|THE CRYSTAL BALL - CHANGING HORIZONS
|Year : 2017 | Volume
| Issue : 2 | Page : 125-133
Tuberculosis: Emerging skies in diagnostics, therapeutics and preventive strategies
Department of Pulmonary Medicine, Poona Hospital and Research Centre, Pune, Maharashtra, India
|Date of Web Publication||30-Nov-2017|
Department of Pulmonary Medicine, Poona Hospital and Research Centre, Pune, Maharashtra
Source of Support: None, Conflict of Interest: None
The diagnosis, treatment, and prevention of tuberculosis (TB) are on the anvil of a paradigm shift. While the diagnosis and treatment are likely to undergo a remarkable change with genotypic (improved Genexpert ultra and line probe assay) methods which assure rapid and accurate identification of drug sensitive and drug resistant pulmonary tuberculosis, the focus of preventive strategy is likely to shift to effective vaccines in the making and possible diagnosis of latent tubercular infections through improved Interferon-Gamma Release Assays (IGRAs) that would allow elimination of the disease in the bud. A number of injectable and aerosol vaccines are currently undergoing human trials, and could be marketed as early as next year. Concurrently, the integration of high dose Rifapentine/Rifampicin to the treatment regimen has the capability to shorten the duration of TB treatment. The compliance of patients with drug resistant TB could improve dramatically with shortening of the length of MDR and XDR TB treatments to 6 and 9 months respectively.
Keywords: Bedaquiline, delamanid, future tuberculosis regimens, high-dose rifapentine/rifampicin, pretomanid, tuberculosis vaccines
|How to cite this article:|
Abhyankar N. Tuberculosis: Emerging skies in diagnostics, therapeutics and preventive strategies. Astrocyte 2017;4:125-33
| Introduction|| |
Even though the skies of tuberculosis research have been a witness to many bitter-sweet moons, and a number of diagnostic techniques, antitubercular drugs and the good old BCG vaccine have worked to lessen the gloom, the emergence of multidrug-resistant (MDR) and extensively drug-resistant tuberculosis (XDR-TB) has conspired to unveil new far more grave challenges. Standing up to these dark threats, and given the large global population at risk, there is a crying need to fashion new diagnostic techniques with high specificity, develop novel drug molecules capable of decimating the regular and resistant tubercular strains, and carve true vaccines, which can place tuberculosis on a tight leash. This paper, based on World Health Organization (WHO) global TB report 2016, presents a detailed insight into the ongoing work in the realm of tuberculosis research in the areas of diagnostics, therapeutics and protective vaccines.
| Future Advances in Diagnosis|| |
Defining critical concentration of drugs
The emergence of MDR-TB and XDR-TB makes it necessary to ensure that antimicrobial susceptibility testing of Mycobacterium tuberculosis produce results that are clinically meaningful and technically reproducible. The antimicrobial susceptibility testing breakpoint – also known as the “critical concentration” – in the case of M. tuberculosis, is defined as “the lowest concentration of drug that will inhibit 95% (90% for pyrazinamide) of wild strains of M. tuberculosis that have never been exposed to drugs, while at the same time not inhibiting clinical strains of M. tuberculosis that are considered to be resistant (e.g. from patients who are not responding to therapy)”.
Best determined by breakpoint committees composed of specialists in clinical trial science and in pharmacokinetics and pharmacodynamics, population simulation tools, resistance mechanisms, antimicrobial susceptibility testing methods and bacterial population dynamics, a robust understanding of antimicrobial susceptibility testing breakpoints is essential for achieving favorable outcomes in clinical practice. While the critical concentration for rifampicin and isoniazid have been studied and documented extensively, determination of critical concentrations of such therapeutic molecules as quinolones and repurposed drugs like linezolid and clofazimine can help combat MDR and XDR TB. The World Health Organization (WHO) is currently in the process of collating the epidemiological data on “critical concentration” of drugs used in the treatment of TB from across the globe and is likely to deliver its mandate shortly.
Drug susceptibility test vs molecular sequencing
Mutations which occur in the bacterial genome are vastly responsible for the emergence of drug-resistant strains of Mycobacterium tuberculosis (DR TB). This may lead us to think that molecular sequencing tests should become the new gold standards of the future. However, the jury is still out to determine the relative significance of individual vs. multiple mutations, mechanisms which produce resistance, and the small but certain discrepancies which exist between genotypic and phenotypic resistance. This make us fall short on confidence on this important switch.
