DR52.1 DataRelease
Release Date: July 2024
New Studies: 29
Updated Studies: 109
New Studies
| SDY1879: Molecular Heterogeneity of SLE Disease Activity | ||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||
| Description: | In this study, a broad multi-omic analysis of differences in SLE disease activity by race was used to determine differences in the cellular and molecular presentation of disease. Data from CyTOF (immunophenotyping & phospho-Cytof), multioplex soluble mediators (both baseline plasma and stimulated secreted), EpiTOF, and scRNA-Seq/51-plex CITE-Seq are systematically collected from the sample subjects at the same visits across a very deeply clinically phenotyped cohort matched for age, race and sex. | |||||||||||||||||||||
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| DOI: | 10.21430/M3JWL5OZEV | |||||||||||||||||||||
| Subjects: | 58 | |||||||||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||||||||
| SDY2464: Metabolomics in urine and serum of 4Gy exposed NHP (2 year followup) | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | Nonhuman primates exposed to total body irradiation of 4 Gy gamma were followed for two years after exposure. Urine and serum were collected at various time points up until 2 years after exposure, and appropriately age matched controls were identified for the later time points. Metabolomic analysis was conducted through untargeted metabolomics and metabolic fingerprinting, based on published radiation biomarkers. The radiation signal persisted for at least 2 years after exposure with high sensitivity and specificity. | ||||||||||||||||||
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| DOI: | 10.21430/M3RAB4X3PW | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Publications: | None | ||||||||||||||||||
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| Assays: | None | ||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||
| SDY2465: NHP 4Gy and age matched controls | |||||||||||||
| Status: | New | ||||||||||||
| Description: | National security concerns regarding radiological incidents, accidental or intentional in nature, have increased substantially over the past few years. A primary area of intense planning is the assessment of exposed individuals and timely medical management. However, exposed individuals who receive survivable doses may develop delayed effects of acute radiation exposure many months or years later. Therefore, it is necessary to identify such individuals and determine whether their symptoms may have been initiated by radiation, requiring complex medical interventions. We previously developed early response metabolomic biosignatures in biofluids from nonhuman primates exposed to a total body gamma radiation dose of 4 Gy (up to 60 days). A follow-up of these animals has been ongoing with samples consistently collected every few months for up to 2 years after exposure, providing a unique cohort to determine if a radiation signal persists longer than 2 months. Metabolic fingerprinting in urine and serum determined that exposed animals remain metabolically different from pre-exposure levels and from age-matched controls, and the pre-determined biosignature maintains high sensitivity and specificity. Significant perturbations in tricarboxylic acid intermediates, cofactors and nucleotide metabolism were noted, signifying energetic changes that could be attributed to or perpetuate altered mitochondrial dynamics. Importantly, these animals have begun developing diseases such as hypertension much earlier than their age matched controls, further emphasizing that radiation exposure may lead to accelerated aging. This NHP cohort provides important information and highlights the potential of metabolomics in determining persistent changes and a radiation-specific signature that can be correlated to phenotype. | ||||||||||||
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| DOI: | 10.21430/M3219LYSQM | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Publications: | None | ||||||||||||
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| Assays: | None | ||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY2471: U19 CCHI_Project 1. The Role of CD4 Memory Phenotype, Memory, and Effector T Cells in | |||||||||||||
| Status: | New | ||||||||||||
| Description: | The purpose of this study is provide a better understanding of the adaptive immune response to the licensed flu vaccines. We hope the information learned from this study will help identify and describe important factors | ||||||||||||
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| DOI: | 10.21430/M30UY9XYSX | ||||||||||||
| Subjects: | 12 | ||||||||||||
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| Publications: | None | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2497: Effects of Aging on Primary and Secondary Vaccine Responses in a 15-Year Longitudinal Cohort | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Investigators will carry out an in-depth study of human B cell and T cell immune responses to vaccines that the person hasn't previously encountered, as well as to seasonal influenza vaccination, and determine which aspects of immune function are most affected by aging in each case. The research subjects are a well-characterized longitudinal cohort of young and elderly individuals whose influenza vaccine responses have been studied each year for up to 9 years, and who will be vaccinated for Hepatitis A in this new study. Improved understanding of human immune system function obtained by studying individual B cells and T cells and their fates following vaccination will help in the design and testing of new vaccines against emergent diseases. | ||||||||||||
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| DOI: | 10.21430/M3Y7FDJGD6 | ||||||||||||
| Subjects: | 57 | ||||||||||||
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| Publications: | None | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2617: Placental transfer of maternal COVID-19 vaccine-induced antibodies in infants | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Completion of a COVID-19 vaccination series during pregnancy effectively reduces COVID-19 hospitalization among infants less than 6 months of age. The dynamics of transplacental transfer of maternal vaccine-induced antibodies and their persistence in infants at 2,6,9 and 12 months have implications for new vaccine development and optimal timing of vaccine administration in pregnancy. We evaluated anti-COVID antibody IgG subclass, Fc-receptor binding profile, and activity against wild-type Spike and RBD plus five variants of concern (VOCs) in 153 serum samples from 100 infants. Maternal IgG1 and IgG3 responses persisted in 2- and 6-month infants to a greater extent than the other IgG subclasses, with high persistence of antibodies binding placental neonatal Fc-receptor and FcγR3A. Lowest persistence was observed against the Omicron RBD-specific region. Maternal vaccine timing, placental Fc-receptor binding capabilities, antibody subclass, fetal sex, and VOC all impact the persistence of antibodies in infants through 12 months of age. | ||||||||||||
