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As an awardee of the Centers for Disease Control and Prevention's Colorectal Cancer Control Program, the California Department of Public Health partnered with Neighborhood Healthcare to implement evidence-based interventions and provider incentives (incentives offered to support staff, e.g., medical assistants, phlebotomists, front office staff, lab technicians) to improve colorectal cancer screening uptake. The objective of this study was to evaluate the effectiveness and cost of the provider incentive intervention implemented by Neighborhood Healthcare to increase colorectal cancer screening uptake. We collected and analyzed process and cost data to assess fecal immunochemical test (FIT) kit return rates to the health centers and the number of completed FIT kits. We estimated the costs of the preexisting interventions and the new interventions. Analyses were conducted for two time periods: preimplementation and implementation. Most Neighborhood Healthcare health centers experienced an increase in the percentage of FIT kit returns (average of 3.6 percentage points) and individuals screened (an average increase of 111 FIT kits per month) from the baseline period through the implementation period. The cost of the incentive intervention for each additional screen was $66.79. In conclusion, the results indicate that incentive programs can have an overall positive impact on both the percentage of FIT kits returned and the number of individuals screened.
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Neoplasias Colorretais , Motivação , California , Neoplasias Colorretais/diagnóstico , Atenção à Saúde , Detecção Precoce de Câncer , Humanos , Programas de Rastreamento , Sangue OcultoRESUMO
Globally, more people die annually from tuberculosis than from any other single infectious agent. Unfortunately, there is no commercially-available vaccine that is sufficiently effective at preventing acquisition of pulmonary tuberculosis in adults. In this study, pre-exposure prophylactic pulmonary delivery of active aerosolized anti-tuberculosis bacteriophage D29 was evaluated as an option for protection against Mycobacterium tuberculosis infection. An average bacteriophage concentration of approximately 1 PFU/alveolus was achieved in the lungs of mice using a nose-only inhalation device optimized with a dose simulation technique and adapted for use with a vibrating mesh nebulizer. Within 30 minutes of bacteriophage delivery, the mice received either a low dose (â¼50-100 CFU), or an ultra-low dose (â¼5-10 CFU), of M. tuberculosis H37Rv aerosol to the lungs. A prophylactic effect was observed with bacteriophage aerosol pre-treatment significantly decreasing M. tuberculosis burden in mouse lungs 24 hours and 3 weeks post-challenge (p < 0.05). These novel results indicate that a sufficient dose of nebulized mycobacteriophage aerosol to the lungs may be a valuable intervention to provide extra protection to health care professionals and other individuals at risk of exposure to M. tuberculosis.
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BACKGROUND: This report details the cost effectiveness of a non-nurse patient navigation (PN) program that was implemented at the University of Chicago Medical Center to increase colonoscopy-based colorectal cancer (CRC) screening. METHODS: The authors investigated the impact of the PN intervention by collecting process measures. Individuals who received navigation were compared with a historic cohort of non-navigated patients. In addition, a previously validated data-collection instrument was tailored and used to collect all costs related to developing, implementing, and administering the program; and the incremental cost per patient successfully navigated (the cost of the intervention divided by the change in the number who complete screening) was calculated. RESULTS: The screening colonoscopy completion rate was 85.1% among those who were selected to receive PN compared with 74.3% when no navigation was implemented. With navigation, the proportion of no-shows was 8.2% compared with 15.4% of a historic cohort of non-navigated patients. Because the perceived risk of noncompletion was greater among those who received PN (previous no-show or cancellation, poor bowel preparation) than that in the historic cohort, a scenario analysis was performed. Assuming no-show rates between 0% and 50% and using a navigated rate of 85%, the total incremental program cost per patient successfully navigated ranged from $148 to $359, whereas the incremental intervention-only implementation cost ranged from $88 to $215. CONCLUSIONS: The current findings indicate that non-nurse PN can increase colonoscopy completion, and this can be achieved at a minimal incremental cost for an insured population at an urban academic medical center.
