Digital approaches to reducing TB treatment loss to follow-up.

Poor adherence to TB treatment leads to adverse clinical outcomes. A range of digital technologies to support adherence have been developed and the COVID-19 pandemic considerably accelerated the implementation of digital interventions. Here, we review the current evidence on digital adherence support tools and update the findings of a previous review, with evidence published from 2018 to date. Interventional and observational studies, as well as primary and secondary analyses were included, and we summarised available evidence on effectiveness, cost-effectiveness and acceptability. The studies were heterogenous and varied in outcome measures and approaches used. Overall, our findings show that digital approaches, such as digital pillboxes and asynchronous video-observed treatment, are acceptable and have the potential to improve adherence and be cost-effective over time if implemented at scale. Digital tools should be part of multiple strategies to support adherence. Further research to integrate behavioural data on reasons for non-adherence will help to determine how to best implement these technologies in different settings.

Controlled human infection models in COVID-19 and tuberculosis: current progress and future challenges.

Controlled Human Infection Models (CHIMs) involve deliberately exposing healthy human volunteers to a known pathogen, to allow the detailed study of disease processes and evaluate methods of treatment and prevention, including next generation vaccines. CHIMs are in development for both tuberculosis (TB) and Covid-19, but challenges remain in their ongoing optimisation and refinement. It would be unethical to deliberately infect humans with virulent Mycobacteria tuberculosis (M.tb), however surrogate models involving other mycobacteria, M.tb Purified Protein Derivative or genetically modified forms of M.tb either exist or are under development. These utilise varying routes of administration, including via aerosol, per bronchoscope or intradermal injection, each with their own advantages and disadvantages. Intranasal CHIMs with SARS-CoV-2 were developed against the backdrop of the evolving Covid-19 pandemic and are currently being utilised to both assess viral kinetics, interrogate the local and systemic immunological responses post exposure, and identify immune correlates of protection. In future it is hoped they can be used to assess new treatments and vaccines. The changing face of the pandemic, including the emergence of new virus variants and increasing levels of vaccination and natural immunity within populations, has provided a unique and complex environment within which to develop a SARS-CoV-2 CHIM. This article will discuss current progress and potential future developments in CHIMs for these two globally significant pathogens.

Repurposing mucosal delivery devices for live attenuated tuberculosis vaccines.

Tuberculosis (TB) remains one of the most lethal infectious diseases globally. The only TB vaccine approved by the World Health Organization, Bacille Calmette-Guérin (BCG), protects children against severe and disseminated TB but provides limited protection against pulmonary TB in adults. Although several vaccine candidates have been developed to prevent TB and are undergoing preclinical and clinical testing, BCG remains the gold standard. Currently, BCG is administered as an intradermal injection, particularly in TB endemic countries. However, mounting evidence from experimental animal and human studies indicates that delivering BCG directly into the lungs provides enhanced immune responses and greater protection against TB. Inhalation therapy using handheld delivery devices is used for some diseases and allows the delivery of drugs or vaccines directly into the human respiratory tract. Whether this mode of delivery could also be applicable for live attenuated bacterial vaccines such as BCG or other TB vaccine candidates remains unknown. Here we discuss how two existing inhalation devices, the mucosal atomization device (MAD) syringe, used for influenza vaccines, and the Respimat® Soft Mist™ inhaler, used for chronic obstructive pulmonary disease (COPD) therapy, could be repurposed for mucosal delivery of live attenuated TB vaccines. We also outline the challenges and outstanding research questions that will require further investigations to ensure usefulness of respiratory delivery devices that are cost-effective and accessible to lower- and middle-income TB endemic countries.

mRNA vaccines: a new opportunity for malaria, tuberculosis and HIV.

The success of the first licensed mRNA-based vaccines against COVID-19 has created a widespread interest on mRNA technology for vaccinology. As expected, the number of mRNA vaccines in preclinical and clinical development increased exponentially since 2020, including numerous improvements in mRNA formulation design, delivery methods and manufacturing processes. However, the technology faces challenges such as the cost of raw materials, the lack of standardization, and delivery optimization. MRNA technology may provide a solution to some of the emerging infectious diseases as well as the deadliest hard-to-treat infectious diseases malaria, tuberculosis, and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), for which an effective vaccine, easily deployable to endemic areas is urgently needed. In this review, we discuss the functional structure, design, manufacturing processes and delivery methods of mRNA vaccines. We provide an up-to-date overview of the preclinical and clinical development of mRNA vaccines against infectious diseases, and discuss the immunogenicity, efficacy and correlates of protection of mRNA vaccines, with particular focus on research and development of mRNA vaccines against malaria, tuberculosis and HIV.