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| DOI: | 10.21430/M3B6120AR6 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Assays: | None | ||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY2618: Accelerated Weight Gain Among Infants With In Utero COVID-19 exposure | ||||||||||
| Status: | New | |||||||||
| Description: | We conducted a longitudinal cohort study leveraging a prospectively enrolled perinatal biorepository among 149 infants with in-utero COVID-19 exposure and 127 unexposed controls. Weight, length, and body mass index (BMI) were abstracted from health records at 0, 2, 6, and 12 months and standardized using World Health Organization growth charts. Analyses were adjusted for maternal age, ethnicity, parity, insurance, and BMI, as well as infant sex, birthdate, and breastfeeding. After our data collection and analysis, we evidenced that infants with in utero COVID-19 exposure exhibited lower birth weight and accelerated weight gain in the first year of life, which may be harbingers of downstream cardiometabolic pathology. | |||||||||
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| DOI: | 10.21430/M33IM6KHA3 | |||||||||
| Subjects: | 0 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2663: DEGRADATION OF MUTANT CALRETICULIN AND MPL IN MPN | |||||||
| Status: | New | ||||||
| Description: | The goal of the study was to understand the downstream effects of activation of thrombopoietin receptor (MPL) signaling by Myeloproliferative Neoplasm (MPN)-linked mutant Calreticulin (CRT) proteins. We found that platelets from patients with MPN exhibit low surface and total MPL levels which could be a potential biomarker of mutant CRT-linked MPNs. We show in this study that co-expression of mutant CRT protein-Del52 and MPL in cell lines triggers low surface and total MPL levels. We found that inhibition of lysosomal degradation not only rescued surface and total MPL levels but also the mutant CRT protein level in the cells co-expressing MPL and Del52. We next showed that the activation of lysosomal degradation reduces Del52-mediated cytokine-independent proliferation of cells co-expressing MPL and Del52 and also that of primary CD34 cells from patients with MPN. Through our findings, we propose that lysosomal degradation pathway is relevant to the regulation of both MPL and mutant CRT protein levels in mutant CRT-driven MPNs and can form potential target for therapeutic intervention. | ||||||
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| DOI: | 10.21430/M3NSE4ZA86 | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2666: CD27+/- CD8+ T cells | ||||||||||
| Status: | New | |||||||||
| Description: | CD8+ T cells first isolated from PBMCs using magnetic isolation and then the cells were sorted from five children with T1D and five healthy controls into CD27- and CD27+CD8+ T-cell subsets to enrich the rare CD27- memory T cells. We analyzed the cells both directly ex vivo as well as after a 90 min stimulation with PMA and ionomycin. We profiled the expression of 475 immune genes at the mRNA level together with the expression of 14 surface protein targets using the BD Rhapsody Single-Cell Analysis system. Separate datasets for ex vivo and stimulated samples, single cells from each individual can be traced back to each donor as sample multiplexing was performed using BD Sample Tags. | |||||||||
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| DOI: | 10.21430/M3EOYVHU3W | |||||||||
| Subjects: | 20 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2706: Assessing the effectiveness of RIG-I and TLR-7/8 agonists as adjuvants, when co-administered with a licensed quadrivalent inactivated influenza vaccine | |||||||||||
| Status: | New | ||||||||||
| Description: | For each animal, 1.5mg HA equivalent of QIV was mixed with 1mg SDI-RNA (with 40ug nanogel; 1:40 ratio) or 100 mg IMDQ-PEG-Chol (equivalent to 10 mg core IMDQ) or both and vortexed for 30 seconds. Unadjuvanted or adjuvanted QIV was administered intramuscularly in a total of 100ml per mouse, divided equally over both hind legs. The control group were administered with equal volume of PBS instead of vaccine or vaccine/ adjuvant mixture, divided over both hind legs. All animals received QIV+IMDQ-PEG-Chol as booster, irrespective of the prime vaccination. | ||||||||||
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| DOI: | 10.21430/M34NTD7EV7 | ||||||||||
| Subjects: | 144 | ||||||||||
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| SDY2707: Safety and immunogenicity of NDV-HXP-S, phase 1 trial | |||||||
| Status: | New | ||||||
| Description: | There remains a shocking imbalance in the global distribution of coronavirus disease 2019 (COVID-19) vaccines. To achieve control of the COVID-19 pandemic in low- and middle-income countries (LMICs) where most of the global population resides, there must be a great increase in sustainable supply of affordable vaccines. To enable these manufacturers to respond to the COVID-19 pandemic, we developed a COVID-19 vac- cine for production in eggs, based on a recombinant NDV expressing the ectodomain of a novel membrane-anchored, prefusion-stabilized SARS-CoV-2 spike (S) protein construct, wherein virions are purified and inactivated (NDV-HXP-S). | ||||||
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| DOI: | 10.21430/M3AMG8LVJQ | ||||||
| Subjects: | 210 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2709: Tcell Transcripts | ||||||||||
| Status: | New | |||||||||
| Description: | Influenza vaccination Signatures | |||||||||
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| DOI: | 10.21430/M3IIM8AERS | |||||||||
| Subjects: | 221 | |||||||||
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| SDY2710: Sequential intrahost evolution and onward transmission of SARS-CoV-2 variants | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Here we describe sequential persistent SARS-CoV-2 infections that led to the emergence and continued evolution of a new Omicron sublineage, BA.1.23, over an eight-month period. | ||||||||||||
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| DOI: | 10.21430/M3KB0X24TW | ||||||||||||
| Subjects: | 21 | ||||||||||||
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| SDY2711: Immunometabolic status of B cells | |||||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||||
