Advances in the development of new vaccines for tuberculosis and Brazil's role in the effort forward the end TB strategy.

Tuberculosis (TB) continues to be the world's leading killer of infectious diseases. Despite global efforts to gradually reduce the number of annual deaths and the incidence of this disease, the coronavirus disease 19 (COVID-19) pandemic caused decreased in TB detection and affected the prompt treatment TB which led to a setback to the 2019 rates. However, the development and testing of new TB vaccines has not stopped and now presents the possibility of implanting in the next five years a new vaccine that is affordable and might be used in the various key vulnerable populations affected by TB. Then, this assay aimed to discuss the main vaccines developed against TB that shortly could be selected and used worldwide, and additionally, evidence the Brazilian potential candidates' vaccines in developing in Brazil that could be considered among those in level advanced to TB end.

Co-regulation of innate and adaptive immune responses induced by ID93+GLA-SE vaccination in humans.

Introduction: Development of an effective vaccine against tuberculosis is a critical step towards reducing the global burden of disease. A therapeutic vaccine might also reduce the high rate of TB recurrence and help address the challenges of drug-resistant strains. ID93+GLA-SE is a candidate subunit vaccine that will soon be evaluated in a phase 2b efficacy trial for prevention of recurrent TB among patients undergoing TB treatment. ID93+GLA-SE vaccination was shown to elicit robust CD4+ T cell and IgG antibody responses among recently treated TB patients in the TBVPX-203 Phase 2a study (NCT02465216), but the mechanisms underlying these responses are not well understood. Methods: In this study we used specimens from TBVPX-203 participants to describe the changes in peripheral blood gene expression that occur after ID93+GLA-SE vaccination. Results: Analyses revealed several distinct modules of co-varying genes that were either up- or down-regulated after vaccination, including genes associated with innate immune pathways at 3 days post-vaccination and genes associated with lymphocyte expansion and B cell activation at 7 days post-vaccination. Notably, the regulation of these gene modules was affected by the dose schedule and by participant sex, and early innate gene signatures were correlated with the ID93-specific CD4+ T cell response. Discussion: The results provide insight into the complex interplay of the innate and adaptive arms of the immune system in developing responses to vaccination with ID93+GLA-SE and demonstrate how dosing and schedule can affect vaccine responses.

Antibodies as key mediators of protection against Mycobacterium tuberculosis.

Tuberculosis (TB) is caused by infection with the bacterial pathogen Mycobacterium tuberculosis (M.tb) in the respiratory tract. There was an estimated 10.6 million people newly diagnosed with TB, and there were approximately 1.3 million deaths caused by TB in 2022. Although the global prevalence of TB has remained high for decades and is an annual leading cause of death attributed to infectious diseases, only one vaccine, Bacillus Calmette-Guérin (BCG), has been approved so far to prevent/attenuate TB disease. Correlates of protection or immunological mechanisms that are needed to control M.tb remain unknown. The protective role of antibodies after BCG vaccination has also remained largely unclear; however, recent studies have provided evidence for their involvement in protection against disease, as biomarkers for the state of infection, and as potential predictors of outcomes. Interestingly, the antibodies generated post-vaccination with BCG are linked to the activation of innate immune cascades, providing further evidence that antibody effector functions are critical for protection against respiratory pathogens such as M.tb. In this review, we aim to provide current knowledge of antibody application in TB diagnosis, prevention, and treatment. Particularly, this review will focus on 1) The role of antibodies in preventing M.tb infections through preventing Mtb adherence to epithelium, antibody-mediated phagocytosis, and antibody-mediated cellular cytotoxicity; 2) The M.tb-directed antibody response generated after vaccination and how humoral profiles with different glycosylation patterns of these antibodies are linked with protection against the disease state; and 3) How antibody-mediated immunity against M.tb can be further explored as early diagnosis biomarkers and different detection methods to combat the global M.tb burden. Broadening the paradigm of differentiated antibody profiling and antibody-based detection during TB disease progression offers new directions for diagnosis, treatment, and preventative strategies. This approach involves linking the aforementioned humoral responses with the disease state, progression, and clearance.

