To reduce the incidence of tuberculosis, it is insufficient to simply understand the dynamics of tuberculosis transmission. Rather, we must design and rigorously evaluate interventions to halt transmission, prioritizing those interventions most likely to achieve population-level impact. Synergy in reducing tuberculosis transmission may be attainable by combining interventions that shrink the reservoir of latent Mycobacterium tuberculosis infection (preventive therapy), shorten the time between disease onset and treatment initiation (case finding and diagnosis), and prevent transmission in key settings, such as the built environment (infection control). In evaluating efficacy and estimating population-level impact, cluster-randomized trials and mechanistic models play particularly prominent roles. Historical and contemporary evidence suggests that effective public health interventions can halt tuberculosis transmission, but an evidence-based approach based on knowledge of local epidemiology is necessary for success. We provide a roadmap for designing, evaluating, and modeling interventions to interrupt the process of transmission that fuels a diverse array of tuberculosis epidemics worldwide.
High rates of tuberculosis transmission are driving the ongoing global tuberculosis epidemic, and there is a pressing need for research focused on understanding and, ultimately, halting transmission. The ongoing tuberculosis-human immunodeficiency virus (HIV) coepidemic and rising rates of drug-resistant tuberculosis in parts of the world add further urgency to this work. Success in this research will require a concerted, multidisciplinary effort on the part of tuberculosis scientists, clinicians, programs, and funders and must span the research spectrum from biomedical sciences to the social sciences, public health, epidemiology, cost-effectiveness analyses, and operations research. Heterogeneity of tuberculosis disease, both among individual patients and among communities, poses a substantial challenge to efforts to interrupt transmission. As such, it is likely that effective interventions to stop transmission will require a combination of approaches that will vary across different epidemiologic settings. This research roadmap summarizes key gaps in our current understanding of transmission, as laid out in the preceding articles in this series. We also hope that it will be a call to action for the global tuberculosis community to make a sustained commitment to tuberculosis transmission science. Halting transmission today is an essential step on the path to end tuberculosis tomorrow.
Cardiovascular Diseases (12), Immune System Diseases (1) Tuberculosis (11), Communicable Diseases (1), Drug-Resistant Tuberculosis (1), more mentions
Hematopoietic cell transplantation (HCT) offers definitive management for a wide variety of malignant and nonmalignant diseases. Conditioning regimens and therapies used to prevent and treat GvHD are immune suppressive, often increasing the risk of developing fungal disease due to yeasts or molds. Antifungal prophylaxis may be useful in preventing morbidity and mortality during and after HCT. In this article, we review the epidemiology and current literature regarding strategies for prevention of invasive fungal disease (IFD) in the pre-engraftment and post-engraftment settings, and propose future direction for scientific discovery.Bone Marrow Transplantation advance online publication, 23 October 2017; doi:10.1038/bmt.2017.222.
The devastating 2010 cholera epidemic in Haiti prompted the government to introduce oral cholera vaccine (OCV) in two high-risk areas of Haiti. We evaluated the direct costs associated with the government's first vaccine campaign implemented in August-September 2013. We analyzed data for major cost categories and assessed the efficiency of available campaign resources to vaccinate the target population. For a target population of 107,906 persons, campaign costs totaled $624,000 and 215,295 OCV doses were dispensed. The total vaccine and operational cost was $2.90 per dose; vaccine alone cost $1.85 per dose, vaccine delivery and administration $0.70 per dose, and vaccine storage and transport $0.35 per dose. Resources were greater than needed-our analyses suggested that approximately 2.5-6 times as many persons could have been vaccinated during this campaign without increasing the resources allocated for vaccine delivery and administration. These results can inform future OCV campaigns in Haiti.
Background: Observational post-marketing studies are important to assess vaccine effectiveness (VE). We estimated VE from the bivalent human papillomavirus (HPV) vaccine against HPV positivity of vaccine and non-vaccine types in a high-risk population.
Methods: We included all vaccine-eligible women from the PASSYON study, a biennial cross-sectional survey in Dutch sexually transmitted infection clinics. Vaginal swabs were analyzed using a PCR-based assay (SPF10-LiPA25) able to detect the 12 high-risk HPV (hrHPV) types 16/18/31/33/35/39/45/51/52/56/58/59. We compared hrHPV positivity between self-reported vaccinated (≥1 dose) and unvaccinated women, and estimated VE by a logistic mixed model.