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Colonoscopia/economia , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/economia , Navegação de Pacientes/economia , Adulto , Idoso , Chicago/epidemiologia , Colonoscopia/estatística & dados numéricos , Neoplasias Colorretais/economia , Neoplasias Colorretais/epidemiologia , Análise Custo-Benefício , Detecção Precoce de Câncer/normas , Detecção Precoce de Câncer/estatística & dados numéricos , Feminino , Hospitais Universitários , Humanos , Masculino , Programas de Rastreamento/economia , Programas de Rastreamento/métodos , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Navegação de Pacientes/organização & administração , Navegação de Pacientes/normas , Participação do Paciente/economia , Participação do Paciente/estatística & dados numéricosRESUMO
Unlike most pathogens, many of the immunodominant epitopes from Mycobacterium tuberculosis are under purifying selection. This startling finding suggests that M. tuberculosis may gain an evolutionary advantage by focusing the human immune response against selected proteins. Although the implications of this to vaccine development are incompletely understood, it has been suggested that inducing strong Th1 responses against Ags that are only weakly recognized during natural infection may circumvent this evasion strategy and increase vaccine efficacy. To test the hypothesis that subdominant and/or weak M. tuberculosis Ags are viable vaccine candidates and to avoid complications because of differential immunodominance hierarchies in humans and experimental animals, we defined the immunodominance hierarchy of 84 recombinant M. tuberculosis proteins in experimentally infected mice. We then combined a subset of these dominant or subdominant Ags with a Th1 augmenting adjuvant, glucopyranosyl lipid adjuvant in stable emulsion, to assess their immunogenicity in M. tuberculosis-naive animals and protective efficacy as measured by a reduction in lung M. tuberculosis burden of infected animals after prophylactic vaccination. We observed little correlation between immunodominance during primary M. tuberculosis infection and vaccine efficacy, confirming the hypothesis that subdominant and weakly antigenic M. tuberculosis proteins are viable vaccine candidates. Finally, we developed two fusion proteins based on strongly protective subdominant fusion proteins. When paired with the glucopyranosyl lipid adjuvant in stable emulsion, these fusion proteins elicited robust Th1 responses and limited pulmonary M. tuberculosis for at least 6 wk postinfection with a single immunization. These findings expand the potential pool of M. tuberculosis proteins that can be considered as vaccine Ag candidates.
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Epitopos Imunodominantes/imunologia , Mycobacterium tuberculosis/imunologia , Proteínas Recombinantes de Fusão/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose Pulmonar/imunologia , Adjuvantes Imunológicos , Animais , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Feminino , Camundongos , Células Th1/imunologia , Tuberculose Pulmonar/prevenção & controle , VacinaçãoRESUMO
BACKGROUND: Mycobacterium tuberculosis infects one third of the world's population and causes >8 million cases of tuberculosis annually. New vaccines are necessary to control the spread of tuberculosis. T cells, interferon γ (IFN-γ), and tumor necrosis factor (TNF) are necessary to control M. tuberculosis infection in both humans and unvaccinated experimental animal models. However, the immune responses necessary for vaccine efficacy against M. tuberculosis have not been defined. The multifunctional activity of T-helper type 1 (TH1) cells that simultaneously produce IFN-γ and TNF has been proposed as a candidate mechanism of vaccine efficacy. METHODS: We used a mouse model of T-cell transfer and aerosolized M. tuberculosis infection to assess the contributions of TNF, IFN-γ, and inducible nitric oxide synthase (iNOS) to vaccine efficacy. RESULTS: CD4(+) T cells were necessary and sufficient to transfer protection against aerosolized M. tuberculosis, but neither CD4(+) T cell-produced TNF nor host cell responsiveness to IFN-γ were necessary. Transfer of Tnf(-/-) CD4(+) T cells from vaccinated donors to Ifngr(-/-) recipients was also sufficient to confer protection. Activation of iNOS to produce reactive nitrogen species was not necessary for vaccine efficacy. CONCLUSIONS: Induction of TH1 cells that coexpress IFN-γ and TNF is not a requirement for vaccine efficacy against M. tuberculosis, despite these cytokines being essential for control of M. tuberculosis in nonvaccinated animals.