Improving access to tuberculosis preventive treatment for children in Ethiopia: designing a home-based contact management intervention for the CHIP-TB trial through formative research.

BACKGROUND: Tuberculosis (TB) preventive treatment (TPT) is a long-standing recommendation for children exposed to TB but remains poorly implemented. Home-based contact management may increase access and coverage of TPT among children exposed to TB in their households. METHODS: Sixty in-depth interviews were conducted with key informants including program managers, TB providers (known as TB focal persons), health extension workers and caregivers whose children had recently engaged with TB prevention services in Oromia, Ethiopia in 2021 to understand the barriers and facilitators to providing home-based TB prevention services for children aged < 15 years. Thematic content analysis was conducted including systematically coding each interview. RESULTS: Home-based services were considered a family-centered intervention, addressing the time and financial constraints of clients. Stakeholders proposed a task-shared intervention between health extension workers and facility-based TB focal persons. They recommended that TB services be integrated into other home-based services, including HIV, nutrition, and vaccination services to reduce workload on the already overstretched health extension workers. Community awareness was considered essential to improve acceptability of home-based services and TPT in general among community members. CONCLUSIONS: Decentralization of TPT should be supported by task-sharing initiation and follow up between health extension workers and facility-based TB focal persons and integration of home-based services. Active community engagement through several existing mechanisms can help improve acceptability for both home-based interventions and TPT promotion overall for children. TRIAL REGISTRATION: The results presented here were from formative research related to the CHIP-TB Trial (Identifier NCT04369326) registered on April 30, 2020. This qualitative study was separately registered at NCT04494516 on 27 July 2020.

Assessing the effect of health system resources on HIV and tuberculosis programmes in Malawi: a modelling study.

BACKGROUND: Malawi is progressing towards UNAIDS and WHO End TB Strategy targets to eliminate HIV/AIDS and tuberculosis. We aimed to assess the prospective effect of achieving these goals on the health and health system of the country and the influence of consumable constraints. METHODS: In this modelling study, we used the Thanzi la Onse (Health for All) model, which is an individual-based multi-disease simulation model that simulates HIV and tuberculosis transmission, alongside other diseases (eg, malaria, non-communicable diseases, and maternal diseases), and gates access to essential medicines according to empirical estimates of availability. The model integrates dynamic disease modelling with health system engagement behaviour, health system use, and capabilities (ie, personnel and consumables). We used 2018 data on the availability of HIV and tuberculosis consumables (for testing, treatment, and prevention) across all facility levels of the country to model three scenarios of HIV and tuberculosis programme scale-up from Jan 1, 2023, to Dec 31, 2033: a baseline scenario, when coverage remains static using existing consumable constraints; a constrained scenario, in which prioritised interventions are scaled up with fixed consumable constraints; and an unconstrained scenario, in which prioritised interventions are scaled up with maximum availability of all consumables related to HIV and tuberculosis care. FINDINGS: With uninterrupted medical supplies, in Malawi, we projected HIV and tuberculosis incidence to decrease to 26 (95% uncertainty interval [UI] 19-35) cases and 55 (23-74) cases per 100 000 person-years by 2033 (from 152 [98-195] cases and 123 [99-160] cases per 100 000 person-years in 2023), respectively, with programme scale-up, averting a total of 12·21 million (95% UI 11·39-14·16) disability-adjusted life-years. However, the effect was compromised by restricted access to key medicines, resulting in approximately 58 700 additional deaths (33 400 [95% UI 22 000-41 000] due to AIDS and 25 300 [19 300-30 400] due to tuberculosis) compared with the unconstrained scenario. Between 2023 and 2033, eliminating HIV treatment stockouts could avert an estimated 12 100 deaths compared with the baseline scenario, and improved access to tuberculosis prevention medications could prevent 5600 deaths in addition to those achieved through programme scale-up alone. With programme scale-up under the constrained scenario, consumable stockouts are projected to require an estimated 14·3 million extra patient-facing hours between 2023 and 2033, mostly from clinical or nursing staff, compared with the unconstrained scenario. In 2033, with enhanced screening, 188 000 (81%) of 232 900 individuals projected to present with active tuberculosis could start tuberculosis treatment within 2 weeks of initial presentation if all required consumables were available, but only 8600 (57%) of 15 100 presenting under the baseline scenario. INTERPRETATION: Ignoring frailties in the health-care system, in particular the potential non-availability of consumables, in projections of HIV and tuberculosis programme scale-up might risk overestimating potential health impacts and underestimating required health system resources. Simultaneous health system strengthening alongside programme scale-up is crucial, and should yield greater benefits to population health while mitigating the strain on a heavily constrained health-care system. FUNDING: Wellcome and UK Research and Innovation as part of the Global Challenges Research Fund.