Results: We included 1087 women of which 53% were hrHPV positive and 60% reported to be vaccinated. The adjusted pooled VE against HPV-16/18 was 89.9% (81.7-94.4). Moreover, we calculated significant VE against non-vaccine types HPV-45 (91%), HPV-35 (57%), HPV-31 (50%) and HPV-52 (37%). Among women who were offered vaccination 5/6 years ago, we estimated similar VE against HPV-16/18 (92%) and all hrHPV types (35%) compared to women who were offered vaccination <5 years ago (83% and 33% respectively).
Conclusion: We demonstrated high VE of the bivalent vaccine against HPV-16/18 and cross-protection against HPV-45/35/31/52. Protection against HPV-16/18 was sustained up to six years post-vaccination.
The effectiveness of the annual influenza vaccine has declined in recent years, especially for the H3N2 component, and is a concern for global public health. A major cause for this lack in effectiveness has been attributed to the egg-based vaccine production process. Substitutions on the hemagglutinin glycoprotein (HA) often arise during virus passaging that change its antigenicity and hence vaccine effectiveness. Here, we characterize the effect of a prevalent substitution, L194P, in egg-passaged H3N2 viruses. X-ray structural analysis reveals that this substitution surprisingly increases the mobility of the 190-helix and neighboring regions in antigenic site B, which forms one side of the receptor binding site (RBS) and is immunodominant in recent human H3N2 viruses. Importantly, the L194P substitution decreases binding and neutralization by an RBS-targeted broadly neutralizing antibody by three orders of magnitude and significantly changes the HA antigenicity as measured by binding of human serum antibodies. The receptor binding mode and specificity are also altered to adapt to avian receptors during egg passaging. Overall, these findings help explain the low effectiveness of the seasonal vaccine against H3N2 viruses, and suggest that alternative approaches should be accelerated for producing influenza vaccines as well as isolating clinical isolates.
RATIONALE: Tumor chemotherapy could weaken the immune system of patients, which might enhance the body sensitivities to the exogenous pathogens, among which the hepatitis B virus (HBV) infection should be concerned because of the higher chances of infection and the severe outcomes, especially in East Asia. The titer level of hepatitis B surface antibody (HBsAb) higher than 10 IU/L is considered to offer immunocompetent individuals adequate protection. However, whether this level is enough to the tumor patients during chemotherapy remains unclear.
PATIENT CONCERNS: A 58-year-old female lymphoma patient was admitted to our hospital for asthenia, nausea, vomiting, and abnormal liver function lasting over 1 week and diagnosed as acute hepatitis B. The patient just finished a course of chemotherapy with CHOP regimen and had recent record (78.61 IU/L) of HBsAb positive. The only risk of infection we could found was that the patient had received blood transfusion shortly after chemotherapy from a donor who was recovering from an asymptomatic acute HBV infection.
INTERVENTION: The patient was administered with entecavir and glycyrrhizic acid agent, and then the disease was resolved successfully with hepatitis B surface antigen serological conversion.
LESSONS: Tumor chemotherapy might have weakened the immune system of the patient and enhanced the body sensitivities to hepatitis B virus, then led to the infection. We concluded that HBsAb-positive status, at least "weakly positive," might not enough to provide protection for tumor patients on chemotherapy though this level was enough for health individuals and donors recuperating from subclinical acute hepatitis B might be another potential risk of HBV infection.
Infectious Diseases (11), Immune System Diseases (1) Hepatitis B (11), Infections (7), Neoplasms (4), more mentions
INTRODUCTION: Nonsmall cell lung cancer accounts for approximately 80% of all lung cancers, and approximately 75% of cases are diagnosed in the middle and late stages of disease. Unfortunately, limited treatment does not improve the prognosis of advanced disease. Monoclonal antibodies targeting programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) represent a new treatment paradigm for nonsmall cell lung cancer. Nevertheless, the immune-related adverse events (irAEs) associated with PD-1 and PD-L1 inhibitors are unique, and early recognition and treatment of these events are essential.