| Description: | Aging is characterized by chronic systemic inflammation and metabolic changes. We compare the metabolic status of B cells from young and elderly donors and found that aging induces higher oxygen consumption rates, and especially higher extracellular acidification rates, measures of oxidative phosphorylation and of anaerobic glycolysis, respectively. Importantly, this higher metabolic status, which reflects age-associated expansion of pro-inflammatory B cells, is found associated with higher secretion of lactate and autoimmune antibodies after in vitro stimulation. B cells from elderly individuals induce in vitro polarization of CD4+ T cells from young individuals into pro-inflammatory CD4+ T cells through metabolic pathways mediated by lactate, which can be inhibited by targeting lactate enzymes and transporters, as well as signaling pathways supporting anaerobic glycolysis. Lactate also induces immunosenescent B cells that are glycolytic, express transcripts for multiple pro-inflammatory molecules, and are characterized by a higher metabolic status. These results altogether may have relevant clinical implications and suggest alternative targets for therapeutic interventions in the elderly and patients with inflammatory conditions and diseases. | ||||||||||||||||||||||||
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| DOI: | 10.21430/M3RA0B6YOY | ||||||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||||||
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| Publications: | None | ||||||||||||||||||||||||
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| Assays: | None | ||||||||||||||||||||||||
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| SDY2712: CD4 Depletion Reinfection | |||||||
| Status: | New | ||||||
| Description: | Immunological priming (either in the context of prior infection or vaccination) elicits protective responses against subsequent Mycobacterium tuberculosis (Mtb) infection. However, the changes that occur in the lung cellular milieu post-primary Mtb infection and their contributions to protection upon reinfection remain poorly understood. Here, using clinical and microbiological endpoints in a non-human primate reinfection model, we demonstrate that prior Mtb infection elicits a long-lasting protective response against subsequent Mtb exposure and that the depletion of CD4-positive T cells prior to Mtb rechallenge significantly abrogates this protection. Leveraging microbiologic, PET-CT, flow cytometric, and single-cell RNA-seq data from primary infection, reinfection, and reinfection-CD4-positive T cell depleted granulomas, we identify differential cellular and microbial features of control. The data collectively demonstrate that the presence of CD4-positive T cells in the setting of reinfection results in a reduced inflammatory lung milieu characterized by reprogrammed CD8-positive T cell activity, reduced neutrophilia, and blunted type-1 immune signaling among myeloid cells, mitigating Mtb disease severity. These results open avenues for developing vaccines and therapeutics that not only target CD4-positive and CD8-positive T cells, but also modulate innate immune cells to limit Mtb disease. | ||||||
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| DOI: | 10.21430/M36F5NU0HZ | ||||||
| Subjects: | 0 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2713: COBRA HA Prepandemic | |||||||||
| Status: | New | ||||||||
| Description: | Mice were vaccinated with COBRA HA VLPs plus Addavax and assessed for Immune responses | ||||||||
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| DOI: | 10.21430/M3GOR4VH6Z | ||||||||
| Subjects: | 144 | ||||||||
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| SDY2717: Cancer Screening Practices Among Healthcare Workers During the COVID-19 Pandemic | ||||||||||
| Status: | New | |||||||||
| Description: | The COVID-19 pandemic has the potential to impact long-standing efforts to increase adherence to cancer screening guidelines. Healthcare workers (HCWs) experienced significant hardship, but generally have greater access to preventive services, making them a particularly relevant population in which to understand cancer screening behaviors during the pandemic. We report data from 794 HCWs enrolled in the NCI-funded Serological Sciences Network for Coronavirus Associations and Longitudinal Evaluation Study from December 2020 to April 2021. Participants reported lifestyle and screening behaviors during relevant look-back periods which included the pandemic timeframe. Among women between the ages of 40 and 74, 25.7% were overdue for mammographic breast cancer screening. Among participants 50–75 years old, 38.9% were overdue for colorectal cancer screening. The proportion over-due varied according to race/ethnicity. Lifetime low-dose computed tomography lung cancer screening among HCWs age 50–80 years who were smokers was 10.9%. Strategies to address screening disruptions are needed to minimize the impact of later stage of diagnosis. | |||||||||
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| DOI: | 10.21430/M3GVWWV52G | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2718: Oropharyngeal microbiome profiled at admission is predictive of the need for respiratory support among COVID-19 patients | |||||||
| Status: | New | ||||||
| Description: | The oropharyngeal microbiome, the collective genomes of the community of microorganisms that colonizes the upper respiratory tract, is thought to influence the clinical course of infection by respiratory viruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Infectious Disease 2019 (COVID-19). In this study, we examined the oropharyngeal microbiome of suspected COVID-19 patients presenting to the Emergency Department and an inpatient COVID-19 unit with symptoms of acute COVID-19. Of 115 initially enrolled patients, 50 had positive molecular testing for COVID-19+ and had symptom duration of 14 days or less. These patients were analyzed further as progression of disease could most likely be attributed to acute COVID-19 and less likely a secondary process. Of these, 38 (76%) went on to require some form of supplemental oxygen support. To identify functional patterns associated with respiratory illness requiring respiratory support, we applied an interpretable random forest classification machine learning pipeline to shotgun metagenomic sequencing data and select clinical covariates. When combined with clinical factors, both species and metabolic pathways abundance-based models were found to be highly predictive of the need for respiratory support (F1-score 0.857 for microbes and 0.821 for functional pathways). To determine biologically meaningful and highly predictive signals in the microbiome, we applied the Stable and Interpretable RUle Set to the output of the models. This analysis revealed that low abundance of two commensal organisms, Prevotella salivae or Veillonella infantium (< 4.2 and 1.7% respectively), and a low abundance of a pathway associated with LPS biosynthesis (< 0.1%) were highly predictive of developing the need for acute respiratory support (82 and 91.4% respectively). These findings suggest that the composition of the oropharyngeal microbiome in COVID-19 patients may play a role in determining who will suffer from severe disease manifestations. | ||||||