Shared challenges to the control of complex intracellular neglected pathogens.

The complex intracellular pathogens Mycobacterium tuberculosis, Mycobacterium leprae, Leishmania spp., and Burkholderia pseudomallei, which cause tuberculosis, leprosy, leishmaniasis, and melioidosis respectively, represent major health threats with a significant global burden concentrated in low- and middle-income countries. While these diseases vary in their aetiology, pathology and epidemiology, they share key similarities in the biological and sociodemographic factors influencing their incidence and impact worldwide. In particular, their occurrence in resource-limited settings has important implications for research and development, disease prevalence and associated risk factors, as well as access to diagnostics and therapeutics. In accordance with the vision of the VALIDATE (VAccine deveLopment for complex Intracellular neglecteD pAThogeEns) Network, we consider shared challenges to the effective prevention, diagnosis and treatment of these diseases as shaped by both biological and social factors, illustrating the importance of taking an interdisciplinary approach. We further highlight how a cross-pathogen perspective may provide valuable insights for understanding and addressing challenges to the control of all four pathogens.

Making social protection a reality for people with TB: a perspective on new global guidance.

TB disproportionately affects poorer, vulnerable people and communities, and has severe social and economic impacts on those affected. However, many countries do not yet include social protection in their programmatic response to TB. Here, we provide a critical perspective on the guidance developed by the WHO and the International Labour Organization (ILO) to help countries implement social protection programmes. The guidance emphasises the need for a multisectoral response to TB, and includes practical information on how to design appropriate social protection programmes that respond to the needs of people affected by TB.

Smoking cessation to prevent death and tuberculosis recurrence after treatment: A prospective cohort study with a seven-year follow-up in China.

Background: Although there is consistent evidence that smoking is a risk factor associated with tuberculosis (TB), whether smoking cessation improves treatment outcomes and reduces the risk of TB recurrence remains understudied. Methods: We conducted a prospective cohort study with a seven-year follow-up in China. We recruited newly-diagnosed TB patients and classified them as non-smokers, ex-smokers, and current smokers. Current smokers were invited to participate in a smoking cessation intervention programme. We used a Cox proportional hazards model to assess the risk of death among TB patients and the risk of recurrence among successfully treated patients. Results: In total, 634 (79.2%) patients completed anti-TB treatments and 115 (14.4%) patients died. We confirmed the existence of a dose-response relationship between smoking frequency and the risk of TB recurrence (the slope of the fitted line >0; P < 0.05). Compared to those who continued smoking, the risk of death and recurrent TB for the patients who quit smoking during treatment decreased. The HR of mortality for smokers who smoked 30 or more cigarettes was 2.943 (95% confidence interval (CI) = 1.035-8.368), while the HR of mortality for those who smoked 30 or more cigarettes, but quit during treatment was 2.117 (95% CI = 1.157-3.871). However, the risk of recurrence remained high for ex-smokers who had a smoking history of 25 years or more. Conclusions: Our study provides further evidence supporting the World Health Organization's call for co-management of smoking and other risk factors as part of routine TB treatment.