As a drug molecule, pyrazinamide is a perfect example which figures in both the first- and second-line anti-TB therapies, and yet, its drug susceptibility test is still not 100% standardized. Resistance for pyrazinamide is currently not routinely investigated as a part of diagnostic and surveillance efforts. That's because of the limitation of the presently available phenotypic test (MGIT 960), which is expensive, difficult to perform, and poorly reproducible. For this reason, little information currently exists about the extent of resistance to pyrazinamide within the population.
If molecular sequencing tests were to prove equal to and substitute drug susceptibility tests, they could become the ballpark of deciding upon the appropriate choice of anti-TB agents.
A new version of the Xpert MTB/RIF assay, called Xpert Ultra, is currently a work in progress. The current assay is being modified in order to improve its sensitivity for TB detection and augment its specificity for detection of RIF resistance. The sensitivity of Xpert Ultra in smear positive cases approaches 100% and is 93% in smear negative cases.
Xpert Ultra can be used on the Omni platform. The primary data on Xpert Ultra gathered by the Foundation for Innovative New Diagnostics (FIND) is currently being processed by the WHO. As a first step, a rapid noninferiority (i.e. equivalence) study is being conducted, which compares and validates the new Xpert Ultra assay in relation to the current Xpert MTB/RIF assay. If noninferiority is demonstrated, the Xpert Ultra assay will be recommended as a replacement for the current Xpert MTB/RIF assay. From 2017 onwards, multicountry studies shall be taken up.
This is likely to be available in India soon. This simplifies the platform, is more portable, battery operable, needs lesser technical know how to handle, and may bring the cost further down. GeneXpert Omni platform can, therefore, reach remote areas with ease. For example, a primary care center in a village making a firm diagnosis of TB, including identification of RIF-resistant strain within hours, shall be a quantum leap for making an early diagnosis of TB and MDR-TB in the future.
Line probe assays
Hain Lifesciences has launched GenoType MTBDRplus Version 2.0. This can detect the presence of tubercular DNA and resistance to both RIF and INH within 5 h. It can also be used on smear negative specimens. Being technically demanding, makes it more appropriate for a tertiary care lab setting. In a recent study, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of Genotype MTB-DR plus Version 2.0 LPA were 96.4%, 100%, 100%, and 96.9%, respectively, for the detection of MDR-TB from direct smear positive sputum samples. The sensitivity, specificity, PPV, and NPV of Genotype MTBDR plus Version 2.0 LPA were 77.8%, 97.2%, 82.4%, and 97.2%, respectively, for the detection of MTB from direct smear negative sputum samples. LPA Version 2 is preferred in all smear positive pulmonary specimens and GeneXpert is superior in direct smear negative pulmonary specimens.
LPA also seems to hold promise to deliver on speciation of mycobacteria. A quick two-strip test confirming MTB or 34 Mycobacteria other than TB species shall surely add value in the rapid diagnosis of TB.
Diagnosis of latent tuberculosis
Soon as the active TB epidemic comes under check, the next major challenge shall be to detect and treat the latent TB infection (LTBI). Diagnosing LTBI is rather difficult. However, it offers the opportunity of nipping the disease in the bud. Some 5–15% of people carrying a latent infection tend to develop active TB during their lifetime, typically within the first 2–5 years after the initial infection.
The currently available tools for diagnosing LTBI are tuberculin skin test (TST) and the interferon gamma release assays (IGRA). These tests are immunity based, and have limited ability to predict disease or to identify which individuals with TB infection are likely to progress to active TB disease. They also have limited sensitivity in people with HIV infection, and these tests cannot sort recent from remote infection. A positive test cannot differentiate between a person who has been reinfected and the one who is reexposed to TB.
Current IGRA assays are based on CD4 T-cell response. However, a new generation assay, the QuantiFERON-TB Plus (QFT-Plus, Qiagen, Hilden, Germany), has been developed. The assay method stimulates gamma interferon (IFN-g) production by both CD4 and CD8 T cells. Early results indicate that the CD8 T-cell response may be able to identify people at greater risk of progression to active TB. QuantiFERON-TB Plus has acquired the US Food and Drug Administration approval recently in June 2017.
A delay in relaying of available information relating to diagnosis and sensitivity can cost dearly. Improved usage of digital interface with innovative methods for plugging the gaps in information, diagnosis, treatment decisions, monitoring treatment adherence, adverse events, and feedback loops are going to play important role in END TB mission.
| Future of Therapeutics|| |
Currently, there are nine new or repurposed drugs in Phase I, II, or III trials for the treatment of drug-susceptible TB, MDR-TB, or LTBI. Of these, five are new compounds (bedaquiline, delamanid, PBTZ169, Q 203, pretomanid, and sutezolid) and three are drugs that have been already approved or repurposed and are undergoing further testing (linezolid, rifampicin, and rifapentine).
