée de la Tuberculose Infantile study involving >2000 children under the age of 5 years living in households with ≥1 tuberculosis-infected individual. This study demonstrated that the shortened combination regimen of isoniazid and rifampicin for 3 months, instead of 6 months, prevented 95% of expected tuberculosis cases among the household contacts [11].

In 2019, NIAID launched a large, phase 3 clinical trial titled, “Protecting Households on Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients” (PHOENIx MDR-TB) (https://clinicaltrials.gov/ct2/show/NCT03568383) in 12 countries. This study compares oral delamanid with oral isoniazid plus vitamin B6 daily for 26 weeks to prevent active MDR tuberculosis disease in adults, adolescents, and children at high risk who are exposed to adult household members with MDR tuberculosis. Results from this innovative study will inform new tuberculosis prevention guidelines to avert the pain, disability, and death associated with MDR tuberculosis [12].

In 2019, a new antituberculosis drug was added to the treatment options when the US Food and Drug Administration approved pretomanid for use together with bedaquiline and linezolid in the treatment of MDR and XDR tuberculosis. A recent clinical study showed that this combination of drugs resulted in an 89% success rate for treatment of MDR and XDR tuberculosis [13]. Importantly, the regimen was only 6 months in duration and represents a significant advance in the treatment of drug-resistant tuberculosis, previously considered to be nearly untreatable [14]. Ongoing studies are evaluating pretomanid in simpler treatment regimens for MDR tuberculosis [4].

In view of the results from these recent clinical studies, WHO issued a rapid communication with key changes to the treatment of MDR and XDR tuberculosis [15], in advance of the updated WHO treatment guidelines. These updates provide for shorter, all-oral, bedaquiline containing regimens for eligible patients with MDR/rifampicin-resistant tuberculosis and the use of the novel bedaquiline-pretomanid-linezolid regimen under operational research conditions for XDR tuberculosis [15]. By the end of 2019, there were several new potential therapeutic compounds in the pipeline, representing 16 drug classes in various stages of development, including new formulations of older drugs and new chemical moieties with unique mechanisms of action [16].

DIAGNOSTICS

In the arena of tuberculosis diagnostics, the WHO-endorsed GeneXpert MTB/rifampicin resistance assay (Cepheid) is currently used in 48 nations worldwide [4]. In 2019, the WHO issued new recommendations for use of the lateral flow urine lipoarabinomannan antigen assay to assist in the diagnosis of active tuberculosis in adults, adolescents, and children with HIV in in-patient and outpatient settings [17]. In addition, the Food and Drug Administration in 2019 approved a new qualitative indirect diagnostic assay for M. tuberculosis infection, for use in conjunction with radiography, risk assessment, and other standard medical and diagnostic evaluations. The assay is based on detection of interferon γ to identify immune responses to 2 peptide antigens (early secreted antigen target 6 [ESAT-6] and culture filtrate protein 10 [CFP-10 proteins]) associated with M. tuberculosis infection [18]. In addition, the large-scale M. tuberculosis genome sequencing project at the Broad Institute continues to provide crucial data on genetic diversity and gene mutations that may result in drug resistance. These findings inform the urgently needed innovative, point-of-care diagnostics and rapid antibiotic susceptibility assays for drug-sensitive, MDR, and XDR tuberculosis [19].

CONCLUSIONS

Although the scientific advances and remarkable accomplishments in 2019 represent significant steps toward ending tuberculosis, clearly more remains to be done. Urgently needed are rapid, accurate, inexpensive, point-of-care diagnostics, new and more effective antituberculosis drugs and improved and shorter therapeutic regimens, and vaccine strategies to prevent tuberculosis and latent tuberculosis infection and the transition to active tuberculosis disease. To achieve the goal of ending tuberculosis, a concerted, collective, and collaborative effort is required involving government, academia, industry, and civil society at all levels. In 2020, we must build on the momentum of the past year and accelerate our efforts to advance critical basic and clinical research, leading to the development of new and better tools and the refinement of current diagnostics, vaccines, and therapeutics to prevent and treat tuberculosis. Finally, we must simultaneously increase the implementation of these strategies by tuberculosis control programs if we are to achieve our collective goal of ending tuberculosis within a generation.

Notes

Financial support. This work was supported by the Office of the Director, National Institute of Allergy and Infectious Diseases.

Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.