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| DOI: | 10.21430/M3WU3LHBZ0 | ||||||
| Subjects: | 0 | ||||||
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| SDY2719: The intestinal microbiota predicts COVID-19 severity and fatality regardless of hospital feeding method | |||||||||||||
| Status: | New | ||||||||||||
| Description: | SARS-CoV-2-positive patients exhibit gut and oral microbiome dysbiosis, which is associated with various aspects of COVID-19 disease (1–4). Here, we aim to identify gut and oral microbiome markers that predict COVID-19 severity in hospitalized patients, specifically severely ill patients compared to moderately ill ones. Moreover, we investigate whether hospital feeding (solid versus enteral), an important cofounder, influences the microbial composition of hospitalized COVID-19 patients. We used random forest classification machine learning models with interpretable secondary analyses. The gut, but not the oral microbiota, was a robust predictor of both COVID-19-related fatality and severity of hospitalized patients, with a higher predictive value than most clinical variables. In addition, perturbations of the gut microbiota due to enteral feeding did not associate with species that were predictive of COVID-19 severity. IMPORTANCE SARS-CoV-2 infection leads to wide-ranging, systemic symptoms with sometimes unpredictable morbidity and mortality. It is increasingly clear that the human microbiome plays an important role in how individuals respond to viral infections. Our study adds to important literature about the associations of gut microbiota and severe COVID-19 illness during the early phase of the pandemic before the availability of vaccines. Increased understanding of the interplay between microbiota and SARS-CoV-2 may lead to innovations in diagnostics, therapies, and clinical predictions. | ||||||||||||
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| DOI: | 10.21430/M39GUOBBEJ | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2720: Estimated Excess Deaths Due to COVID-19 Among the Urban Population of Mainland China, December 2022 to January 2023 | |||||||
| Status: | New | ||||||
| Description: | Background: Mainland China experienced a major surge in SARS-CoV-2 infections in December 2022-January 2023, but its impact on mortality was unclear given the underreporting of coronavirus disease 2019 deaths. Methods: Using obituary data from the Chinese Academy of Engineering (CAE), we estimated the excess death rate among senior CAE members by taking the difference between the observed rate of all-cause death in December 2022-January 2023 and the expected rate for the same months in 2017-2022, by age groups. We used this to extrapolate an estimate of the number of excess deaths in December 2022-January 2023 among urban dwellers in Mainland China. Results: In December 2022-January 2023, we estimated excess death rates of 0.94 per 100 persons (95% confidence interval [CI] = -0.54, 3.16) in CAE members aged 80-84 years, 3.95 (95% CI = 0.50, 7.84) in 85-89 years, 10.35 (95% CI = 3.59, 17.71) in 90-94 years, and 16.88 (95% CI = 0.00, 34.62) in 95 years and older. Using our baseline assumptions, this extrapolated to 917,000 (95% CI = 425,000, 1.45 million) excess deaths among urban dwellers in Mainland China, much higher than the 81,000 in-hospital deaths officially reported from 9 December 2022 to 30 January 2023. Conclusions: As in many jurisdictions, we estimate that the coronavirus disease 2019 pandemic had a much wider impact on mortality than what was officially documented in Mainland China. | ||||||
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| DOI: | 10.21430/M3NFEX6VZT | ||||||
| Subjects: | 0 | ||||||
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| SDY2721: Reduced COVID-19 hospitalizations among New York City residents following age-based SARS-CoV-2 vaccine eligibility: Evidence from a regression discontinuity design | |||||||
| Status: | New | ||||||
| Description: | Background: In clinical trials, several SARS-CoV-2 vaccines were shown to reduce risk of severe COVID-19 illness. Local, population-level, real-world evidence of vaccine effectiveness is accumulating. We assessed vaccine effectiveness for community-dwelling New York City (NYC) residents using a quasi-experimental, regression discontinuity design, leveraging a period (January 12-March 9, 2021) when ≥ 65-year-olds were vaccine-eligible but younger persons, excluding essential workers, were not. Methods: We constructed segmented, negative binomial regression models of age-specific COVID-19 hospitalization rates among 45-84-year-old NYC residents during a post-vaccination program implementation period (February 21-April 17, 2021), with a discontinuity at age 65 years. The relationship between age and hospitalization rates in an unvaccinated population was incorporated using a pre-implementation period (December 20, 2020-February 13, 2021). We calculated the rate ratio (RR) and 95% confidence interval (CI) for the interaction between implementation period (pre or post) and age-based eligibility (45-64 or 65-84 years). Analyses were stratified by race/ethnicity and borough of residence. Similar analyses were conducted for COVID-19 deaths. Results: Hospitalization rates among 65-84-year-olds decreased from pre- to post-implementation periods (RR 0.85, 95% CI: 0.74-0.97), controlling for trends among 45-64-year-olds. Accordingly, an estimated 721 (95% CI: 126-1,241) hospitalizations were averted. Residents just above the eligibility threshold (65-66-year-olds) had lower hospitalization rates than those below (63-64-year-olds). Racial/ethnic groups and boroughs with higher vaccine coverage generally experienced greater reductions in RR point estimates. Uncertainty was greater for the decrease in COVID-19 death rates (RR 0.85, 95% CI: 0.66-1.10). Conclusion: The vaccination program in NYC reduced COVID-19 hospitalizations among the initially age-eligible ≥ 65-year-old population by approximately 15% in the first eight weeks. The real-world evidence of vaccine effectiveness makes it more imperative to improve vaccine access and uptake to reduce inequities in COVID-19 outcomes. | ||||||
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| DOI: | 10.21430/M3MORBFJTU | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