Since much is known about bedaquiline, delamanid and linezolid, this paper shall limit itself to evaluate the prospects of the newer molecules.
A new series of piperazine-containing benzothiazinone (PBTZ) molecules have demonstrated high anti-mycobacterial activity. PBTZ169 is a piperazinobenzothiazinone derivative optimized by medicinal chemistry from the lead BTZ043.
PBTZ169 has several advantages compared to BTZ043: due to the absence of chiral centers it is easier to synthesize it chemically, its cost is less, and it enjoys better pharmacodynamics. PBTZ169 covalently inhibits DprE1, an enzyme essential for the biosynthesis of key cell wall components of MTB.
The drug has shown potent activity against drug-susceptible and drug-resistant TB. PBTZ169 is compatible with all TB drugs and appears to have synergies with bedaquiline and clofazimine. A Phase I trial of PBTZ169 was completed in the Russian Federation in July 2016, and a second Phase I trial shall be undertaken in Switzerland in 2017.
Sutezolid (PNU-100480) is an oxazolidinone and an analog of linezolid. A recent study which evaluated its bactericidal activity during the early phase of treatment has demonstrated that it is capable of producing a significant reduction in counts of colony forming units (CFUs) compared with the baseline levels following 14 days of treatment. Sutezolid is still awaiting entry into Phase IIb, nearly 5 years after showing promise in Phase IIa.
Pretomanid is a nitroimidazole developed by the Global Alliance for TB drug development (TB Alliance). It is currently being tested as a part of three potential combination regimens for the treatment of both drug-susceptible and drug-resistant TB.
A new compound, a member of the imidazopyridine class, Q203 targets the respiratory cytochrome bc1 complex, inhibiting the synthesis and homeostasis of adenosine triphosphate, thereby crippling the energy conversion system in both replicating and nonreplicating TB bacteria. This drug entered clinical testing in late 2015. Q203's phase I, single-dose, dose-escalating study has completed enrollment. Results shall be shared in 2017, leading to phase II trials. Q203 brings much-needed diversity to the antitubercular drugs currently in pipeline. Qurient Therapeutics, a biotech company, is developing Q203 with support of the Korea Drug Development Fund. It is partnering with Infectex to develop the drug for Russian and the other Commonwealth of Independent States market.
Repurposed rifapentine regimens for drug-sensitive TB
Encouraging results with TB Trial Consortium (TBTC) studies 29 and 29X have paved the way for further studies on high-dose rifapentine-based regimens. The primary target is to shorten the course of therapy for drug-sensitive TB from 6 to 4 months.
TBTC study 31/A5349 is currently investigating the possibility of shortening the treatment of drug-susceptible pulmonary TB to 4 months by using rifapentine, with or without moxifloxacin. This study, which began recruitment in January 2016, is being conducted at 15–20 centers internationally along with 4–5 centers in the United States. Some 2500 participants are to be enrolled by 2018. A highdose rifapentine and moxifloxacin combination is expected to shorten the effective TB treatment to a 4-month regimen.
High-dose repurposed rifampicin regimens for drug-sensitive TB
A recent 2-month study testing the safety of high doses of rifampicin together with standard treatment for drug-susceptible TB showed no significant increase in adverse events at doses of 10, 15, and 20 mg/kg. Rifampicin doses up to 35 mg/kg and even 40 mg/kg for 2 weeks have been found to be tolerated and safe.
New regimens for TB
Current treatments for MDR-TB are long (up to 24 months), ineffective (only 50% success), and may proceed serious side effects, ranging from acute psychosis to permanent deafness. A patient must endure months of painful, daily shots, and ingest up to 14,000 pills. The high cost, long duration, and potential side effects of the treatment makes such regimens hard to implement, especially in many high-burden countries. To set off these hurdles, several new potential drugs and new combinations are being evaluated in several Phase II or Phase III trials.
The PaMZ trail
The TB Alliance is currently investigating the efficacy, safety, and tolerability of pretomanid in combination with moxifloxacin and pyrazinamide (PaMZ). Following the encouraging early results of the 2-month NC-002 Phase IIb trial, the combination is being put through the next phase of trial.