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Linfócitos T CD4-Positivos/imunologia , Interferon gama/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/imunologia , Tuberculose/prevenção & controle , Fator de Necrose Tumoral alfa/imunologia , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Óxido Nítrico Sintase Tipo II/imunologia , Receptores de Interleucina-17/imunologia , Vacinas contra a Tuberculose/farmacologiaRESUMO
An effective protein-based vaccine for tuberculosis will require a safe and effective adjuvant. There are few adjuvants in approved human vaccines, including alum and the oil-in-water-based emulsions MF59 (Novartis Vaccines and Diagnostics), AS03 and AS04 (GlaxoSmithKline Biologics), AF03 (Sanofi), and liposomes (Crucell). When used with pure, defined proteins, both alum and emulsion adjuvants are effective at inducing primarily humoral responses. One of the newest adjuvants in approved products is AS04, which combines monophosphoryl lipid A, a TLR-4 agonist, with alum. In this study, we compared two adjuvants: a stable oil-in-water emulsion (SE) and a stable oil-in-water emulsion incorporating glucopyranosyl lipid adjuvant, a synthetic TLR-4 agonist (GLA-SE), each together with a recombinant protein, ID93. Both the emulsion SE and GLA-SE adjuvants induce potent cellular responses in combination with ID93 in mice. ID93/SE induced Th2-biased immune responses, whereas ID93/GLA-SE induced multifunctional CD4(+) Th1 cell responses (IFN-γ, TNF-α, and IL-2). The ID93/GLA-SE vaccine candidate induced significant protection in mice and guinea pigs, whereas no protection was observed with ID93/SE, as assessed by reductions in bacterial burden, survival, and pathology. These results highlight the importance of properly formulating subunit vaccines with effective adjuvants for use against tuberculosis.
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Adjuvantes Imunológicos/administração & dosagem , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/administração & dosagem , Vacinas contra a Tuberculose/imunologia , Tuberculose Pulmonar/prevenção & controle , Animais , Emulsões , Feminino , Cobaias , Lipídeo A/administração & dosagem , Lipídeo A/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sobrevida , Células Th1/imunologia , Células Th2/imunologia , Vacinas contra a Tuberculose/síntese química , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/síntese química , Vacinas de Subunidades Antigênicas/imunologiaRESUMO
BACKGROUND: Recent advances in rational adjuvant design and antigen selection have enabled a new generation of vaccines with potential to treat and prevent infectious disease. The aim of this study was to assess whether therapeutic immunization could impact the course of Mycobacterium tuberculosis infection with use of a candidate tuberculosis vaccine antigen, ID93, formulated in a synthetic nanoemulsion adjuvant, GLA-SE, administered in combination with existing first-line chemotherapeutics rifampicin and isoniazid. METHODS: We used a mouse model of fatal tuberculosis and the established cynomolgus monkey model to design an immuno-chemotherapeutic strategy to increase long-term survival and reduce bacterial burden, compared with standard antibiotic chemotherapy alone. RESULTS: This combined approach induced robust and durable pluripotent antigen-specific T helper-1-type immune responses, decreased bacterial burden, reduced the duration of conventional chemotherapy required for survival, and decreased M. tuberculosis-induced lung pathology, compared with chemotherapy alone. CONCLUSIONS: These results demonstrate the ability of therapeutic immunization to significantly enhance the efficacy of chemotherapy against tuberculosis and other infectious diseases, with implications for treatment duration, patient compliance, and more optimal resource allocation.
