7. TB research and innovation
Tuberculosis (TB) research and innovation is essential to achieve global TB targets for reductions in TB incidence and TB deaths. The targets of the WHO End TB Strategy (1), adopted in 2014, required a global rate of decline in TB incidence of
17% per year between 2025 and 2035, compared with a baseline level of 2% per year in 2015 and 10% per year by 2025 (the best achieved at national level, historically). It was recognized that such an unprecedented rate of decline from 2025 would require
a major technological breakthrough by 2025, such as a new TB vaccine that is effective both before and after exposure to infection (2). “Intensified research and innovation” is the third pillar of the End TB Strategy.
The political declaration at the first UN high-level meeting on TB, held in 2018, included the first global funding target for TB research to be agreed by all UN Member States: US$ 2 billion per year in the period 2018–2022. Although
funding has been slowly increasing (Fig. 7.1), the latest published data show that only US$ 915 million was available in 2020 (3), less than half of the
global target.
Fig. 7.1 Funding for TB research, 2015–2020
WHO continues to promote and monitor progress in the development of new TB vaccines, diagnostics and medicines. The diagnostic pipeline has expanded considerably in terms of the number of tests, products or methods in development (Table 7.1). These include
molecular tests for the detection of TB disease and drug resistance, interferon gamma release assays (IGRAs) for the detection of TB infection, biomarker-based assays for detection of TB disease, computer-aided detection (CAD) for TB screening using
digital chest radiography, and a new class of aerosol-capture technologies for detection of TB disease. Three new antigen-based skin tests for TB infection that perform better than tuberculin skin tests (particularly in terms of specificity) were
evaluated and recommended by WHO in 2022; these are the Cy-Tb skin test, Serum Institute of India, India; C-TST, Anhui Zhifei Longcom Biopharmaceutical Co. Ltd, China; and Diaskintest, JSC Generium, Russian Federation. WHO plans to evaluate the following
tests in the coming year: culture-free, targeted-sequencing solutions to test for drug resistance directly from sputum specimens; broth microdilution methods for drug-susceptibility testing (DST); and new IGRAs to test for TB infection.
In
September 2022, there were 26 drugs for the treatment of TB disease in Phase I, Phase II or Phase III trials (Table 7.2). These drugs comprise 17 new chemical entities, two drugs that have received accelerated regulatory approval, one drug that was
recently approved by the United States (US) Food and Drug Administration under the limited population pathway for antibacterial and antifungal drugs, and six repurposed drugs. Various combination regimens with new or repurposed drugs, as well as host-directed
therapies, are in Phase II or Phase III trials.
Table 7.1 An overview of progress in the development of TB diagnostics, September 2022
| Technologies in development | On the market (Not yet evaluated by WHO) | Technologies under evaluation by WHO | Technologies endorsed by WHO |
|---|---|---|---|
Molecular detection of TB disease and drug resistance detection
Aerosol capture technologies for TB disease detection
Interferon gamma release assays (IGRAs) for TB infection detection
Biomarker based assays for TB disease detection
Computer-aided detection (CAD) for digital chest radiography
Other artificial-intelligence (AI)-based tools
| Molecular detection of TB disease and/or drug resistance detection
Interferon gamma release assays (IGRAs) for TB infection detection
Computer-aided detection (CAD) for digital chest radiography
| Culture-based drug susceptibility testing
Culture-free, targeted-sequencing solutions for detection of TB drug resistance
Biomarker based assays for TB disease detection
Interferon gamma release assays (IGRAs) for TB infection detection
| Molecular detection of TB disease and/or drug resistance