The STAND trial
STAND trial was launched in February 2015. This was a Phase III trial on the safety and efficacy of Pa (100 mg) MZ for 4 months, Pa (200 mg) MZ for 4 months, and Pa (200 mg) MZ for 6 months in patients with drug-susceptible TB; and of Pa (200 mg) MZ for 6 months in patients with drug-resistant TB. In late 2015, the enrollment was suspended due to three deaths relating to high liver toxicity. Subsequently, the TB Alliance has been working with the regulatory authorities and the trial's data safety and monitoring committee to determine whether to restart enrollment.
The NC-005 trial
A Phase IIb trial (NC-005) to test all-oral combination regimens began in October 2014. The regimens being tested are bedaquiline (at two different doses), pretomanid, and pyrazinamide for patients with drugsusceptible TB, and the same drugs in combination with moxifloxacin for patients with MD-RTB. The trial is in progress at 10 centers across Uganda, South Africa, and Tanzania. If successful, the results of NC-005 shall lead to a global Phase 3 trial that could lead to the worldwide registration of the BPaZ (bedaquiline, pretomanid, and pyrazinamide) and/or BPaMZ (bedaquiline, pretomanid, moxifloxacin, and pyrazinamide) treatment. Enrollment was completed toward the end of 2015, and results are expected in late 2018. The interim data were presented in CROI conference in 2017 and seemed encouraging. The BPaMZ regimen in MDR-TB patients produced highest level of bactericidal activity in all treatment arms. The BPaZ regimen was well tolerated and showed a significantly higher bactericidal activity in DS-TB patients compared to treatment with isoniazid, rifampin, pyrazinamide, and ethambutol. BPaZ and BPaMZ represent promising, simplified regimens to treat both DS-TB and MDR-TB.
The Nix-TB trial
Nix-TB trial is the first clinical trial to test a novel regimen that holds the potential to be a shorter, all oral, affordable treatment for XDR-TB. The trial being conducted by the TB Alliance in South Africa is constituted by a regimen of drugs with minimal resistance: pretomanid, bedaquiline, and linezolid. Participants are being treated with the intent to cure in 6–9 months. An open label trial that enables patient assessment at regular intervals the Nix-TB trial has an adaptive design, which can accommodate addition of new treatments or treatment protocols during the course of study, based on new information coming to the fore. The primary endpoint is the incidence of bacteriologic failure (relapse or clinical failure) 6 months after completion of treatment, with a long-term follow-up for 24 months after the completion of treatment. The trend of current results presented in CROI in early 2017 look promising in relation to drug safety and efficacy.
The Linezolid trial
The efficacy of linezolid in different doses, from 300 mg/day up to 1200 mg/day over a period of 2 weeks is also currently under investigation. As the results flow in, necessary adjustments shall have to be incorporated in the ongoing trials.
The End-TB trial
The End-TB trial was initiated in end 2016. The first patient began treatment in Georgia in March 2017. A Phase III trial funded by UNITAID, and implemented by Partners in Health and Medicines Sans Frontiers (MSF) it shall attempt to compare several regimens in the treatment of MDR-TB or XDR-TB upholding the current WHO standard of care. The trial shall enroll a total of 750 patients across six countries: Georgia, Kazakhstan, Kyrgyzstan, Lesotho, Peru, and South Africa.
The regimens undergoing evaluation include bedaquiline or delamanid (or both), moxifloxacin or levofloxacin, and pyrazinamide plus linezolid or clofazimine (or both), in various combinations. This is an ambitious trial with six arms which aims to compare all possible permutations and combinations.
The NCT02583048 and NCT02754765 trials
A larger experience is required with the combined usage of bedaquiline and delamanid. Two clinical trials NCT02583048 (recruiting) and NCT02754765 (planned) may shed more light on this combination and their possible interactions. The first preliminary data from the first trial may be available shortly.
The TB-PRACTECAL trial
The TB-PRACTECAL trial is a Phase II/III adaptive trial being conducted on adults with MDR-TB or XDR-TB. The aim is to evaluate the safety and efficacy of 6-month regimens that contain bedaquiline, pretomanid, and linezolid, with or without moxifloxacin or clofazimine. The trial funded by MSF is being conducted in Belarus, Uzbekistan, and may percolate to other countries in southern Africa. The first patient was enrolled in Uzbekistan in February 2017. The trial shall run in two stages. The first stage is a Phase II trial which gets completed in 2018. This trial shall test three different regimes which contain the new drugs bedaquiline and pretomanid. The second stage shall be a Phase III trial, which will test the two most successful regimes and shall end in 2020.