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| SDY2722: Selection, Characterization, Calibration, and Distribution of the U.S. Serology Standard for Anti-SARS-CoV-2 Antibody Detection | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | The SARS-CoV-2 pandemic resulted in a demand for highly specific and sensitive serological testing to evaluate seroprevalence and antiviral immune responses to infection and vaccines. Hence, there was an urgent need for a serology standard to harmonize results across different natural history and vaccine studies. The Frederick National Laboratory for Cancer Research (FNLCR) generated a U.S. serology standard for SARS-CoV-2 serology assays and subsequently calibrated it to the WHO international standard (National Institute for Biological Standards and Control [NIBSC] code 20/136) (WHO IS). The development included a collaborative study to evaluate the suitability of the U.S. serology standard as a calibrator for SARS-CoV-2 serology assays. The eight laboratories participating in the study tested a total of 17 assays, which included commercial and in-house-derived binding antibody assays, as well as neutralization assays. Notably, the use of the U.S. serology standard to normalize results led to a reduction in the inter-assay coefficient of variation (CV) for IgM levels (pre-normalization range, 370.6% to 1,026.7%, and post-normalization range, 52.8% to 242.3%) and a reduction in the inter-assay CV for IgG levels (pre-normalization range, 3,416.3% to 6,160.8%, and post-normalization range, 41.6% to 134.6%). The following results were assigned to the U.S. serology standard following calibration against the WHO IS: 246 binding antibody units (BAU)/mL for Spike IgM, 764 BAU/mL for Spike IgG, 1,037 BAU/mL for Nucleocapsid IgM, 681 BAU/mL for Nucleocapsid IgG assays, and 813 neutralizing international units (IU)/mL for neutralization assays. The U.S. serology standard has been made publicly available as a resource to the scientific community around the globe to help harmonize results between laboratories. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3L0AGMHT3 | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2723: Development, Validation, and Utilization of a Luminex-Based SARS-CoV-2 Multiplex Serology Assay | |||||||||||||
| Status: | New | ||||||||||||
| Description: | SARS-CoV-2 antibody testing is important for seroprevalence studies and for evaluating vaccine immune responses. We developed and validated a Luminex bead-based multiplex serology assay for measuring IgG levels of anti-SARS-CoV-2 antibodies against full-length spike (S), nucleocapsid (N), and receptor-binding domains (RBDs) of wild-type, RBD N501Y mutant, RBD E484K mutant, RBD triple mutant SARS-CoV-2 proteins, Sars-CoV-1, MERS-CoV, and common human coronaviruses, including SARS-CoV-2, OC43, 229E, HKU1, and NL63. Assay cutoff values, sensitivity, and specificity were determined using samples from 160 negative controls and 60 PCR-confirmed, SARS-CoV-2-infected individuals. The assay demonstrated sensitivities of 98.3%, 95%, and 100% and specificities of 100%, 99.4%, and 98.8% for anti-(S), -N, and -RBD, respectively. Results are expressed as IgG antibody concentrations in BAU/mL, using the WHO international standard (NIBSC code 20/136) for anti-SARS-CoV-2 IgG antibodies. When the multiplex assay was performed and compared with singleplex assays, the IgG antibody measurement geometric mean ratios were between 0.895 and 1.122, and no evidence of interference was observed between antigens. Lower and upper IgG concentration limits, based on accuracy (between 80% and 120%), precision (percent relative standard deviation, ≤25%), and sample dilutional linearity (between 75% and 125%), were used to establish the assay range. Precision was established by evaluating 24 individual human serum samples obtained from vaccinated and SARS-CoV-2-infected individuals. The assay provided reproducible, consistent results with typical coefficients of variation of ≤20% for all assays, irrespective of the run, day, or analyst. Results indicate the assay has high sensitivity and specificity and thus is appropriate for use in measuring SARS-CoV-2 IgG antibodies in infected and vaccinated individuals. IMPORTANCE The SARS-CoV-2 pandemic resulted in the development and validation of multiple serology tests with variable performance. While there are multiple SARS-CoV-2 serology tests to detect SARS-CoV-2 antibodies, the focus is usually either on only one antigen at a time or multiple proteins from only one SARS-CoV-2 variant. These tests usually do not evaluate antibodies against viral proteins from different SARS-CoV-2 variants or from other coronaviruses. Here, we evaluated a multiplex serology test based on Luminex technology, where antibodies against multiple domains of SARS-CoV-2 wild type, SARS-CoV-2 mutants, and common coronavirus antibodies are detected simultaneously in a single assay. This Luminex-based multiplex serology assay can enhance our understanding of the immune response to SARS-CoV-2 infection and vaccination. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3NXSR3X2R | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2724: Protection against SARS-CoV-2 Omicron BA.1 variant challenge in macaques by prime-boost vaccination with Ad26.COV2.S and SpFN | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | Emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and waning immunity call for next-generation vaccine strategies. Here, we assessed the immunogenicity and protective efficacy of two SARS-CoV-2 vaccines targeting the WA1/2020 spike protein, Ad26.COV2.S (Ad26) and Spike ferritin Nanoparticle (SpFN), in nonhuman primates, delivered as either a homologous (SpFN/SpFN and Ad26/Ad26) or heterologous (Ad26/SpFN) prime-boost regimen. The Ad26/SpFN regimen elicited the highest CD4 T cell and memory B cell responses, the SpFN/SpFN regimen generated the highest binding and neutralizing antibody responses, and the Ad26/Ad26 regimen generated the most robust CD8 T cell responses. Despite these differences, protective efficacy against SARS-CoV-2 Omicron BA.1 challenge was similar for all three regimens. After challenge, all vaccinated monkeys showed significantly reduced peak and day 4 viral loads in both bronchoalveolar lavage and nasal swabs as compared with sham animals. The efficacy conferred by these three immunologically distinct vaccine regimens suggests that both humoral and cellular immunity contribute to protection against SARS-CoV-2 Omicron challenge. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M388JO4T6O | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2725: Prior cycles of anti-CD20 antibodies affect antibody responses after repeated SARS-CoV-2 mRNA vaccination | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | BACKGROUND While B cell depletion is associated with attenuated antibody responses to SARS-CoV-2 mRNA vaccination, responses vary among individuals. Thus, elucidating the factors that affect immune responses after repeated vaccination is an important clinical need.METHODSWe evaluated the quality and magnitude of the T cell, B cell, antibody, and cytokine responses to a third dose of BNT162b2 or mRNA-1273 mRNA vaccine in patients with B cell depletion. RESULTS In contrast with control individuals (n = 10), most patients on anti-CD20 therapy (n = 48) did not demonstrate an increase in spike-specific B cells or antibodies after a third dose of vaccine. A third vaccine elicited significantly increased frequencies of spike-specific non-naive T cells. A small subset of B cell-depleted individuals effectively produced spike-specific antibodies, and logistic regression models identified time since last anti-CD20 treatment and lower cumulative exposure to anti-CD20 mAbs as predictors of those having a serologic response. B cell-depleted patients who mounted an antibody response to 3 vaccine doses had persistent humoral immunity 6 months later. CONCLUSION These results demonstrate that serial vaccination strategies can be effective for a subset of B cell-depleted patients. | |||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3MN72BTB3 | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||
| SDY2726: A Trans-Governmental Collaboration to Independently Evaluate SARS-CoV-2 Serology Assays | |||||||||||||
| Status: | New | ||||||||||||
| Description: | The emergence of SARS-CoV-2 created a crucial need for serology assays to detect anti-SARS-CoV-2 antibodies, which led to many serology assays entering the market. A trans-government collaboration was created in April 2020 to independently evaluate the performance of commercial SARS-CoV-2 serology assays and help inform U.S. Food and Drug Administration (FDA) regulatory decisions. To assess assay performance, three evaluation panels with similar antibody titer distributions were assembled. Each panel consisted of 110 samples with positive (n = 30) serum samples with a wide range of anti-SARS-CoV-2 antibody titers and negative (n = 80) plasma and/or serum samples that were collected before the start of the COVID-19 pandemic. Each sample was characterized for anti-SARS-CoV-2 antibodies against the spike protein using enzyme-linked immunosorbent assays (ELISA). Samples were selected for the panel when there was agreement on seropositivity by laboratories at National Cancer Institute's Frederick National Laboratory for Cancer Research (NCI-FNLCR) and Centers for Disease Control and Prevention (CDC). The sensitivity and specificity of each assay were assessed to determine Emergency Use Authorization (EUA) suitability. As of January 8, 2021, results from 91 evaluations were made publicly available (https://open.fda.gov/apis/device/covid19serology/, and https://www.cdc.gov/coronavirus/2019-ncov/covid-data/serology-surveillance/serology-test-evaluation.html). Sensitivity ranged from 27% to 100% for IgG (n = 81), from 10% to 100% for IgM (n = 74), and from 73% to 100% for total or pan-immunoglobulins (n = 5). The combined specificity ranged from 58% to 100% (n = 91). Approximately one-third (n = 27) of the assays evaluated are now authorized by FDA for emergency use. This collaboration established a framework for assay performance evaluation that could be used for future outbreaks and could serve as a model for other technologies. IMPORTANCE The SARS-CoV-2 pandemic created a crucial need for accurate serology assays to evaluate seroprevalence and antiviral immune responses. The initial flood of serology assays entering the market with inadequate performance emphasized the need for independent evaluation of commercial SARS-CoV-2 antibody assays using performance evaluation panels to determine suitability for use under EUA. Through a government-wide collaborative network, 91 commercial SARS-CoV-2 serology assay evaluations were performed. Three evaluation panels with similar overall antibody titer distributions were assembled to evaluate performance. Nearly one-third of the assays evaluated met acceptable performance recommendations, and two assays had EUAs revoked and were removed from the U.S. market based on inadequate performance. Data for all serology assays evaluated are available at the FDA and CDC websites (https://open.fda.gov/apis/device/covid19serology/, and https://www.cdc.gov/coronavirus/2019-ncov/covid-data/serology-surveillance/serology-test-evaluation.html). | ||||||||||||
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| DOI: | 10.21430/M3SK8ANYK1 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2727: Assay Harmonization Study To Measure Immune Response to SARS-CoV-2 Infection and Vaccines: a Serology Methods Study | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | The Coronavirus disease 2019 (COVID-19) pandemic presented the scientific community with an immediate need for accurate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology assays, resulting in an expansion of assay development, some without following a rigorous quality control and validation, and with a wide range of performance characteristics. Vast amounts of data have been gathered on SARS-CoV-2 antibody response; however, performance and ability to compare the results have been challenging. This study seeks to analyze the reliability, sensitivity, specificity, and reproducibility of a set of widely used commercial, in-house, and neutralization serology assays, as well as provide evidence for the feasibility of using the World Health Organization (WHO) International Standard (IS) as a harmonization tool. This study also seeks to demonstrate that binding immunoassays may serve as a practical alternative for the serological study of large sample sets in lieu of expensive, complex, and less reproducible neutralization assays. In this study, commercial assays demonstrated the highest specificity, while in-house assays excelled in antibody sensitivity. As expected, neutralization assays demonstrated high levels of variability but overall good correlations with binding immunoassays, suggesting that binding may be reasonably accurate as well as practical for the study of SARS-CoV-2 serology. All three assay types performed well after WHO IS standardization. The results of this study demonstrate there are high performing serology assays available to the scientific community to rigorously dissect antibody responses to infection and vaccination. IMPORTANCE Previous studies have shown significant variability in SARS-CoV-2 antibody serology assays, highlighting the need for evaluation and comparison of these assays using the same set of samples covering a wide range of antibody responses induced by infection or vaccination. This study demonstrated that there are high performing assays that can be used reliably to evaluate immune responses to SARS-CoV-2 in the context of infection and vaccination. This study also demonstrated the feasibility of harmonizing these assays against the International Standard and provided evidence that the binding immunoassays may have high enough correlation with the neutralization assays to serve as a practical proxy. These results represent an important step in standardizing and harmonizing the many different serological assays used to evaluate COVID-19 immune responses in the population. | |||||||||||||||