Performance evaluation of the national tuberculosis control program 2016-2020: Souss-Massa region, Morocco.

BACKGROUND: Tuberculosis constitutes a public health problem in Morocco. In an environment where results-based management and the evaluation of public policies become an imperative; the evaluation of the performance of the national tuberculosis control program finds its interest. OBJECTIVES: This study aims to analyze the performance of the tuberculosis control program in the Souss Massa region, based on the systemic approach model over a five-year period 2016-2020. METHODS: This is a descriptive secondary data analysis carried out in the Souss-Massa region in southern Morocco over a five year period 2016-2020. Data collection was carried out through the health information system of the NTCP and the various periodic reports produced by the primary health care establishments and diagnostic centers for tuberculosis and respiratory diseases, the delegations and the regional health directorate of the Ministry of Health. RESULTS: The incidence of tuberculosis has fluctuated between 63 and 72 cases/100,000 inhabitants; the average number of cases detected is 1871 cases per year; the survey completion rate is 57.10%; the therapeutic success rate varies between 82% and 89%, the treatment failure rate varies between 0.62% and 2.32%; the death rate varies between 0.63% and 2.92%; the failure rate for tuberculosis/HIV cases is between 3.10% and 6.09%. CONCLUSIONS: The results of the program tracer indicators at the level of the Souss-Massa region show that the latter combs to achieve the target objectives.

TB prevention and immunization in pediatrics.

Tuberculosis (TB) is one of the main contributors to global mortality and morbidity. Prevalence of TB is more in developing countries. It is one of the airborne diseases that has always been a major health problem. It is caused by organisms of the Mycobacterium tuberculosis (MTB) complex affecting different organ systems. The proverb prevention is better than cure best applies to TB and it has been practiced from ancient periods. However, modalities of prevention have varied much depending upon the advancement in research and technology. TB preventive practice reduces the load of TB significantly and it was used as the theme for world TB Day for the year 2013. Bacille Calmette-Guérin (BCG) vaccination is one of the modalities to prevent TB and it's been practiced for decades with a lot of modifications from synthesis, schedule and method of administration. BCG mainly prevents serious TB with a less known effect on TB prevention. Other uses of BCG vaccination are being studied. In the modern era, heterologous effects of BCG vaccination have brought BCG once again into the limelight. TB prevention strategies start from basic health education and vaccination. Newer vaccines are under trial to improve the efficacy of TB vaccination and yet to be used for general practice. Prevention and immunization against TB have been modified in immunocompromised children. The concept of drug resistance has to be kept in mind before using anti tubercular drugs without any bacteriological evidence for tuberculosis. National Tuberculosis Elimination Programme (NTEP) focuses on contact tracing and treatment of latent TB infection as a resort to prevent further spread of TB in India. This review article has been authored following an exhaustive examination of the existing literature, with the aim of enhancing comprehension regarding tuberculosis prevention and immunization.

Tuberculosis vaccine - A timely analysis of the drawbacks for the development of novel vaccines.

The BCG vaccine, Bacille Calmette Guerin, holds the distinction of being the most widely administered vaccine. Remarkably, a century has passed since its discovery; however, puzzlingly, questions persist regarding the effectiveness of the immune response it triggers. After years of diligent observation, it has been deduced that BCG imparts immunity primarily to a specific age group, namely children. This prompts a significant query: the rationale behind BCG's limited efficacy against TB in particular age groups and populations remains elusive. Beyond vaccinations, drug therapy has emerged as an alternative route for TB prevention. Nonetheless, this approach faces challenges in the contemporary landscape, marked by the emergence of new instances of MDR-TB and XDR-TB, compounded by the financial burden of treatment. It's noteworthy that BCG remains the sole WHO-approved vaccine for TB. This comprehensive review delves into several aspects, encompassing the immune response during infection, the shortcomings of BCG in conferring immunity, and the various factors contributing to its limitations. Within this discourse, we explore potential explanations for the observed deficiencies of the BCG vaccine and consider how these insights could catalyze the development of future vaccines. The current landscape of novel vaccine development for TB is illuminated, including a spotlight on the latest vaccine candidates.