METHODS AND ANALYSIS: A systematic literature search will be performed using the EMBASE, MEDLINE, and Cochrane databases to identify relevant articles published in any language. Randomized clinical trials, case series, and case reports of PD-1 and PD-L1 inhibitors in the treatment of nonsmall cell lung cancer will be included. All meta-analyses will be performed using RevMan software. The quality of the studies will be evaluated using the guidelines listed in the Cochrane Handbook. If the necessary data are available, then subgroup analyses will be performed for high-, median-, and low-dose cohorts. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements will be followed until the findings of the systematic review and meta-analysis are reported.
CONCLUSIONS: This will be the first systematic review and meta-analysis to describe previously reported irAEs related to PD-1 and PD-L1 inhibitors in the treatment of nonsmall cell lung cancer.
Neisseria meningitidis is the causative agent of invasive meningococcal disease (IMD). A recombinant vaccine called Bexsero® incorporates four subcapsular antigens (fHbp, NHBA, NadA and PorA) which are used to assign a Bexsero® antigen sequence type (BAST) to each meningococcal strain. The vaccine elicits an immune response against combinations of variants of these antigens which have been grouped into specific BAST profiles that have been shown to have different distributions within geographical locations thus potentially affecting the efficacy of the vaccine. In this study, invasive meningococcal disease isolates from the western seaboard of Australia (Western Australia; WA) were compared to those from the south-eastern seaboard (Victoria; VIC) from 2008 to 2012. Whole-genome sequencing (WGS) of 131 meningococci from VIC and 70 meningococci from WA were analysed for MLST, FetA and BAST profiling. Serogroup B predominated in both jurisdictions and a total of 10 MLST clonal complexes (cc) were shared by both states. Isolates belonging to cc22, cc103 and cc1157 were unique to VIC whilst isolates from cc60 and cc212 were unique to WA. Clonal complex 41/44 represented one-third of the meningococcal population in each state but the predominant ST was locally different: ST-6058 in VIC and ST-146 in WA. Of the 108 BAST profiles identified in this collection, only 9 BASTs were simultaneously observed in both states. A significantly larger proportion of isolates in VIC harboured alleles for the NHBA-2 peptide and fHbp-1, antigenic variants predicted to be covered by the Bexsero® vaccine. The estimate for vaccine coverage in WA (47.1% [95% CI: 41.1-53.1%]) was significantly lower than that in VIC (66.4% [95% CI: 62.3-70.5%]). In conclusion, the antigenic structure of meningococci causing invasive disease in two geographically distinct states of Australia differed significantly during the study period which may affect vaccine effectiveness and highlights the need for representative surveillance when predicting potential impact of meningococcal B vaccines.
Our laboratory previously used the SEREX method in U937 cells and identified a novel leukemia-associated gene MLAA-34, a novel splice variant of CAB39L associated with acute monocytic leukemia, that exhibited anti-apoptotic activities in U937 cells. Whether MLAA-34 has an anti-apoptotic role in other tumor cells has not yet been reported. We explored whether MLAA-34 exhibited anti-apoptotic effects in HeLa cervical cancer cells and the possible mechanism of action. We generated a HeLa cell line stably expressing MLAA-34 and found that MLAA-34 overexpression had no effect on the growth, apoptosis and cell cycle of HeLa cells. However, upon treatment with arsenic trioxide (ATO) to induce apoptosis, the cell viability and colony formation ability of ATO-treated MLAA-34 stable HeLa cells were significantly higher than that of ATO-treated controls, and the apoptosis rate and proportion of G2/M cells also decreased. We found that ATO treatment of HeLa cells resulted in significant decreases in the expression of β-catenin mRNA and protein and the downstream target factors c-Myc, cyclin B1, and cyclin D1 in the Wnt signaling pathway. Notably, ATO-treated MLAA-34 stable HeLa cells showed a significant reduction in the ATO-mediated downregulation of these factors. In addition, MLAA-34 overexpression significantly increased the expression of nuclear β-catenin protein in ATO-treated cells compared with HeLa cells treated only with ATO. Thus, here we have found that the Wnt/β-catenin signaling pathway is involved in ATO-induced apoptosis in HeLa cells. MLAA-34 reduces ATO-induced apoptosis and G2/M arrest, and the anti-apoptotic effect may be achieved by activating the Wnt/β-catenin signaling pathway in HeLa cells.