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Antígenos de Bactérias/imunologia , Antituberculosos/farmacologia , Mycobacterium tuberculosis/imunologia , Rifampina/farmacologia , Vacinas contra a Tuberculose/uso terapêutico , Tuberculose Pulmonar/terapia , Adjuvantes Imunológicos/administração & dosagem , Animais , Antígenos de Bactérias/administração & dosagem , Antituberculosos/imunologia , Proteínas de Bactérias/imunologia , Quimioterapia Adjuvante/métodos , Modelos Animais de Doenças , Feminino , Isoniazida/administração & dosagem , Isoniazida/farmacologia , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Macaca fascicularis/imunologia , Macaca fascicularis/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/patogenicidade , Rifampina/administração & dosagem , Prevenção Secundária , Análise de Sobrevida , Fatores de Tempo , Vacinas contra a Tuberculose/imunologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/imunologia , VacinaçãoRESUMO
Prophylactic efficacy of two different delivery platforms for vaccination against Mycobacterium avium (M. avium) were tested in this study; a subunit and an RNA-based vaccine. The vaccine antigen, ID91, includes four mycobacterial antigens: Rv3619, Rv2389, Rv3478, and Rv1886. We have shown that ID91+GLA-SE is effective against a clinical NTM isolate, M. avium 2-151 smt. Here, we extend these results and show that a heterologous prime/boost strategy with a repRNA-ID91 (replicon RNA) followed by protein ID91+GLA-SE boost is superior to the subunit protein vaccine given as a homologous prime/boost regimen. The repRNA-ID91/ID91+GLA-SE heterologous regimen elicited a higher polyfunctional CD4+ TH1 immune response when compared to the homologous protein prime/boost regimen. More significantly, among all the vaccine regimens tested only repRNA-ID91/ID91+GLA-SE induced IFN-γ and TNF-secreting CD8+ T cells. Furthermore, the repRNA-ID91/ID91+GLA-SE vaccine strategy elicited high systemic proinflammatory cytokine responses and induced strong ID91 and an Ag85B-specific humoral antibody response a pre- and post-challenge with M. avium 2-151 smt. Finally, while all prophylactic prime/boost vaccine regimens elicited a degree of protection in beige mice, the heterologous repRNA-ID91/ID91+GLA-SE vaccine regimen provided greater pulmonary protection than the homologous protein prime/boost regimen. These data indicate that a prophylactic heterologous repRNA-ID91/ID91+GLA-SE vaccine regimen augments immunogenicity and confers protection against M. avium.
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Mycobacterium tuberculosis , Vacinas de DNA , Animais , Camundongos , Linfócitos T CD8-Positivos , Mycobacterium avium/metabolismo , Mycobacterium tuberculosis/genética , Vacinação/métodos , Citocinas/metabolismo , Imunização Secundária/métodosRESUMO
Mycobacterium tuberculosis (M.tb), a bacterial pathogen that causes tuberculosis disease (TB), exerts an extensive burden on global health. The complex nature of M.tb, coupled with different TB disease stages, has made identifying immune correlates of protection challenging and subsequently slowing vaccine candidate progress. In this work, we leveraged two delivery platforms as prophylactic vaccines to assess immunity and subsequent efficacy against low-dose and ultra-low-dose aerosol challenges with M.tb H37Rv in C57BL/6 mice. Our second-generation TB vaccine candidate ID91 was produced as a fusion protein formulated with a synthetic TLR4 agonist (glucopyranosyl lipid adjuvant in a stable emulsion) or as a novel replicating-RNA (repRNA) formulated in a nanostructured lipid carrier. Protein subunit- and RNA-based vaccines preferentially elicit cellular immune responses to different ID91 epitopes. In a single prophylactic immunization screen, both platforms reduced pulmonary bacterial burden compared to the controls. Excitingly, in prime-boost strategies, the groups that received heterologous RNA-prime, protein-boost or combination immunizations demonstrated the greatest reduction in bacterial burden and a unique humoral and cellular immune response profile. These data are the first to report that repRNA platforms are a viable system for TB vaccines and should be pursued with high-priority M.tb antigens containing CD4+ and CD8+ T-cell epitopes.