Catastrophic "costs": A hindrance to eliminate tuberculosis.

Globally, one quarter of the population is infected with TB; and only a small proportion of those infected will become sick. Tuberculosis along with poverty disproportionately affects the households causing a financial burden and catastrophic costs (if the total costs incurred by a household's exceeds 20% of its annual income), which could be direct or indirect and procuring detrimental effects on the effective strategic plans. Out of all diseases, India accounts for 18% of the catastrophic health expenditure including tuberculosis. Therefore, an utmost need for a national cost survey either separately or combined with other health surveys should be held for the comprehension of the baseline burden of Tuberculosis in the affected households, to identify the predictors of catastrophic costs, and simultaneously, intensive research and appropriate innovations are needed to assess the effectiveness of the measures undertaken for the reduction of the proportionate patients who overlook catastrophic costs.

Tuberculosis infection prevention and control in rural Papua New Guinea: an evaluation using the infection prevention and control assessment framework.

BACKGROUND: Papua New Guinea (PNG) is one of the 14 countries categorised as having a triple burden of tuberculosis (TB), multidrug-resistant TB (MDR TB), and TB-human immunodeficiency virus (HIV) co-infections. TB infection prevention and control (TB-IPC) guidelines were introduced in 2011 by the National Health Department of PNG. This study assesses the implementation of this policy in a sample of district hospitals in two regions of PNG. METHODS: The implementation of TB-IPC policy was assessed using a survey method based on the World Health Organization (WHO) IPC assessment framework (IPCAF) to implement the WHO's IPC core components. The study included facility assessment at ten district hospitals and validation observations of TB-IPC practices. RESULTS: Overall, implementation of IPC and TB-IPC guidelines was inadequate in participating facilities. Though 80% of facilities had an IPC program, many needed more clearly defined IPC objectives, budget allocation, and yearly work plans. In addition, they did not include senior facility managers in the IPC committee. 80% (n = 8 of 10) of hospitals had no IPC training and education; 90% had no IPC committee to support the IPC team; 70% had no surveillance protocols to monitor infections, and only 20% used multimodal strategies for IPC activities. Similarly, 70% of facilities had a TB-IPC program without a proper budget and did not include facility managers in the TB-IPC team; 80% indicated that patient flow poses a risk of TB transmission; 70% had poor ventilation systems; 90% had inadequate isolation rooms; and though 80% have personal protective equipment available, frequent shortages were reported. CONCLUSIONS: The WHO-recommended TB-IPC policy is not effectively implemented in most of the participating district hospitals. Improvements in implementing and disseminating TB-IPC guidelines, monitoring TB-IPC practices, and systematic healthcare worker training are essential to improve TB-IPC guidelines' operationalisation in health settings to reduce TB prevalence in PNG.

Tuberculosis vaccines update: Is an RNA-based vaccine feasible for tuberculosis?

OBJECTIVES: Despite concerted efforts, Mycobacterium tuberculosis (M.tb), the pathogen that causes tuberculosis (TB), continues to be a burden on global health, regaining its dubious distinction in 2022 as the world's biggest infectious killer with global COVID-19 deaths steadily declining. The complex nature of M.tb, coupled with different pathogenic stages, has highlighted the need for the development of novel immunization approaches to combat this ancient infectious agent. Intensive efforts over the last couple of decades have identified alternative approaches to improve upon traditional vaccines that are based on killed pathogens, live attenuated agents, or subunit recombinant antigens formulated with adjuvants. Massive funding and rapid advances in RNA-based vaccines for immunization have recently transformed the possibility of protecting global populations from viral pathogens, such as SARS-CoV-2. Similar efforts to combat bacterial pathogens such as M.tb have been significantly slower to implement. METHODS: In this review, we discuss the application of a novel replicating RNA (repRNA)-based vaccine formulated and delivered in nanostructured lipids. RESULTS: Our preclinical data are the first to report that RNA platforms are a viable system for TB vaccines and should be pursued with high-priority M.tb antigens containing cluster of differentiation (CD4+) and CD8+ T-cell epitopes. CONCLUSION: This RNA vaccine shows promise for use against intracellular bacteria such as M.tb as demonstrated by the feasibility of construction, enhanced induction of cell-mediated and humoral immune responses, and improved bacterial burden outcomes in in vivo aerosol-challenged preclinical TB models.

How the corona pandemic affects the global fight against tuberculosis and how to react.