The NeXT trial
The NeXT study is an open label trial. It comprises of a 6–9-month injection-free regimen which contains bedaquiline, ethionamide or high-dose isoniazid, linezolid, levofloxacin, and pyrazinamide. It is a close alternative to the WHO-recommended 12 month shorter regimen for MDR-TB treatment. The recruitment started in South Africa in 2016 and the trial is likely to complete sometime in 2019.
STREAM trials and bedaquiline
STREAM stage 1
STREAM stage 1 is the first randomized controlled trial  to evaluate alternative MDRTB regimens in multiple high-burden settings. This trial compared the standard WHO regimen with the modified Bangladesh regimen.
The aim of STREAM was to compare, in a noninferiority design, the efficacy and safety of a 9-month regimen based on the one studied in Bangladesh (regimen B) with the WHO-recommended standard of care (regimen A). Regimen B was constituted by moxifloxacin, clofazimine, ethambutol, and pyrazinamide for 9 months (40 weeks) with kanamycin, isoniazid, and prothionamide used during the 4 months (16 weeks) intensive phase. The intensive phase is extendable by 4 or 8 weeks in the event of delayed sputum smear conversion. Regimen doses are prescribed as per the weight bands, as in the Bangladesh regimen.
Since the study regimen has demonstrated good results, it is expected to provide a new standard of care for MDR-TB, and is likely to become a part of new WHO guidelines for treatment of MDR TB.
However, this regimen suffers from a potential limitation that its success could be adversely impacted by high prevalence of fluoroquinolone and pyrazinamide resistance.
STREAM stage 2
This trial compared the effectiveness of two new bedaquiline containing short course regimens, an all oral regimen and a shorter 6month regimen.
Stage 2 regimens
Regimen C is a fully oral 9-month regimen in which bedaquiline replaced kanamycin and is administered throughout the 9 months, and levofloxacin replaces moxifloxacin. The duration of the intensive phase and the use of the other drugs is the same as in regimen B.
Regimen D is a 6-month regimen where bedaquiline, clofazimine, pyrazinamide, and levofloxacin are prescribed for 28 weeks, and are supplemented by isoniazid and kanamycin for the first 8 weeks. The use of levofloxacin instead of moxifloxacin became necessary to reduce the potential risk of QT prolongation which bedaquiline and moxifloxacin co-administration is liable to produce.
If these regimens prove superior to the Stage 1 study regimen, it would represent an even greater advancement for patients with MDRTB.
The safety and efficacy of bedaquiline as a part of short MDRTB regimens of 6 and 9 months', compared with the current standard of care recommended by the WHO, is currently being investigated in the second stage of the Phase III STREAM trial that started recruitment in March 2016. The first results are expected toward the end of 2020.
The NCT02583048 (DELIBARATE) trial, which is studying the drug interactions between bedaquiline and delamanid, is still in the recruitment phase.
On the basis of the current trials, it can easily be prophesied that the anti-tubercular treatments shall soon change into relatively short course regimens, and that oral TB medications shall hold the upper hand. Most future anti-TB regimens shall use bedaquiline, delamanid, moxifloxacin, pretomanid, and clofazimine and shall aim to cure MDR and XDR TB in short courses of 6–9 months.
| Future of Preventive Approaches|| |
Currently, the only TB vaccine approved for human use is the Mycobacterium bovis Bacille Calmette-Guérin (BCG), a live attenuated vaccine dating to the 1920s. BCG has been proven effective in preventing severe disseminated disease in children but does not protect against pulmonary TB in adults. Additionally, the live attenuated BCG vaccine is unsafe for administration to HIV-positive or other immunocompromised individuals due to the possibility of developing regional BCG infection (BCG-itis) or disseminated BCG (BCG-osis).,,,
The BCG vaccine was developed through repeated subculture. The loss of the RD1 region—the principal genetic basis for its attenuation—encodes a secretion system to export the major Tcell antigen complex/virulence factor ESAT-6/CFP-10. Moreover, when compared to clinical isolates of MTB complex, BCG lacks more than 100 genes. This includes the critical immunodominant antigen proteins considered important in generating an effective long-lasting immune response. Some of these antigens are employed in different subunit TB vaccines for use in BCG-vaccinated individuals, currently undergoing clinical trials.
The mission of achieving the End-TB target of less than 10 cases per 100,000 per year in 2035 shall be greatly served if a more effective vaccine against TB were to become available by 2025.