Interferon gamma release assays (IGRAs) for TB infection detection
Mycobacterium tuberculosis antigen-based skin tests
Culture-based technologies
Microscopy
Biomarker based assays
Computer-aided detection (CAD) for digital chest radiography
|
Table 7.2 The global clinical development pipeline for new anti-TB drugs and drug regimens to treat TB disease, September 2022
| Phase Ia | Phase IIa | Phase IIIa |
|---|---|---|
| Macozinoneb | BTZ-043b | Bedaquiline–delamanid–linezolid–levofloxacin–clofazimine (6-month oral regimen for RR-TB) or bedaquiline–delamanid–linezolid–clofazimine (6–9 month oral regimen for pre-XDR and XDR-TB) (BEAT TB trial)g |
| BVL-GSK098b | GSK-3036656b | Bedaquiline–pretomanid–moxifloxacin–pyrazinamide (BPaMZ) (SimpliciTB trial) |
| GSK-286 (GSK 2556286)b | OPC-167832b | Bedaquiline with two OBRsc (all-oral, 9 months; with injectable, 6 months) (STREAM Stage 2) |
| TBAJ-587b | SPR720 (Fobrepodacin)b | Bedaquiline and delamanid with various existing regimens for MDR-TB and XDR-TB (endTB trial) |
| TBAJ-876b | Telacebec-(Q203)b | Bedaquiline-delamanid-linezolid-clofazimine for fluoroquinolone-resistant MDR-TB (endTB-Q) |
| TBI-166b | TBA-7371b | Rifampicin High-dose rifampicin and linezolid to reduce mortality among people with TB meningitis (INTENSE-TBM)g High-dose rifampicin to shorten drug-susceptible TB treatment (Hi-DoRi-3) High-dose rifampicin with standard regimen for drug-susceptible TB treatment (RIFASHORT) |
| TBI-223b | Delpazolidb Delpazolid dosing in combination With bedaquiline, delamanid, and moxifloxacin (PanACEA-DECODE-01) EBA, Safety and PK of delpazolid | Several 2-month regimens for drug-susceptible TB (TRUNCATE-TB) |
| High dose isoniazid for isoniazid-resistant or drug-susceptible TB (ACTG A5312) | SQ109b | Short intensive treatment for children with TB meningitis (6 months of daily rifampicin, isoniazid, pyrazinamide and levofloxacin (SURE)e,f,g |
| Sutezolidb | Ultra-short treatment for fluoroquinolone sensitive MDR-TB (TB-TRUST) | |
| Sudapyridine (WX-081)b | ||
| Bedaquiline PK, safety and tolerability of bedaquiline with OBR c in HIV-infected and uninfected children with MDR-TB (IMPAACT P1108)e,f,g PK and safety of bedaquiline with OBR c in HIV-uninfected children with MDR-TB (TMC207-C211)e,f,g | ||
| Delamanid PK, safety and tolerability of delamanid with OBR c in HIV-infected and uninfected children with MDR-TB (IMPAACT 2005)e,f,g | ||
| Rifampicin High-dose rifampicin for drug-susceptible TB (PanACEA-MAMS-TB-01) High-dose rifampicin for TB meningitis (ReDEFINe) | ||
| Linezolid Efficacy and tolerability of two doses of linezolid, combined with bedaquiline, delamanid, and clofazimine (Linezolid dosing) | ||
| Clofazimine PK, safety, tolerability and acceptability of child-friendly formulations of clofazimine and moxifloxacin to treat children with RR-TB (CATALYST)e,f,g PK, safety, and acceptability of clofazimine in children with RR-TB (Clofazimine Kids Study)e,f,g | ||
| Bedaquiline and pretomanid with existing and re-purposed anti-TB drugs for MDR-TB (TB PRACTECAL Phase II/III trial)) | ||
| Efficacy and Tolerability of Bedaquiline, Delamanid, Levofloxacin, Linezolid, and Clofazimine (DRAMATIC)f,g | ||
| Shorter regimens including clofazimine and rifapentine for drug-susceptible TB (CLO-FAST trial/A5362) | ||
| Pretomanid-containing regimens to shorten treatment for drug-susceptible TB (APT trial) | ||
| Delamanid–linezolid–levofloxacin– pyrazinamide for fluoroquinolone- susceptible MDR-TB (MDR-END trial) | ||
| Levofloxacin with OBRc for MDR-TB (Opti-Q) | ||
| 4-month treatment for drug-susceptible TB (PredicTB trial) | ||
| Pravastatind | ||
| Imatinibd | ||
| Metformind | ||
| Multiple adjunctive host-directed TB therapies for drug-susceptible TB (TBHDT)d |
a New drug compounds are listed first, followed by repurposed drugs, treatment regimens, and then host direct therapies.
b New chemical entity.
c Optimized Background Regimen.
d Host directed therapies.
e Includes infants (aged <12 months).
f Includes children (aged <10 years).
g Includes adolescents (aged 10–19 years).