My tuberculosis epidemiology journey: Implications for TB program interventions, activities and strategy.

Key learnings from some landmark studies that the author has been associated with and their implications on program strategies are highlighted. Learnings from prevalence surveys provide justification for active TB Case finding (ACF), role of Chest X-ray screening, justification of the elderly as a key vulnerable population and suggest re-think of the methods of sub-national certification for progress towards tuberculosis free status. Risk of infection studies suggest 14 million people acquiring new tuberculous infection each year in India suggesting a re-think on the targets for TB elimination. Justification is given for 'TB deaths averted' as a parameter for monitoring program impact, reviving risk of infection surveys using CyTB and higher emphasis on careful analysis of routine surveillance data for monitoring epidemiological trends rather than oft-repeated surveys. The modelling outputs suggest higher focus on reducing transmission of infection in urban and reducing treatment delay in rural areas and the need to scale up active case finding and TB preventive treatment in order to achieve End TB targets. Case finding studies justify upfront molecular diagnostics, need to confirm a single sputum result by another specimen or radiology during ACF and futility of X-ray based diagnosis during ACF. High rates of recurrence with intermittent treatment regimen providing evidence in favor of daily regimen, role of family centric approach to nutritional supplementation to prevent TB mortality and reduce TB incidence among household contacts are highlighted besides the need to address high proportion of families suffering catastrophic expenses during pre-treatment period.

Management of tuberculosis patients and the role of forensic medicine in COVID-19 pandemic.

Tuberculosis and Coronaviral disease-19 had a global impact in 2020 and still predominating, both infectious diseases similar to the lethal pandemics spread in one route, likely airborne transmission, the infected person could spread to healthy people. However, tuberculosis slightly varies from COVID-19. Though the primordial disease of the tuberculosis epidemic has had a vast impact on this society, besides the COVID-19 pandemic with other co-morbidities, conditions faced numerous complications. This review exemplified the impact of two lethal diseases in changing patient care, diagnostic issues, and forensic sciences roles. The diagnosis of tuberculosis with a massive concern due to standard testing methods, leading to inaccuracy, sensitivity, and prolonged time consumption. In addition, unavailability of testing kits, equipment failure, over-crowd in hospitals and fewer healthcare workers, a prolonged testing period, and finally, anxiety about COVID-19. Also, the contribution of forensic sciences in the autopsy of the exact cause of infectious diseases is crucial. Likewise, during this pandemic, there has been a drastic reduction in tuberculosis incidence in high-burden countries and a synergistic effect of both diseases. So, this review summarized the overall burden of tuberculosis management during COVID-19 and followed the guidelines of various nations' healthcare authorities to mitigate the consequences of tuberculosis diagnosis and prognosis during the pandemic.

A second-generation recombinant BCG strain combines protection against murine tuberculosis with an enhanced safety profile in immunocompromised hosts.

Bacille Calmette-Guérin (BCG) remains the only licensed vaccine against tuberculosis (TB). While BCG protects against TB in children, its protection against pulmonary TB in adults is suboptimal, and the development of a better TB vaccine is a global health priority. Previously, we reported two recombinant BCG strains effective against murine TB with low virulence and lung pathology in immunocompromised mice and guinea pigs. We have recently combined these two recombinant BCG strains into one novel vaccine candidate (BCGΔBCG1419c::ESAT6-PE25SS) and evaluated its immunogenicity, efficacy and safety profile in mice. This new vaccine candidate is non-inferior to BCG in protection against TB, presents reduced pro-inflammatory immune responses and displays an enhanced safety profile.

Immunoproteomic discovery of Mycobacterium bovis antigens, including the surface lipoprotein Mpt83 as a T cell antigen useful for vaccine development.