Such potential future vaccines includes recombinant BCGs, whole-cell derived vaccines, recombinant viral-vectored platforms, protein and adjuvant combinations, and mycobacterial extracts.
The strategy of utilizing whole-cell vaccines for TB has gained interest due to the ongoing difficulties in identifying individual antigens critical to generating protective immune responses against MTB. The complexity of the organism is an important determinant in this regard. Moreover, as whole organisms, these vaccines tend to induce a more diversified immune response than the subunit-based vaccines, including both humoral and cellular immune responses to a range of protein, lipid, and antigens. Some vaccines aim to prevent infection (preexposure), while others aim to prevent primary progression to disease or reactivation of LTBI (postexposure).
Vaccines undergoing phase II/III trials
M72/AS01E is made by GlaxoSmithKline (GSK). This vaccine is a recombinant fusion protein of the MTB antigens 32A and 39A with the AS01E adjuvant. A phase II, observer-blind, randomized study has compared the safety, reactogenicity, and immunogenicity of M72/AS01E in three cohorts: tuberculosisnaïve adults (n = 80), adults previously treated for tuberculosis (n = 49), and adults who have completed the intensive phase of tuberculosis treatment (n = 13). In each cohort, the participating 18–59 year-old adults were randomized (1:1) to receive two doses of M72/AS01E (n = 71) or placebo (n = 71) and followed-up for 6 months following the second dose. Safety and reactogenicity were assessed during the follow up. Recruitment for the study ended prematurely because of a high incidence of large injection site redness and (or) swelling reactions in M72/AS01E-vaccinated adults undergoing tuberculosis treatment. No additional clinically relevant adverse events were observed. Robust and persistent M72specific humoral and polyfunctional CD4(+) T-cell-mediated immune responses were observed post-M72/AS01E vaccination in each cohort.
A large randomized placebo-controlled Phase IIb trial, conducted by GSK and Aeras, is currently underway in Kenya, South Africa, and Zambia. Pulmonary TB-negative, IGRA-positive, and HIV-negative adults are being enrolled for this trial. The primary end-point is the protective efficacy of two doses of M72/AS01E against pulmonary TB disease. Secondary end-points include safety and immunogenicity.
Being developed as a booster vaccine to BCG by Sanofi Pasteur, this vaccine is made up of a fusion protein using Ag85B and TB104, with IC31 as adjuvant. It is being tested in South Africa in a Phase II preproof of concept TB prevention study among IGRA-negative, HIV-negative adolescents at high risk of acquiring MTB infection. The same population is undergoing an intensive immunogenicity study as well. H4:IC31 is also being evaluated in Phase I and II trial in infants.
This is an adjuvant subunit vaccine that combines three MTB antigens (Ag85B, ESAT-6, and Rv2660c) with Valneva's IC31 adjuvant. This vaccine has undergone a phase I study to evaluate its safety and immunogenicity in HIV-negative adults with and without LTBI and with no history or evidence of TB. This phase 1 trial demonstrated an acceptable safety profile and found the vaccine to be immunogenic with all studied doses.
Two phase I trials have been completed which documents the safety and immunogenicity profile of H56:IC31 in HIV-negative, BCG-vaccinated adults with and without LTBI, and in patients who have recently been treated for pulmonary TB.
A Phase II trial including H4:IC31, H56:IC31, and BCG in 84 adolescents is currently under way.
VPM1002 is the only recombinant BCG vaccine currently undergoing clinical trials. VPM1002 is designed to provide enhanced immunogenicity as compared to BCG due to the (1) insertion in the BCG DNA of a gene for listeriolysin and (2) the deletion of a urease gene. This is a live recombinant vaccine that was originally developed at the Max Planck Institute of Infection Biology, Germany, with further development by Vakzine Projekt Management, the Tuberculosis Vaccine Initiative and the Serum Institute of India. A phase II trial was completed in South Africa to assess the safety and immunogenicity of the vaccine in HIV exposed and unexposed neonates. A phase III trial for prevention of TB in adults is being rolled out in India.
This vaccine holds the following likely advantages over the conventional BCG vaccine:
- It does not interfere with the results of TB diagnostic tests.
- It has the capability to induce both CD4 + and CD8+ immune responses.
- It has the capability to induce multifunctional T-cells (interleukin-2; IFN-γ; tumor necrosis factor-α).
- It appears to be safer than BCG in immunocompromised patient population.
VPM1002 is expected to enter the market sometime in 2018–2019.
