Controlled Human Infection Models: Is it Really Feasible to Give People Tuberculosis?
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ABSTRACT:
SUBMITTER: McShane H
PROVIDER: S-EPMC7233336 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
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Controlled Human Infection Models: Is it Really Feasible to Give People Tuberculosis?
American journal of respiratory and critical care medicine 20200501 10
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Project description: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.
| S-EPMC10248465 | biostudies-literature
Project description:Human challenge experiments could accelerate tuberculosis vaccine development. This requires a safe Mycobacterium tuberculosis (Mtb) strain that can both replicate in the host and be reliably cleared. Here we genetically engineered Mtb strains encoding up to three kill switches: two mycobacteriophage lysin operons negatively regulated by tetracycline and a degron domain-NadE fusion, which induces ClpC1-dependent degradation of the essential enzyme NadE, negatively regulated by trimethoprim. The triple-kill-switch (TKS) strain showed similar growth kinetics and antibiotic susceptibilities to wild-type Mtb under permissive conditions but was rapidly killed in vitro without trimethoprim and doxycycline. It established infection in mice receiving antibiotics but was rapidly cleared upon cessation of treatment, and no relapse was observed in infected severe combined immunodeficiency mice or Rag-/- mice. The TKS strain had an escape mutation rate of less than 10-10 per genome per generation. These findings suggest that the TKS strain could be a safe, effective candidate for a human challenge model.
| S-EPMC11790485 | biostudies-literature
Project description:The timelines for developing vaccines against infectious diseases are lengthy, and often vaccines that reach the stage of large phase 3 field trials fail to provide the desired level of protective efficacy. The application of controlled human challenge models of infection and disease at the appropriate stages of development could accelerate development of candidate vaccines and, in fact, has done so successfully in some limited cases. Human challenge models could potentially be used to gather critical information on pathogenesis, inform strain selection for vaccines, explore cross-protective immunity, identify immune correlates of protection and mechanisms of protection induced by infection or evoked by candidate vaccines, guide decisions on appropriate trial endpoints, and evaluate vaccine efficacy. We prepared this report to motivate fellow scientists to exploit the potential capacity of controlled human challenge experiments to advance vaccine development. In this review, we considered available challenge models for 17 infectious diseases in the context of the public health importance of each disease, the diversity and pathogenesis of the causative organisms, the vaccine candidates under development, and each model's capacity to evaluate them and identify correlates of protective immunity. Our broad assessment indicated that human challenge models have not yet reached their full potential to support the development of vaccines against infectious diseases. On the basis of our review, however, we believe that describing an ideal challenge model is possible, as is further developing existing and future challenge models.
| S-EPMC9491212 | biostudies-literature
Project description:Tuberculosis (TB) is a heterogeneous disease manifesting in a subset of individuals infected with aerosolized Mycobacterium tuberculosis (Mtb). Unlike human TB, murine infection results in uniformly high lung bacterial burdens and poorly organized granulomas. To develop a TB model that more closely resembles human disease, we infected mice with an ultra-low dose (ULD) of between 1-3 founding bacteria, reflecting a physiologic inoculum. ULD-infected mice exhibited highly heterogeneous bacterial burdens, well-circumscribed granulomas that shared features with human granulomas, and prolonged Mtb containment with unilateral pulmonary infection in some mice. We identified blood RNA signatures in mice infected with an ULD or a conventional Mtb dose (50-100 CFU) that correlated with lung bacterial burdens and predicted Mtb infection outcomes across species, including risk of progression to active TB in humans. Overall, these findings highlight the potential of the murine TB model and show that ULD infection recapitulates key features of human TB.
| S-EPMC7854984 | biostudies-literature
Project description:China has implemented a free-service policy for tuberculosis. However, patients still have to pay a substantial proportion of their annual income for treatment of this disease. This study describes the economic burden on patients with tuberculosis; identifies related factors by comparing two areas with different management models; and provides policy recommendation for tuberculosis control reform in China.There are three tuberculosis management models in China: the tuberculosis dispensary model, specialist model and integrated model. We selected Zhangjiagang (ZJG) and Taixing (TX) as the study sites, which correspond to areas implementing the integrated model and dispensary model, respectively. Patients diagnosed and treated for tuberculosis since January 2010 were recruited as study subjects. A total of 590 patients (316 patients from ZJG and 274 patients from TX) were interviewed with a response rate of 81%. The economic burden attributed to tuberculosis, including direct costs and indirect costs, was estimated and compared between the two study sites. The Mann-Whitney U Test was used to compare the cost differences between the two groups. Potential factors related to the total out-of-pocket costs were analyzed based on a step-by-step multivariate linear regression model after the logarithmic transformation of the costs.The average (median, interquartile range) total cost was 18793.33 (9965, 3200-24400) CNY for patients in ZJG, which was significantly higher than for patients in TX (mean: 6598.33, median: 2263, interquartile range: 983-6688) (Z = 10.42, P < 0.001). After excluding expenses covered by health insurance, the average out-of-pocket costs were 14304.4 CNY in ZJG and 5639.2 CNY in TX. Based on the multivariable linear regression analysis, factors related to the total out-of-pocket costs were study site, age, number of clinical visits, residence, diagnosis delay, hospitalization, intake of liver protective drugs and use of the second-line drugs.Under the current "free of diagnosis and treatment" policy, the financial burden remains heavy on tuberculosis patients. Policy makers need to consider appropriate steps to lessen the burden of out-of-pocket costs for tuberculosis patients in China and how best to improve service delivery for poor patients.