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INTRODUCTION: This randomized, double-blind, placebo-controlled, phase 2a trial was conducted to evaluate the safety and immunogenicity of the ID93 + glucopyranosyl lipid adjuvant (GLA)-stable emulsion (SE) vaccine in human immunodeficiency virus (HIV)-negative, previously Bacillus Calmette-Guérin (BCG)-vaccinated, and QuantiFERON-TB-negative healthy adults in South Korea. METHODS: Adults (n = 107) with no signs or symptoms of tuberculosis were randomly assigned to receive three intramuscular injections of 2 µg ID93 + 5 µg GLA-SE, 10 µg ID93 + 5 µg GLA-SE, or 0.9% normal saline placebo on days 0, 28, and 56. For safety assessment, data on solicited adverse events (AEs), unsolicited AEs, serious AEs (SAEs), and special interest AEs were collected. Antigen-specific antibody responses were measured using serum enzyme-linked immunosorbent assay. T-cell immune responses were measured using enzyme-linked immunospot and intracellular cytokine staining. RESULTS: No SAEs, deaths, or AEs leading to treatment discontinuation were found. The solicited local and systemic AEs observed were consistent with those previously reported. Compared with adults administered with the placebo, those administered with three intramuscular vaccine injections exhibited significantly higher antigen-specific antibody levels and Type 1 T-helper cellular immune responses. CONCLUSION: The ID93 + GLA-SE vaccine induced antigen-specific cellular and humoral immune responses, with an acceptable safety profile in previously healthy, BCG-vaccinated, Mycobacterium tuberculosis-uninfected adult healthcare workers. TRIAL REGISTRATION: This clinical trial was retrospectively registered on 16 January 2019 at Clinicaltrials.gov (NCT03806686).
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The increase of global cases of drug resistant (DR) Mycobacterium tuberculosis (M.tb) is a serious problem for the tuberculosis research community and the goals to END TB by 2030. Due to the need for advancing and screening next generation therapeutics and vaccines, we aimed to design preclinical DR models of Beijing lineage M.tb HN878 strain in different mouse backgrounds. We found escalating sensitivities of morbidity due to low dose aerosol challenge (50-100 bacilli) in CB6F1, C57BL/6 and SWR mice, respectively. We also observed that pulmonary bacterial burden at morbidity endpoints correlated inversely with survival over time between mouse strains. Interestingly, with in vitro passaging and in the process of selecting individual DR mutant colonies, we observed a significant decrease in in vivo HN878 strain virulence, which correlated with the acquisition of a large genetic duplication. We confirmed that low passage infection stocks with no or low prevalence of the duplication, including stocks directly acquired from the BEI resources biorepository, retained virulence, measured by morbidity over time. These data help confirm previous reports and emphasize the importance of monitoring virulence and stock fidelity.
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Mycobacterium tuberculosis , Tuberculose dos Linfonodos , Tuberculose Resistente a Múltiplos Medicamentos , Camundongos , Animais , Virulência/genética , Camundongos Endogâmicos C57BLRESUMO
Mycobacterium tuberculosis (M.tb) has led to approximately 1.3 million deaths globally in 2020 according to the World Health Organization (WHO). More effective treatments are therefore required to prevent the transmission of M.tb. Although Bacille Calmette-Guérin (BCG), a prophylactic vaccine against M.tb, already exists, other vaccines are being developed that could help boost BCG's noted incomplete protection. This includes ID93 + GLA-SE, an adjuvanted protein vaccine which is being tested in Phase 2 clinical trials. The aim of this study was to test new lipid-based adjuvant formulations with ID93 in the context of a therapeutic vaccine, which we hypothesize would act as an adjunct to drug treatment and provide better outcomes, such as survival, than drug treatment alone. The recent success of another adjuvanted recombinant protein vaccine, M72 + AS01E (GlaxoSmithKline Biologicals), which after 3 years provided approximately 50% efficacy against TB pulmonary disease, is paving the way for new and potentially more effective vaccines. We show that based on selected criteria, including survival, T helper 1 cytokine responses, and resident memory T cells in the lung, that a liposomal formulation of GLA with QS-21 (GLA-LSQ) combined with ID93 provided enhanced protection over drug treatment alone.