Tuberculosis (TB) is one of the leading causes of death from infectious diseases, killing approximately 1.3 million people worldwide in 2022 alone. The current vaccine for TB contains a live attenuated bacterium, Mycobacterium bovis BCG (Bacille Calmette-Guérin). The BCG vaccine is highly effective in preventing severe forms of childhood TB but does not protect against latent infection or disease in older age groups. A new or improved BCG vaccine for prevention of pulmonary TB is urgently needed. In this study, we infected murine bone marrow derived dendritic cells from C57BL/6 mice with M. bovis BCG followed by elution and identification of BCG-derived MHC class I and class II-bound peptides using tandem mass spectrometry. We identified 1436 MHC-bound peptides of which 94 were derived from BCG. Fifty-five peptides were derived from MHC class I molecules and 39 from class II molecules. We tested the 94 peptides for their immunogenicity using IFN- γ ELISPOT assay with splenocytes purified from BCG immunized mice and 10 showed positive responses. Seven peptides were derived from MHC II and three from MHC class I. In particular, MHC class II binding peptides derived from the mycobacterial surface lipoprotein Mpt83 were highly antigenic. Further evaluations of these immunogenic BCG peptides may identify proteins useful as new TB vaccine candidates.

Assessing the impact of COVID-19 non-pharmaceutical interventions and relaxation policies on Class B respiratory infectious diseases transmission in China.

This study investigates the incidence of Class B respiratory infectious diseases (RIDs) in China under the Coronavirus disease 2019 (COVID-19) epidemic and examines variations post-epidemic, following the relaxation of non-pharmaceutical interventions (NPIs). Two-stage evaluation was used in our study. In the first stage evaluation, we established counterfactual models for the pre-COVID-19 period to estimate expected incidences of Class B RIDs without the onset of the epidemic. In the second stage evaluation, we constructed seasonal autoregressive integrated moving average intervention (SARIMA-Intervention) models to evaluate the impact on the Class B RIDs after NPIs aimed at COVID-19 pandemic were relaxed. The counterfactual model in the first stage evaluation suggested average annual increases of 10.015%, 78.019%, 70.439%, and 67.799% for tuberculosis, scarlet fever, measles, and pertussis respectively, had the epidemic not occurred. In the second stage evaluation, the total relative reduction in 2023 of tuberculosis, scarlet fever, measles and pertussis were - 35.209%, - 59.184%, - 4.481%, and - 9.943% respectively. The actual incidence declined significantly in the first stage evaluation. However, the results of the second stage evaluation indicated that a rebound occurred in four Class B RIDs after the relaxation of NPIs; all of these showed a negative total relative reduction rate.

Methods for the Inactivation of Mycobacterium tuberculosis: a Systematic Review of the Literature.

To systematize published laboratory methods to inactivate Mycobacterium tuberculosis (MTB) and to describe their effectiveness. We carried out a review of the scientific literature to identify the publications that reported methods for the inactivation of MTB, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. The search addressed inactivation methodologies used in Public health laboratories for the treatment of biological material and only included studies reporting the efficacy of the method. The database used were PubMed (National Library of Medicine) and LILACS (Latin American and Caribbean Literature in Health Sciences). We evaluated the quality of the studies with the JBI (Joanna Briggs Institute) Critical Instrument Appraisal Checklist. We included 14 publications meeting the established inclusion and exclusion criteria. These 14 studies actually described a total of 35 inactivation methods. Most of them combined heat treatment with some chemical or enzymatic agent, and there were very few applying a single strategy. Twenty-four (68.57%) methods demonstrated significant efficacy in inactivating MTB. The systematic review identified 35 methods of inactivation of MTB, published in 14 studies. Most of the methods combined physical treatment techniques, especially heat, with chemical and/or enzymatic treatment techniques, obtaining mostly good results in preventing the reproduction of the microorganism. PROSPERO (International Prospective Register of Ongoing Systematic Reviews) (Code CRD42024503621).