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| DOI: | 10.21430/M3OL8R66OB | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||
| SDY2728: Longitudinal Assessment of BNT162b2- and mRNA-1273-Induced Anti-SARS-CoV-2 Spike IgG Levels and Avidity Following Three Doses of Vaccination | ||||||||||||||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||||||||||||||
| Description: | SARS-CoV-2 vaccination-induced protection against infection is likely to be affected by functional antibody features. To understand the kinetics of antibody responses in healthy individuals after primary series and third vaccine doses, sera from the recipients of the two licensed SARS-CoV-2 mRNA vaccines were assessed for circulating anti-SARS-CoV-2 spike IgG levels and avidity for up to 6 months post-primary series and 9 months after the third dose. Following primary series vaccination, anti-SARS-CoV-2 spike IgG levels declined from months 1 to 6, while avidity increased through month 6, irrespective of the vaccine received. The third dose of either vaccine increased anti-SARS-CoV-2 spike IgG levels and avidity and appeared to enhance antibody level persistence— generating a slower rate of decline in the 3 months following the third dose compared to the decline seen after the primary series alone. The third dose of both vaccines induced significant avidity increases 1 month after vaccination compared to the avidity response 6 months post-primary series vaccination (p ≤ 0.001). A significant difference in avidity responses between the two vaccines was observed 6 months post-third dose, where the BNT162b2 recipients had higher antibody avidity levels compared to the mRNA-1273 recipients (p = 0.020). | |||||||||||||||||||||||||||||||||
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| DOI: | 10.21430/M36Q446TZ2 | |||||||||||||||||||||||||||||||||
| Subjects: | 0 | |||||||||||||||||||||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||||||||||||||||||||
| SDY2733: rAAV expressing COBRA HA generates protective and durable immune response | ||||||||||
| Status: | New | |||||||||
| Description: | Development of a recombinant adenovirus-associated virus (rAAV) vector expressing a computationally optimized broadly reactive antigen (COBRA) Y2 derived influenza H1 hemagglutinin (HA) with enriched CpG motif. The evaluation of the vaccine immune response was performed using animal models, where ferrets and mice were vaccinated with various dosages of rAAV vectors, Flucelvax, or GFP. It was demonstrated the utility of rAAV as an effective platform to improve influenza vaccine, where rAAV expressing a COBRA induces a strong neutralizing and broad protective antibodies and long-lasting immune response. | |||||||||
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| DOI: | 10.21430/M3Z6VEFGAT | |||||||||
| Subjects: | 0 | |||||||||
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Updated Studies
| SDY1: Efficacy and Safety Evaluation of Allergen Immunotherapy Co-Administered with Omalizumab (an anti-IgE Monoclonal Antibody) (ITN019AD) | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Allergic rhinitis affects 20 to 40 million Americans annually. Allergy symptoms, which can range from mild to seriously debilitating, may affect quality of life. Left untreated, allergic rhinitis can exacerbate or trigger more serious conditions, such as asthma and sinus inflammation. Individuals with allergies react to harmless particles such as dust or pollen. Proteins in the blood called IgE antibodies treat the harmless particles as invaders and trigger an immune system response. The immune response results in harmful inflammation of healthy tissues. In ragweed allergy, inflammation occurs in the airways and causes familiar allergy symptoms like sneezing, coughing, and general discomfort. Omalizumab is an investigational drug that has been shown to block the effects of IgE antibodies. The blocking effect of omalizumab is temporary, but giving the drug to people before their regular allergy shots may make the shots more effective. Participants in this study will be randomly assigned to receive injections of omalizumab or a placebo before an accelerated course of allergy shots (given over 12 weeks). The participants will return for follow-up for up to one year, and they may have as many as 27 study visits. |
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| DOI: | 10.21430/M38Y09R3R9 | ||||||||||||
| Subjects: | 159 | ||||||||||||
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| SDY2: Immune Response to Varicella Vaccination in Subjects with Atopic Dermatitis Compared to Nonatopic Controls (VAR 05) | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | This is a mechanistic, double-aim, non-randomized study that will be conducted at 2 sites, Children's Hospital Boston and National Jewish Medical and Research Center. Study participants 12 to 36 months of age with AD and without AD will be enrolled to assess immune response after varicella vaccination. Estimated Study Duration: The study is scheduled to be completed in 36 months. Subjects will only complete one scheduled study visit. Study Population: Subjects will be enrolled over a 12 month period. Subjects will be recruited at Children's Hospital Boston and National Jewish Medical and Research Center. |
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| DOI: | 10.21430/M3G33VVU77 | ||||||||||||
| Subjects: | 71 | ||||||||||||
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| SDY4: Risk Factors in Atopic Dermatitis for the Development of Eczema Herpeticum (ADEH 06) | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | DETAILED_DESCRIPTION AD is characterized by skin inflammation and recurrent skin infections. In addition, people with AD may have a severe and sometimes fatal reaction to the smallpox vaccine called EV. KLH is a carrier protein that can be used to deliver antibodies to the body. However KLH itself, may cause an immune response. The purpose of this study is to determine the body's reaction to pure KLH in people without AD. This will be used to establish a baseline immune response and may be compared to the immune response in people with AD during future studies. This study will last 8 weeks and will have 11 study visits. Participants in this study will be randomly assigned to 1 of 4 groups. All participants will receive their immunizations at Visits 5 and 6.