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This article describes the articulation, development, and deployment of a machine learning (ML) model-driven value solution for chronic kidney disease (CKD) in a health system. The ML model activated an electronic medical record (EMR) trigger that alerted CKD patients to seek primary care. Simultaneously, primary care physicians (PCPs) received an alert that a CKD patient needed an appointment. Using structured checklists, PCPs addressed and controlled comorbid conditions, reconciled drug dosing and choice to CKD stage, and ordered prespecified laboratory and imaging tests pertinent to CKD. After completion of checklist prescribed tasks, PCPs referred patients to nephrology. CKD patients had multiple comorbidities and ML recognition of CKD provided a facile insight into comorbid burden. Operational results of this program have exceeded expectations and the program is being expanded to the entire health system. This paradigm of ML-driven, checklist-enabled care can be used agnostic of EMR platform to deliver value in CKD through structured engagement of complexity in health systems.
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Nefrologia , Insuficiência Renal Crônica , Registros Eletrônicos de Saúde , Humanos , Nefrologia/métodos , Atenção Primária à Saúde/métodos , Encaminhamento e Consulta , Insuficiência Renal Crônica/terapiaRESUMO
The nontuberculous mycobacteria (NTM) Mycobacterium avium is a clinically significant pathogen that can cause a wide range of maladies, including tuberculosis-like pulmonary disease. An immunocompromised host status, either genetically or acutely acquired, presents a large risk for progressive NTM infections. Due to this quietly emerging health threat, we evaluated the ability of a recombinant fusion protein ID91 combined with GLA-SE [glucopyranosyl lipid adjuvant, a toll like receptor 4 agonist formulated in an oil-in-water stable nano-emulsion] to confer protection in both C57BL/6 (wild type) and Beige (immunocompromised) mouse models. We optimized an aerosol challenge model using a clinical NTM isolate: M. avium 2-151 smt, observed bacterial growth kinetics, colony morphology, drug sensitivity and histopathology, characterized the influx of pulmonary immune cells, and confirmed the immunogenicity of ID91 in both mouse models. To determine prophylactic vaccine efficacy against this M. avium isolate, mice were immunized with either ID91 + GLA-SE or bacillus Calmette-Guérin (BCG). Immunocompromised Beige mice displayed a delayed influx of innate and adaptive immune cells resulting in a sustained and increased bacterial burden in the lungs and spleen compared to C57BL/6 mice. Importantly, both ID91 + GLA-SE and BCG vaccines significantly reduced pulmonary bacterial burden in both mouse strains. This work is a proof-of-concept study of subunit vaccine-induced protection against NTM.
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Vacina BCG/administração & dosagem , Modelos Animais de Doenças , Hospedeiro Imunocomprometido/imunologia , Mycobacterium avium/patogenicidade , Tuberculose/prevenção & controle , Vacinas de Subunidades Antigênicas/administração & dosagem , Animais , Vacina BCG/imunologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium avium/metabolismo , Tuberculose/imunologia , Tuberculose/microbiologia , Vacinação , Vacinas de Subunidades Antigênicas/imunologiaRESUMO
An estimated 10 million people developed tuberculosis (TB) disease in 2019 which underscores the need for a vaccine that prevents disease and reduces transmission. The aim of our current studies is to characterize and test a prophylactic tuberculosis vaccine comprised of ID93, a polyprotein fusion antigen, and a liposomal formulation [including a synthetic TLR4 agonist (glucopyranosyl lipid adjuvant, GLA) and QS-21] in a preclinical mouse model of TB disease. Comparisons of the ID93+GLA-LSQ vaccines are also made to the highly characterized ID93+GLA-SE oil-in-water emulsion adjuvant, which are also included these studies. The recent success of vaccine candidate M72 combined with adjuvant AS01E (GlaxoSmithKline Biologicals) in reducing progression to active disease is promising and has renewed excitement for experimental vaccines currently in the TB vaccine pipeline. The AS01E adjuvant contains monophosphoryl lipid A (MPL) and QS-21 (a saponin) in a liposomal formulation. While AS01E has demonstrated potent adjuvant activity as a component of both approved and experimental vaccines, developing alternatives to this adjuvant system will become important to fill the high demand envisioned for future vaccine needs. Furthermore, replacement sources of potent adjuvants will help to supply the demand of a TB vaccine [almost one-quarter of the world's population are estimated to have latent Mycobacterium tuberculosis (Mtb) according to the WHO 2019 global TB report], addressing (a) cost of goods, (b) supply of goods, and (c) improved efficacy of subunit vaccines against Mtb. We show that both ID93+GLA-SE (containing an emulsion adjuvant) and ID93+GLA-LSQ (containing a liposomal adjuvant) induce ID93-specific TH1 cellular immunity including CD4+CD44+ T cells expressing IFNγ, TNF, and IL-2 (using flow cytometry and intracellular cytokine staining) and vaccine-specific IgG2 antibody responses (using an ELISA). In addition, both ID93+GLA-SE and ID93+GLA-LSQ effectively decrease the bacterial load within the lungs of mice infected with Mtb. Formulations based on this liposomal adjuvant formulation may provide an alternative to AS01 adjuvant systems.