| S-EPMC4439067 | biostudies-other
Project description:IntroductionLeishmaniasis is a neglected tropical disease that is defined by the World Health Organization as vaccine preventable. Although several new candidate vaccines are in development, no vaccine has successfully reached the market for human use. Several species of Leishmania cause human disease and have co-evolved with their respective sand fly vectors. These unique relationships have implications for initiation of infection and vaccine development. An approach to vaccine development for many infectious diseases is the use of controlled human infection models (CHIMs).Areas coveredWe describe the history and recent development of experimental and deliberate infection using Leishmania in humans and the rationale for developing a new sand fly-initiated CHIM to progress leishmaniasis vaccine development. Examples from other infectious diseases are discussed in the context of the development of a new leishmaniasis CHIM. We also reflect upon the manufacture of the challenge agent, practical considerations, safety, ethics, and regulatory issues.Expert opinionA new cutaneous Leishmania CHIM is being developed to enable testing of vaccines in the development pipeline. Questions remain about the use of such CHIMs to determine effectiveness of vaccines against visceral leishmaniasis. However, such a CHIM will be invaluable in expediting time to market for vaccines.
| S-EPMC9835556 | biostudies-literature
Project description:Purpose of reviewThe present review describes recent advances in the treatment of drug-susceptible tuberculosis (DS-TB) among people living with human immunodeficiency virus (PLWH).Recent findingsHigher than standard rifampicin doses (>10 mg/kg/day) are well tolerated and have improved sterilizing activity. Standard pyrazinamide doses may result in low drug exposures; modeling reveals that higher doses (>25 mg/kg/day) may be required to reach target levels, although safety is unknown. Four-month fluoroquinolone-containing regimens are not recommended in the 2017 World Health Organization DS-TB treatment guidelines. These guidelines also recommend fixed-dose combination (FDC) therapy over single drug formulations based on patient preference, though FDC is not associated with improved outcomes. Treatment for 6 months is recommended, with an emphasis on expanded antiretroviral therapy (ART) coverage and monitoring for relapse among those not started on ART within 8 weeks of tuberculosis treatment. Directly observed therapy (DOT) is recommended over self-administered therapy, as is daily therapy over intermittent therapy - both are associated with better tuberculosis outcomes.SummaryCurrent WHO tuberculosis treatment guidelines recommend 6 months of daily tuberculosis treatment for PLWH who have DS-TB, and timely ART initiation. Higher rifampin and pyrazinamide doses may enhance treatment effectiveness, but safety data are needed. DOT and FDC therapy are recommended.
| S-EPMC6389504 | biostudies-literature
Project description:ObjectivesDespite 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.MethodsIn this review, we discuss the application of a novel replicating RNA (repRNA)-based vaccine formulated and delivered in nanostructured lipids.ResultsOur 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.ConclusionThis 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.
| S-EPMC10033141 | biostudies-literature
Project description: Not available
| S-EPMC7365362 | biostudies-literature
Project description:Models can be simple for different reasons: because they yield a simple and computationally efficient interpretation of a generic dataset (e.g., in terms of pairwise dependencies)-as in statistical learning-or because they capture the laws of a specific phenomenon-as e.g., in physics-leading to non-trivial falsifiable predictions. In information theory, the simplicity of a model is quantified by the stochastic complexity, which measures the number of bits needed to encode its parameters. In order to understand how simple models look like, we study the stochastic complexity of spin models with interactions of arbitrary order. We show that bijections within the space of possible interactions preserve the stochastic complexity, which allows to partition the space of all models into equivalence classes. We thus found that the simplicity of a model is not determined by the order of the interactions, but rather by their mutual arrangements. Models where statistical dependencies are localized on non-overlapping groups of few variables are simple, affording predictions on independencies that are easy to falsify. On the contrary, fully connected pairwise models, which are often used in statistical learning, appear to be highly complex, because of their extended set of interactions, and they are hard to falsify.
| S-EPMC7512302 | biostudies-literature