RUTI ® is a nonlive and polyantigenic vaccine based on fragmented and detoxified MTB bacteria. It is being developed as an immunotherapeutic vaccine, to be used in conjunction with a short intensive antibiotic therapy, for usage in patients with LTBI. RUTI has demonstrated an ability to generate a polyantigenic response in 16 healthy volunteers, and in HIV-positive and -negative patients with LTBI, after INH treatment for 1 month, in a Phase II clinical trial with 98 patients. A definitive dose was found to be effective (25 μg) and only one shot was required to induce the desired response. The use of vaccine was associated only with local adverse events. Subsequent to this trial, the RUTI production process was changed to include a filtration step to reduce the nodulation at the inoculation site. A phase II trial in South Africa was completed recently, and other clinical trials are being planned.
If this vaccine were to prove effective, many patients would be spared the misery of taking prolonged oral chemoprophylaxis for LTBI.
The DAR-901 booster vaccine is a whole-cell, heatinactivated, nontuberculous mycobacterial vaccine. A phase I booster trial in the United States among BCG-primed adults with and without HIV infection found it to be safe and well tolerated. A larger randomized trial is underway in Tanzania to determine if DAR-901 prevents the earliest stage of infection with tuberculosis, before symptoms become apparent. In February 2016, the 650 adolescents in this “prevention of infection” study completed receiving three doses of DAR-901 or placebo. The vaccine was again observed to be safe and well tolerated. The trial is sponsored by Global Health Innovative Technology Fund (Japan), and the results of vaccine efficacy shall be with us by the end of 2018.
ID93 + GLASE
ID93 + GLA-SE is a new TB vaccine being developed by the Infectious Disease Research Institute (IDRI) in Seattle. The vaccine is made up of recombinant fusion polyprotein, including four TB antigens (Rv2608, Rv3619, Rv3620, and Rv1813) delivered together with the adjuvant GLA-SE.
Three of them are MTB immunodominant antigens (Rv2608, Rv3619, and Rv3620), and one is MTB latencyassociated antigen (Rv1813). A phase I trial in BCG-vaccinated, QuantiFERON-TB-Gold negative and positive healthy adults has been completed in South Africa. ID93 antigen (2 or 10 mg) in combination with GLA-SE adjuvant (2 or 5 mg), given in three doses, was found to have an acceptable safety profile in BCGvaccinated healthy adults (both QuantiFERON negative and QuantiFERON positive). Overall, significantly higher CD4+ responses were observed in all three intervention arms when compared with a placebo.
A phase IIa trial in South Africa, with the support of the Wellcome Trust, is evaluating safety and immunogenicity in HIV-naive TB patients that have recently completed treatment for pulmonary TB disease.
The VaccaeTM vaccine is a specified lysate developed as an immunotherapeutic agent to help shorten TB treatment for patients with drug-susceptible TB.
In a recent meta-analysis, 25 eligible studies involving 2281 subjects were critically evaluated for the effects of M. vaccae as an adjunctive therapy in the treatment of MDRTB patients. The meta-analysis showed that M. vaccae is an effective adjuvant when combined with general chemotherapy for treating MDRTB. M. vaccae can improve the sputum smear conversion, the resorption of TB foci, and hasten the closure of TB cavities.
Phase III trial is being implemented to assess its efficacy and safety in preventing TB in people with LTBI. It is the largest TB vaccine trial to be undertaken in the past decade, and included 10,000 people in the ages of 15–65 years with a TST >15 mm. The trial results are awaited.
Vaccines in Phase I trials
There are currently five vaccines undergoing phase I trials.
MTBVAC is a live MTB strain attenuated via deletions of the phoP and fadD26 genes. It was developed by the University of Zaragoza, Pasteur Institute and Biofabri, with the support of the TB Vaccine Initiative. The primary target population is neonates (as a BCG replacement vaccine), with a secondary target being adolescents and adults (as a booster vaccine). In September 2015, MTBVAC moved into a Phase Ib trial in infants. MTBVAC has been the first and only live attenuated MTB vaccine approved to enter clinical trials. A first-in-human MTBVAC clinical trial (NCT02013245) was recently conducted successfully in healthy adults in Lausanne, Switzerland.
MTBVAC study in adults with and without LTBI in South Africa (A-050) is a work in progress. This study is now open but not yet recruiting. Participants shall receive a single dose of MTBVAC or BCG revaccination administered intradermally on study day 0. MTBVAC at four dose levels: 5 × 10^3, 5 × 10^4, 5 × 10^5, 5 × 10^6 CFU and the active control is BCG (5 × 10^5 CFU). The results shall be with us by the end of 2018.