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Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/uso terapêutico , Tuberculose Pulmonar/prevenção & controle , Adjuvantes Imunológicos/uso terapêutico , Animais , Antígenos de Bactérias/uso terapêutico , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Lipossomos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes de Fusão/uso terapêuticoRESUMO
BACKGROUND AND OBJECTIVES: National workforce models fail to capture the regional effect of residency programs, despite local control over decisions to open or close training sites. In the last 5 years, 37 (nearly 8% of total) family medicine residency programs have closed. We report on a novel approach to measuring the regional effect of residency training programs closures using a combination of quantitative and spatial methods. METHODS: American Medical Association Physician Masterfile records and residency graduate registries for 22 of 37 family medicine residency programs that closed between 2000-2006 were analyzed to determine regional patterns of physician practice, as well as the effect of graduates from closed programs on areas that otherwise would be Health Professional Shortage Areas (HPSAs). Program graduate data from two sampled programs were mapped using geographic information system software to display the distribution "footprint" of graduates regionally. RESULTS: Of the 1,545 graduates of the 22 programs, 21% of graduates practice in rural locations, and 68% are in full-county or partial-county HPSAs. Without the graduates of these programs, there would have been 150 additional full HPSA counties in 15 states. The spatial distribution of the graduates of two closed programs demonstrates their effect across multiple counties and states. CONCLUSIONS: The effect of closing family medicine residency programs is likely to go undetected for many years. Decisions regarding the fate of family medicine programs are often made without benefit of a full assessment. Local and regional effects on physician access are often recognized only after the fact. Novel approaches to analysis and display of local effects of closures are essential for policy decisions concerning physician workforce training.
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Medicina de Família e Comunidade , Internato e Residência , Área Carente de Assistência Médica , Área de Atuação Profissional , Centros Médicos Acadêmicos , Demografia , Humanos , Mudança Social , Recursos HumanosRESUMO
It is estimated that one third of the world's population is infected with Mycobacterium tuberculosis (Mtb). This astounding statistic, in combination with costly and lengthy treatment regimens make the development of therapeutic vaccines paramount for controlling the global burden of tuberculosis. Unlike prophylactic vaccination, therapeutic immunization relies on the natural pulmonary infection with Mtb as the mucosal prime that directs boost responses back to the lung. The purpose of this work was to determine the protection and safety profile over time following therapeutic administration of our lead Mtb vaccine candidate, ID93 with a synthetic TLR4 agonist (glucopyranosyl lipid adjuvant in a stable emulsion (GLA-SE)), in combination with rifampicin, isoniazid, and pyrazinamide (RHZ) drug treatment. We assessed the host inflammatory immune responses and lung pathology 7â»22 weeks post infection, and determined the therapeutic efficacy of combined treatment by enumeration of the bacterial load and survival in the SWR/J mouse model. We show that drug treatment alone, or with immunotherapy, tempered the inflammatory responses measured in brochoalveolar lavage fluid and plasma compared to untreated cohorts. RHZ combined with therapeutic immunizations significantly enhanced TH1-type cytokine responses in the lung over time, corresponding to decreased pulmonary pathology evidenced by a significant decrease in the percentage of lung lesions and destructive lung inflammation. These data suggest that bacterial burden assessment alone may miss important correlates of lung architecture that directly contribute to therapeutic vaccine efficacy in the preclinical mouse model. We also confirmed our previous finding that in combination with antibiotics therapeutic immunizations provide an additive survival advantage. Moreover, therapeutic immunizations with ID93/GLA-SE induced differential T cell immune responses over the course of infection that correlated with periods of enhanced bacterial control over that of drug treatment alone. Here we advance the immunotherapy model and investigate reliable correlates of protection and Mtb control.