In September 2022, at least 22 clinical trials to evaluate drugs and drug regimens for treatment of TB infection were being implemented (Table 7.3). Examples included trials for the prevention of drug-resistant TB among high-risk household contacts of TB patients with multidrug-resistant (MDR) and trials to assess how to optimize the administration of short-course TB preventive treatment (TPT) for very young children and people with HIV.
Table 7.3 The global clinical development pipeline for new drugs and drug regimens to treat TB infection, September 2022
| Phase I/II | Phase III/IV |
|---|---|
| ACTG-A5372 Drug-drug interactions between rifapentine and dolutegravir in HIV and TB co-infected individuals | A5300B/I2003/PHOENIx Efficacy and safety of 26 weeks of delamanid versus isoniazid to prevent TB among high-risk household contacts of MDR-TB patients |
| DOLPHIN and DOLPHIN TOO 3HP versus standard isoniazid preventive therapy among HIV-infected patients taking dolutegravir-based antiretroviral treatment | 1HP vs 3HP among people living with HIV |
| DOLPHIN KIDSa,b,c Study of dolutegravir-based ART and 3HP in children and adolescents living with HIV | PROTID Safety and efficacy of 3HP versus placebo to prevent TB in people with diabetes |
| DOLPHIN Moms 1HP versus 3HP with pharmacokinetics of dolutegravir among pregnant women with HIV | SCRIPT-LGTB Short course rifapentine and isoniazid for the preventive treatment of genital TB |
| IMPAACT P2001 Evaluating pharmacokinetics, tolerability, and safety of rifapentine and isoniazid in pregnant and postpartum women | SDR: 1HP vs 3HP Risk of systemic drug reactions (SDRs) during 3HP versus 1HP administration |
| Impact of 3HP on pharmacokinetics of dolutegravir and darunavir, with cobicistat | TB-CHAMPb Six months of daily levofloxacin for the prevention of TB among children household contacts of people with MDR-TB |
| iTIPSa TB infection prevention study in HIV-exposed uninfected infants | TBTC Study 37/ASTERoid, Phase II/III Safety, tolerability, and effectiveness of 6 weeks of rifapentine to prevent TB infection |
| TBTC Study 35a,b,c Dose finding and safety study of rifapentine and isoniazid in HIV-infected and HIV-uninfected children with TB infection | TPT and rheumatic disease 9H versus 3HP among people with rheumatic disease |
| 2R2c Higher dose rifampin for 2 months versus standard dose rifampin to treat TB infection | Ultra-Curto 1HP versus 3HP among people uninfected with HIV |
| SCRIPT-TB Short course rifapentine and isoniazid for prevention of TB among people with silicosis | V-QUIN MDR triala,b,c Six months of daily levofloxacin for the prevention of TB among household contacts of people with MDR-TB |
| YODA Impact of 3HP on pharmacokinetics of tenofovir alafenamide | WHIP3TBb,c Evaluation of 3HP versus periodic 3HP versus 6H in people living with HIV |
b Includes children (aged <10 years)
c Includes adolescents (aged 10–19 years)
In September 2022, there were 16 vaccine candidates in clinical trials: four in Phase I, eight in Phase II and four in Phase III (Table 7.4). They include candidates to prevent TB infection and TB disease, and candidates to help improve the outcomes of
treatment for TB disease.
Effective vaccines are critical to achieve annual global and national reductions in TB incidence and mortality that are much faster than those achieved historically. WHO has commissioned a full-value assessment
of new TB vaccines to guide investments in late-stage research as well the subsequent introduction and implementation of any that are licensed for use. Preliminary results suggest that vaccine products which meet the preferred product characteristics
of new TB vaccines would have substantive and positive health and economic impacts.