The emergence of the acute pandemic by SARS-CoV-2 is a setback for the fight against chronic pandemics like tuberculosis (TB), malaria, and HIV/AIDS. In fact, after more than a decade of decreasing fatality numbers, 2020 saw a re-increase in the number of people dying from TB. After COVID-19, TB was the infectious disease with the second-highest fatality rate caused by a single pathogen, with 1.6 million deaths in 2021. It is expected by the WHO that the pandemic years to come and even after the pandemic will continue this trend. More efforts are needed to support TB control structures as an integral part of the strengthening measures of the general health care system.

Tuberculosis - United States, 2022.

Incidence of reported tuberculosis (TB) decreased gradually in the United States during 1993-2019, reaching 2.7 cases per 100,000 persons in 2019. Incidence substantially declined in 2020 to 2.2, coinciding with the COVID-19 pandemic (1). Proposed explanations for the decline include delayed or missed TB diagnoses, changes in migration and travel, and mortality among persons susceptible to TB reactivation (1). Disparities (e.g., by race and ethnicity) in TB incidence have been described (2). During 2021, TB incidence partially rebounded (to 2.4) but remained substantially below that during prepandemic years, raising concerns about ongoing delayed diagnoses (1). During 2022, the 50 U.S. states and the District of Columbia (DC) provisionally reported 8,300 TB cases to the National Tuberculosis Surveillance System. TB incidence was calculated using midyear population estimates and stratified by birth origin and by race and ethnicity. During 2022, TB incidence increased slightly to 2.5 although it remained lower than during prepandemic years.* Compared with that in 2021, TB epidemiology in 2022 was characterized by more cases among non-U.S.-born persons newly arrived in the United States; higher TB incidence among non-Hispanic American Indian or Alaska Native (AI/AN) and non-Hispanic Native Hawaiian or other Pacific Islander (NH/OPI) persons and persons aged ≤4 and 15-24 years; and slightly lower incidence among persons aged ≥65 years. TB incidence appears to be returning to prepandemic levels. TB disparities persist; addressing these disparities requires timely TB diagnosis and treatment to interrupt transmission and prevention of TB through treatment of latent TB infection (LTBI).

Implementation of evidence-based multiple focus integrated intensified TB screening to end TB (EXIT-TB) package in East Africa: a qualitative study.

INTRODUCTION: Tuberculosis (TB) remains a major cause of morbidity and mortality, especially in sub-Saharan Africa. We qualitatively evaluated the implementation of an Evidence-Based Multiple Focus Integrated Intensified TB Screening package (EXIT-TB) in the East African region, aimed at increasing TB case detection and number of patients receiving care. OBJECTIVE: We present the accounts of participants from Tanzania, Kenya, Uganda, and Ethiopia regarding the implementation of EXIT-TB, and suggestions for scaling up. METHODS: A qualitative descriptive design was used to gather insights from purposefully selected healthcare workers, community health workers, and other stakeholders. A total of 27, 13, 14, and 19 in-depth interviews were conducted in Tanzania, Kenya, Uganda, and Ethiopia respectively. Data were transcribed and translated simultaneously and then thematically analysed. RESULTS: The EXIT-TB project was described to contribute to increased TB case detection, improved detection of Multidrug-resistant TB patients, reduced delays and waiting time for diagnosis, raised the index of TB suspicion, and improved decision-making among HCWs. The attributes of TB case detection were: (i) free X-ray screening services; (ii) integrating TB case-finding activities in other clinics such as Reproductive and Child Health clinics (RCH), and diabetic clinics; (iii), engagement of CHWs, policymakers, and ministry level program managers; (iv) enhanced community awareness and linkage of clients; (v) cooperation between HCWs and CHWs, (vi) improved screening infrastructure, (vii) the adoption of the new simplified screening criteria and (viii) training of implementers. The supply-side challenges encountered ranged from disorganized care, limited space, the COVID-19 pandemic, inadequate human resources, inadequate knowledge and expertise, stock out of supplies, delayed maintenance of equipment, to absence of X-ray and GeneXpert machines in some facilities. The demand side challenges ranged from delayed care seeking, inadequate awareness, negative beliefs, fears towards screening, to financial challenges. Suggestions for scaling up ranged from improving service delivery, access to diagnostic equipment and supplies, and infrastructure, to addressing client fears and stigma. CONCLUSION: The EXIT-TB package appears to have contributed towards increasing TB case detection and reducing delays in TB treatment in the study settings. Addressing the challenges identified is needed to maximize the impact of the EXIT-TB intervention.