World TB Day: Is TB vaccine and treatment research back on track?
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Key Takeaways:
- Currently, the pipeline for tuberculosis treatments is the largest it has ever been.
- These are 24 TB vaccine candidates being assessed in 29 studies.
Throughout the COVID-19 pandemic, World TB Day, which is observed each year on March 23, has marked the need for more — more research, more testing, more treatment options, and more access for patients globally.
This year, more is still needed, although fortunately, David L. Cohn, MD, Infectious Disease News Editorial Board Member and professor of medicine in the division of infectious diseases at the University of Colorado School of Medicine, said TB treatment and vaccine research are both picking up momentum after being hindered in many places worldwide.
Healio spoke with Cohn and Maria Beumont, MD, vice president and chief medical officer of the TB Alliance, for their thoughts on where TB treatment and vaccine research stand and what progress has been made following disruptions from the COVID-19 pandemic that significantly impacted the fight against TB.
Healio: Is TB vaccine and treatment research back on track after being disrupted by the COVID-19 pandemic?
Beumont: Although many important advances in the treatment of drug-resistant TB have been made in recent years, the statistics have remained almost stagnant, with a recent COVID-19-induced increase in mortality.
Every year, 10 million people fall ill with TB, and in 2021 alone 1.6 million people died. Global funding levels continue to fall far short of what is needed to bring the TB pandemic under control. It is only with resources, funding and a global commitment to protecting global health that we can continue to advance the science of developing life-saving tools and treatments.
Cohn: For the most part, both TB treatment and vaccine research are picking up the pace after being significantly hindered in many sites and countries in terms of participant enrollment and retention, as well as available personnel to conduct the studies. Some units pivoted their resources to COVID-19 research and control; others just slowed or shut down.
That said, a great deal of planning for drug development and clinical protocols continued, albeit via conference calls and virtual meetings. One example of remarkable tenacity during the pandemic is noteworthy. The recently published TRUNCATE-TB trial enrolled 675 participants in 18 sites in five countries in Asia and Africa from March 2018 through January 2020 (pre-pandemic) and was able to achieve 99% follow-up for 96 weeks through December 2021 (during the pandemic).
Healio: What’s in the pipeline as far as new treatments for TB?
Beumont: We currently have the largest pipeline of new TB drugs in history, and we’re working with partners to advance compounds and drugs through all stages of clinical development. We’ve recently announced a new compound, telacebec, that TB Alliance has licensed from South Korea-based Qurient to continue its development as an anti-TB agent.
Cohn: A major focus for TB treatment trials for the past decade has been treatment shortening for both drug-sensitive (DS-TB) and drug-resistant TB (MDR-, XDR-TB) by using licensed anti-TB drugs in new combinations and/or higher doses, along with newer agents, bedaquiline and pretomanid, and one drug not initially developed for TB, linezolid.
After several failed attempts with regimens of less than 6 months for DS-TB and 18 to 24 months for MDR-TB (for the past 40 years), there has been significant progress in the past 2 years.
These success stories include favorable outcomes in the:
tBTC31/ACTG5349 study with rifapentine, moxifloxacin, isoniazid and pyrazinamide given for 17 weeks for DS-TB;
the NIX-TB and XeNIX studies with bedaquiline, pretomanid and linezolid given for 26 weeks for MDR- and XDR-TB;t
the SHINE study for nonsevere pediatric TB with isoniazid, rifampin, pyrazinamide and ethambutol given for 16 weeks; and
the TRUNCATE -TB study with bedaquiline, linezolid, isoniazid, pyrazinamide and ethambutol given for 8 weeks. Other treatment-shortening trials with different combinations of drugs will be completed this year, and several are starting to enroll or in planning stages.
In terms of new drugs in the pipeline, the most recent report from the Working Group on New TB Drugs of the Stop TB Partnership indicates there are 31 novel compounds from 12 different drug classes with different mechanisms of action, of which 13 are in preclinical development, six in phase 1 and 12 in phase 2 studies.
Examples of drugs in phase 2 studies include sutezolid (SUDOCU study) and delpazolid (DECODE study), investigational oxazolidinones that are likely to be less toxic than linezolid, which frequently causes dose-related peripheral neuropathy and myelosuppression.
New TB clinical trial groups have emerged during the pandemic. There are now 11 groups funded by governments, academic centers and the Bill and Melinda Gates Foundation, and at least six pharmaceutical companies are involved.
So, there is much to look forward to, with the likelihood of safer, as effective and shorter drug regimens in future years.
Healio: What’s in the TB vaccine pipeline?
Beumont: In addition to novel therapeutics, new, improved TB vaccines are a priority for the global health community. The existing vaccine — the bacillus Calmette-Guérin (BCG) vaccine — is more than 100 years old and only partially effective. The BCG vaccine is mostly used to prevent the most severe forms of the TB disease in children.
Cohn: Based on the 2022 TB vaccine pipeline grid from the TB Vaccine Initiative, there are 24 vaccine candidates in 29 studies, of which eight are preclinical, six are phase 1, four are phase 2a, five are phase 2b and six are phase 3. These include protein subunit vaccines with adjuvants, live-attenuated strains, inactivated whole cell mycobacteria and viral vector vaccines. Three studies are being conducted in infants and neonates, 18 in adolescents and adults and eight are therapeutic studies.
In a phase 2b trial in South Africa, Kenya and Zambia, the GSK M72/AS01E vaccine (subunit with adjuvant) showed promise, with efficacy of 54% in preventing pulmonary TB in M.tb-infected (positive IGRA) adolescents and young adults, and sustained immunogenicity after 3 years. GSK turned over the vaccine to the Gates Medical Research Institute (MRI) for further development and a potential phase 3 trial in larger and more diverse patient populations.
Before embarking on an expensive and possibly definitive phase 3 trial, Gates MRI is conducting a large epidemiologic study of TB incidence in 50 sites in 14 high-burden countries, enrolling 8,000 15- to 34-year-old participants in order to properly plan on sample size, duration and cost using site-specific data.
Another noteworthy candidate is VPM1002, a recombinant BCG vaccine. In a phase 2b trial in infants, VPM1002 was less reactogenic and immunogenic than BCG, with less lymphadenopathy and scarring, lower interferon gamma levels and lower multifunctional CD4 and CD8 cells. The Serum Institute of India is conducting a phase 3 double-blind trial comparing VPM1002 to BCG and has enrolled 6940 newborns aged younger than14 days old in five African countries, The endpoints are quantiferon conversion at 12 to 36 months and rates of TB disease.
Finally, the spectacular results of messenger RNA vaccines for the prevention of COVID-19-related hospitalizations and deaths have raised the question as to whether this platform could be used for development of a novel TB vaccine. Preliminary work is being conducted, and there are some data to suggest which protein antigens could be produced with RNA technology and might be adequate to generate an immune response for an effective vaccine. There is room for optimism, but it’s too early to tell.
Healio: Realistically, how soon could the world have a better TB vaccine ?
Cohn: Despite these advances and considerable potential, we are still years away from the development, acceptance and licensure of a safe and effective vaccine to replace the 100-plus-year-old BCG vaccine.
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