Ad5 Ag85A is an adenovirus serotype 5 vector developed by McMaster University with support from Can Sino. It has been evaluated for safety and immunogenicity in 24 healthy human volunteers (both BCG-naive and previously BCG-immunized) in Canada. Overall, it has been found to be safe, well-tolerated, and immunogenic in both trial groups, stimulating polyfunctional T-cell responses.
More potent immune response was seen in the previously BCG-vaccinated volunteers. A safety and immunogenicity study of the aerosol administration of this vaccine was recently completed.
TB/FLU-04 L is a recombinant influenza vectored vaccine that has been developed by the Research Institute for Biological Safety Problems and the Research Institute on Influenza in the Russian Federation. A live, influenza virus strain A/Puerto Rico/8/34 (H1N1), attenuated through truncation of the viral NS1 protein, with a benign safety profile in humans and being highly immunogenic, makes it an attractive candidate to serve as a vaccine vector. A genetically stable, replication-deficient influenza viral vector harboring ESAT6-Ag85A was generated, which showed increased antigen-specific IFN-g responses in mice and cynomolgus monkeys. Designed as a mucosal “boost” vaccine for infants, adolescents, and adults, a Phase I trial in BCG-vaccinated QuantiFERON-TB-Gold negative healthy adult volunteers using intranasal administration was recently completed  and a Phase IIa trial is being planned.
ChAdOx1.85A is a simian adenovirus expressing antigen 85A, which was developed at the University of Oxford to boost BCG-induced protection. It is being evaluated in a phase I trial in BCG-vaccinated adults, both alone and as part of a prime-boost strategy with MVA85A.
Safety and immunogenicity shall be evaluated in the two groups of BCG-vaccinated adults who will receive either ChAdOx1.85A alone or ChAdOx1.85A followed by a MVA85A boost.
This is a first-in-man trial for ChAdOx1.85A. The first six volunteers will receive a low dose of the vaccine, and the remaining volunteers will receive a higher dose of vaccine postevaluation of the initial safety data. Volunteers will be followed up between and following vaccinations to assess safety and immune responses by blood sampling. This trial is expected to take place at two sites, the CCVTM, Oxford, and the WTCRF, Birmingham.
MVA85A (Aerosol) is an aerosolized vaccine MVA85A developed at the University of Oxford. Its safety and immunogenicity has been tested in 24 BCG-vaccinated adults in the United Kingdom in a phase I trial. The trial demonstrated that aerosol vaccination with MVA85A is safe and feasible in comparison to intradermal MVA85A, and produces a stronger CD4+ T-cell response than intradermal MVA85A. Further studies assessing the aerosol route are under way in people with LTBI.
TB vaccine trials: Key observations
The current focus largely seems to be on vaccines that contain Ag85 proteins. Six of the eight subunit vaccines presently undergoing trials contain an Ag85 protein (Ag85A or Ag85B). However, the data from clinical efficacy trials is rather scanty to determine whether a focus on this antigen or any other individual antigen is an effective approach or not.
MTB is a complex organism with many protein, lipid, and glycolipid antigens that are known to be immunogenic in the human beings. Induction of immunity across a broad range of molecules is an alternative strategy to the highly focused subunit vaccine approach.
Whole-cell mycobacterial vaccines such as DAR-901, VaccaeTM, VPM1002, and MTBVAC contain a broader range of immunogenic molecules, as compared to viral vectored and protein and adjuvant vaccines, and have the potential advantage of inducing a broader immune response.
Increasing the breadth of an immune response, however, frequently has on the flipside a chance of lowering the magnitude of the immune response to any one individual antigen. Accordingly, strategies that increase the breadth of immune response while maximizing immune strength may be necessary.
| Conclusions|| |
Current research in tuberculosis aims to identify drug-sensitive and drug-resistant tubercular strains with a high degree of sensitivity and specificity and, at the same time, carve out shorter courses of effective treatments. Meeting up to these goals is critically important for countries which carry a high burden of the disease and possess limited resources. The future of tuberculosis treatment shall in all likelihood vest in shorter and standard regimens, be it for the drug sensitive or MDR and XDR disease.
The majority of vaccines currently undergoing trial have been fashioned out of Ag85 protein while a few carry the whole cell mycobacterial antigens. In comparison to the intradermal route, aerosolised vaccines seem to be in favor and are being explored for achieving a better protection response.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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