Background: In October 2016, pembrolizumab became the new standard of care for firstline treatment of patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors express programmed death ligand 1 in at least 50% of cells. The US Food and Drug Administration-recommended dose is 200 mg every three weeks. Multiple studies have demonstrated equivalent efficacy with weight-based doses between 2 mg/kg and 10 mg/kg. The objective of this study was to compare the economic impact of using personalized dosing (2 mg/kg) vs fixed dosing (200 mg) in the firstline setting of mNSCLC.
Methods: We performed a budget impact analysis from the US societal perspective to compare fixed dosing with personalized dosing. We calculated the target population and weight of patients who would be treated with pembrolizumab annually in the firstline setting. Using survival curves from the KEYNOTE 024 trial with Weibull extrapolation, we estimated the mean number of cycles that patients would receive. Using the Medicare average sales price, we calculated the difference in cost between personalized and fixed dosing.
Results: Our base case model demonstrates that the total annual cost of pembrolizumab with fixed dosing is US $3 440 127 429, and with personalized dosing it is US $2 614 496 846. The use of personalized dosing would lead to a 24.0% annual savings of US $825 630 583 in the United States.
Conclusions: Personalized dosing of pembrolizumab may have the potential to save approximately $0.825 billion annually in the United States, likely without impacting outcomes. This option should be considered for the firstline management of PD-L1-positive advanced lung cancer.
Background: Combining bevacizumab with frontline chemotherapy statistically significantly improved progression-free survival (PFS) but not overall survival (OS) in the phase III GOG-0218 trial. Evaluation of candidate biomarkers was an exploratory objective.
Methods: Patients with stage III (incompletely resected) or IV ovarian cancer were randomly assigned to receive six chemotherapy cycles with placebo or bevacizumab followed by single-agent placebo or bevacizumab. Five candidate tumor biomarkers were assessed by immunohistochemistry. The biomarker-evaluable population was categorized into high or low biomarker-expressing subgroups using median and quartile cutoffs. Associations between biomarker expression and efficacy were analyzed. All statistical tests were two-sided.
Results: The biomarker-evaluable population (n = 980) comprising 78.5% of the intent-to-treat population had representative baseline characteristics and efficacy outcomes. Neither prognostic nor predictive associations were seen for vascular endothelial growth factor (VEGF) receptor-2, neuropilin-1, or MET. Higher microvessel density (MVD; measured by CD31) showed predictive value for PFS (hazard ratio [HR] for bevacizumab vs placebo = 0.40, 95% confidence interval [CI] = 0.29 to 0.54, vs 0.80, 95% CI = 0.59 to 1.07, for high vs low MVD, respectively, P interaction = .003) and OS (HR = 0.67, 95% CI = 0.51 to 0.88, vs 1.10, 95% CI = 0.84 to 1.44, P interaction = .02). Tumor VEGF-A was not predictive for PFS but showed potential predictive value for OS using a third-quartile cutoff for high VEGF-A expression.
Conclusions: These retrospective tumor biomarker analyses suggest a positive association between density of vascular endothelial cells (the predominant cell type expressing VEGF receptors) and tumor VEGF-A levels and magnitude of bevacizumab effect in ovarian cancer. The potential predictive value of MVD (CD31) and tumor VEGF-A is consistent with a mechanism of action driven by VEGF-A signaling blockade.
At the moment of the diagnosis of hepatocellular carcinoma (HCC), 70% of patients have only access to palliative treatments, with very few therapeutic options. Liver immunology is very specific, and liver immunotolerance is particularly developed because of the constant and massive influx of antigens. Deregulation of hepatic immunotolerance is implicated in chronic liver diseases development and particularly in liver carcinogenesis. For these reasons, HCC may be an excellent candidate for anticancer immunotherapies such as immune checkpoint inhibitors targeting CTLA-4 and PD-L1/PD-1. Nonetheless, because of the specific immune environment of the liver and the frequent association of HCC with hepatocellular insufficiency, the safety and the efficacy of these new treatments have to be properly studied in this situation. Thus, multiple phase II and III studies are in progress studying immune checkpoint inhibitor monotherapies, combination of different immunotherapies or local strategies such as transarterial chemoembolization combined with immune checkpoint inhibitors. Currently, only the final results of the tremelimumab phase II and the Nivolumab phase I/II study (CheckMate-040) are available. The latter is promising but need to be confirmed by the ongoing phase III studies to confirm the place of immunotherapy in the treatment of HCC. With many new molecular targets and therapeutic combination, immunotherapy represents a new hope in treating HCC patients although serious evaluation is still needed to confirm its interest.