Table 7.4 The global clinical development pipeline for new TB vaccines, September 2022
| Phase I | Phase IIa | Phase IIb | Phase III |
|---|---|---|---|
| AdHu5Ag85Ab McMaster, CanSino | ChAdOx185A-MVA85Ab,i University of Oxford | BCG revaccination to prevent infectiond,j Gates MRI | GamTBvace Ministry of Health, Russian Federation |
| TB/FLU-01Lb TB/FLU-04Lb RIBSP | ID93 + GLA-SE(QTP101)e Quratis U.S. NIH/NIAID | DAR-901 boosterf,j Dartmouth | MIP/Immuvacf,i,j ICMR, Cadila Pharmaceuticals |
| BNT164c BioNTech SE | AEC/BC02e Anhui Zhifei Longcom | H56: IC31e SSI, Valneva, IAVI | MTBVACd,h Biofabri, University of Zaragoza, IAVI, TBVI |
| M72/AS01Ee,j GSK, Gates MRI | VPM1002d,g,i,j SIIPL, VPM | ||
| RUTI®f Archivel Farma, S.L. | BCG vaccination to prevent infection (TIPI)d HJF | ||
| BCG revaccination in children and adolescents (BRiC)d,i,j ICMR |
b Viral Vector.
c Messenger RNA (mRNA)
d Mycobacterial – Live.
e Protein / Adjuvant
f Mycobacterial – Whole Cell or Extract.
g Other trials involving VPM1002 include NCT04351685, NCT03152903.
h Includes infants (aged <12 months).
i Includes children (aged <10 years).
j Includes adolescents (aged 10–19 years).
Recent actions by WHO to support TB research and innovation
- Preparations for a high-level summit about how to accelerate progress in the development of new TB vaccines, drawing on lessons learned during the COVID-19 pandemic. It is anticipated that the summit will be held in early 2023.
- Preparation of a report about the health and economic benefits of new TB vaccines, to guide investments in late-stage research as well as the introduction and implementation of new TB vaccines. This will build on a previous publication (4) and associated journal articles (in preparation).
- In March 2022, convening of a multistakeholder consultation to discuss the emerging needs of Member States for policy guidance, evidence gaps for policy-making, and challenges in the translation of research evidence into policy (7). The aim is to guide decision-makers who fund and implement research to better focus their research agendas on the priorities of TB programmes and affected populations.
- In May 2022, submission of a progress report to the 75th World Health Assembly on the implementation of the Global Strategy for TB Research and Innovation (5).
- Preparation and publication of a consolidated assessment of gaps in TB research that have emerged during the process of reviewing evidence to inform WHO guideline development (6).
- Continued engagement in meetings of the BRICS TB research network (8).
Health Organization. Resolution WHA67.1. Global strategy and targets for tuberculosis prevention, care and control after 2015. Geneva: World Health Organization; 2014 (http://apps.who.int/gb/ebwha/pdf_files/WHA67/A67_R1-en.pdf).
Floyd K, Glaziou P, Houben R, Sumner T, White RG, Raviglione M. Global tuberculosis targets and milestones set for 2016–2035: definition and rationale. Int J Tuberc Lung Dis. 2018;22(7):723–30 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005124/).
Treatment Action Group, Stop TB Partnership. Tuberculosis research funding trends 2005–2020. New York: Treatment Action Group; 2021 (https://www.treatmentactiongroup.org/wp-content/uploads/2021/12/tb_funding_2021.pdf).
Gebreselassie N, Hutubessy R, Vekemans J, den Boon S, Kasaeva T, Zignol M. The case for assessing the full value of new tuberculosis vaccines. European Respiratory Journal. 2020;55(3):1902414 (https://erj.ersjournals.com/content/erj/55/3/1902414.full.pdf).
Global Strategy for Tuberculosis Research and Innovation (A75/10). Consolidated report by the Director-General. Seventy-fifth World Health Assembly. Geneva: World Health Organization; 2022 (https://apps.who.int/gb/ebwha/pdf_files/WHA75/A75_10Rev1-en.pdf).
Evidence and research gaps identified during development of policy guidelines for tuberculosis. Geneva: World Health Organization; 2021 (https://covid.comesa.int/publications/i/item/9789240040472).
Second WHO consultation on the translation of tuberculosis research into global policy guidelines. Geneva: World Health Organization; 2022 (https://covid.comesa.int/publications/i/item/9789240050907).
BRICS TB Research Network. See (http://bricstb.samrc.ac.za).
References