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A number of challenges for developing a protective pre-pandemic influenza A vaccine exists including predicting the target influenza strain and designing the vaccine for an immunologically naïve population. Manufacturing and supply of the vaccine would also require implementing ways to increase coverage for the largest number of people through dose-sparing methods, while not compromising the potency of the vaccine. Previously, our group described a novel hemagglutinin (HA) for H5N1 influenza derived from a methodology termed computationally optimized broadly reactive antigen (COBRA). This report describes a strategy combining a COBRA-based HA vaccine with an oil-in-water emulsion, resulting in a dose-sparing, immunologically broadened, and protective response against multiple H5N1 isolates. Here, we show that an emulsion-based adjuvant enhances the magnitude and breadth of antibody responses with both a wild-type H5HA (H5N1 WT) and the H5N1 COBRA HA VLP vaccines. The H5N1 COBRA HA VLP, combined with an emulsion adjuvant, elicited HAI specific antibodies against a larger panel of H5N1 viruses that resulted in protection against challenge as efficiently as the homologous, matched vaccine.
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Vacinas contra Influenza/uso terapêutico , Animais , Emulsões , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Vacinação/métodosRESUMO
Disparities in health status and health outcomes exist among subpopulations of women; these disparities may be related to socioeconomic status, race, ethnicity, and country of birth. In this paper, we use surveillance data from 2003 and earlier to examine racial and ethnic differences among women in sexually transmitted diseases (STDs) (chlamydia, gonorrhea, and syphilis), human immunodeficiency virus (HIV), and tuberculosis. We also describe prevention programs the Centers for Disease Control and Prevention (CDC) has developed to address the disparities.
Assuntos
Infecções por HIV/etnologia , Infecções Sexualmente Transmissíveis/etnologia , Tuberculose/etnologia , Saúde da Mulher/etnologia , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Asiático/estatística & dados numéricos , Criança , Emigração e Imigração/estatística & dados numéricos , Emigração e Imigração/tendências , Feminino , Infecções por HIV/epidemiologia , Hispânico ou Latino/estatística & dados numéricos , Humanos , Indígenas Norte-Americanos/estatística & dados numéricos , Pessoa de Meia-Idade , Vigilância da População , Infecções Sexualmente Transmissíveis/epidemiologia , Fatores Socioeconômicos , Tuberculose/epidemiologia , Estados Unidos/epidemiologia , População Branca/estatística & dados numéricosRESUMO
Mycobacterium tuberculosis HN878 represents a virulent clinical strain from the W-Beijing family, which has been tested in small animal models in order to study its virulence and its induction of host immune responses following infection. This isolate causes death and extensive lung pathology in infected C57BL/6 mice, whereas lab-adapted strains, such as M. tuberculosis H37Rv, do not. The use of this clinically relevant isolate of M. tuberculosis increases the possibilities of assessing the long-lived efficacy of tuberculosis vaccines in a relatively inexpensive small animal model. This model will also allow for the use of knockout mouse strains to critically examine key immunological factors responsible for long-lived, vaccine-induced immunity in addition to vaccine-mediated prevention of pulmonary immunopathology. In this study, we show that the ID93/glucopyranosyl lipid adjuvant (GLA)-stable emulsion (SE) tuberculosis vaccine candidate, currently in human clinical trials, is able to elicit protection against M. tuberculosis HN878 by reducing the bacterial burden in the lung and spleen and by preventing the extensive lung pathology induced by this pathogen in C57BL/6 mice.