Background: CD73 is an ecto-enzyme that promotes tumor immune escape through the production of immunosuppressive extracellular adenosine in the tumor microenvironment. Several CD73 inhibitors and adenosine receptor antagonists are being evaluated in phase I clinical trials.
Patients and methods: Full-face sections from formalin-fixed paraffin-embedded primary breast tumors from 122 samples of triple-negative breast cancer from the BIG 02-98 adjuvant phase III clinical trial were included in our analysis. Using multiplex immunofluorescence and image analysis, we assessed CD73 protein expression on tumor cells, tumor-infiltrating leukocytes and stromal cells. We investigated the associations between CD73 protein expression with disease-free survival, overall survival and the extent of tumor immune infiltration.
Results: Our results demonstrated that high levels of CD73 expression on epithelial tumor cells were significantly associated with reduced disease-free survival, overall survival and negatively correlated with tumor immune infiltration (Spearman's R= -0.50, p < 0.0001). Patients with high levels of CD73 and low levels of tumor-infiltrating leukocytes had the worse clinical outcome.
Conclusions: Taken together, our study provides further support that CD73 expression is associated with a poor prognosis and reduced anti-tumor immunity in human triple-negative breast cancer and that targeting CD73 could be a promising strategy to reprogram the tumor microenvironment in this breast cancer subtype.
Non-communicable diseases (NCDs) account for 76% of deaths in Iran and this number is on the rise, parallel to global rates. Many risk factors associated with NCDs are preventable; however it is first necessary to conduct observational studies to identify relevant risk factors, and the most appropriate approach to control them. Iran is a multi-ethnic country, therefore the Ministry of Health and Medical Education sought to launch a nationwide cohort study-the Prospective Epidemiological Research Studies in IrAN (PERSIAN)-in order to identify the most prevalent NCDs among Iranian ethnicities, and to investigate effective methods of prevention. The PERSIAN cohort consists of four population-based cohorts, the adult component, presented in this article, is a prospective cohort including 180,000 individuals aged 35-70 years, from 18 distinct areas of Iran. Upon joining, participants respond to interviewer-administered questionnaires. Blood, urine, hair and nail samples are collected and stored. To ensure consistency, centrally-purchased equipment is sent to all sites, and the same team trains all personnel. Routine visits and quality assurance/control measures are taken to ensure protocol adherence. Participants are followed for 15 years post-enrollment. The PERSIAN cohort is currently in the enrollment phase; cohort profiles will soon emerge.
Sipuleucel-T, a therapeutic dendritic-cell vaccine, was Food and Drug Administration-approved for prostate cancer in 2010. No new immunotherapies for prostate cancer have been approved since. However, novel agents and combination approaches offer great promise for improving outcomes for prostate cancer patients. Here we review the latest developments in immunotherapy for prostate cancer. Sipuleucel-T has demonstrated a survival advantage of 4.1 months in metastatic castration-resistant prostate cancer. PSA-TRICOM (PROSTVAC), a prostate-specific antigen-targeted vaccine platform, showed evidence of clinical and immunologic efficacy in early-phase clinical trials, and results from a phase III trial in advanced disease are pending. While immune checkpoint inhibitors appear to have modest activity as monotherapy, preclinical and clinical data suggest that they may synergize with vaccines, poly [ADP-ribose] polymerase inhibitors, and other agents. Several clinical studies that combine these therapies are underway. Combining prostate cancer vaccines with immune checkpoint inhibitors has great potential for improving clinical outcomes in prostate cancer. Such combination approaches may create and then recruit tumor-specific T cells to tumor while also increasing their effector function. Other emerging agents may also enhance immune-mediated tumor destruction.