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| DOI: | 10.21430/M398H5TAXP | ||||||||||||
| Subjects: | 235 | ||||||||||||
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| SDY9: ADVN Biomarker Registry: Neutrophil Substudy | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | To evaluate the chemotactic function of peripheral blood leukocytes such as neutrophils in subjects with ADEH+, ADEH-, and NA controls. | ||||||||||||
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| DOI: | 10.21430/M3OP2QB064 | ||||||||||||
| Subjects: | 62 | ||||||||||||
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| SDY25: Genotyping and gene function in healthy volunteers | |||||||||||
| Status: | Updated | ||||||||||
| Description: | The goal of this study is to create a pool of potential subjects genotyped in a manner identical to that used in the AVA000 trial population. Subjects were screened for exclusion based on history of chronic infectious or immune diseases and to avoid sampling during current acute infection. Genotyping data are available for reference purposes. The subjects agreed to be available to be recalled for sampling of blood for ex vivo studies of differential immunologic function of genetic variants corresponding to those associated with variation in vaccine response. |
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| Program/Contract: |
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| DOI: | 10.21430/M3L5GO913J | ||||||||||
| Subjects: | 1426 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY28: Humoral and Cell-Mediated Immune Responses to Vaccinia Virus Immunization | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | Our broad objective is to examine the role of candidate human immune response gene polymorphisms (and their receptors, expression and function) in inter-individual variability in vaccinia vaccine-induced humoral and cell-mediated immune responses among a cohort of 1,000 recently vaccinated subjects. In Research Area 1, we propose to study associations between specific class I and II HLA alleles (HLA-A, -B, -C, -DRB, -DQA, -DQB, -DPA, -DPB), specific cytokine genes, polymorphisms of the above cytokine receptors, a genome-wide SNP analysis; and variations in immune response to smallpox vaccine. In Research Area 2, we focus on identifying associations between expression and function of these same candidate genes likely to regulate immune response variations and humoral and cell-mediated immune responses following smallpox vaccination in selected human subjects. Both gene products (i.e., secreted proteins), cell surface expression, and measures of gene regulation/activation will be pursued. We focus on gene families involved in initiating, sustaining and regulating innate and adaptive immune responses, as well as those directly involved in directing specific antibody and cytotoxic T cell responses. |
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| DOI: | 10.21430/M3K3UZWK6S | ||||||||||||||
| Subjects: | 1092 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
| SDY33: Impact of immunosuppressive regimens on protective immunity in renal transplant recipients | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | A prospective longitudinal study comparing renal transplant patients with controls to determine the biological mechanisms that underlie the immunosuppressed state associated with immunosuppressive regimens after transplantation. | ||||||||||||
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| DOI: | 10.21430/M3TJ6DJLEY | ||||||||||||
| Subjects: | 116 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY34: Comparison of immune response to influenza vaccine in transplant patients and healthy controls | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | This is a prospective longitudinal study to determine the effects of chronic immunosuppressive therapies on the magnitude and character of the adaptive immune response to influenza vaccination in healthy controls compared to renal transplant patients. | ||||||||||||
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| DOI: | 10.21430/M3KEDFBDQ7 | ||||||||||||
| Subjects: | 97 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY35: Responses to and control of vaccinia in immunosuppressed Rhesus Macaques | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | A detailed mechanistic study of the immune response to vaccinia vaccine in immunosuppressed Rhesus macaques and development of a relevant preclinical model in which the efficacy and safety of vaccines in the setting of transplantation can be evaluated. | ||||||||||||
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| DOI: | 10.21430/M381YQIYXY | ||||||||||||
| Subjects: | 19 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY38: CD8+ T cell immunity to 2009 pandemic and seasonal H1N1 influenza viruses | ||||||||||
| Status: | Updated | |||||||||
| Description: | Flow cytometry was used to measure the expression of IL2, IFN gamma and TNF alpha in CD8+ peripheral blood mononuclear cells isolated from 12 pH1N1 naive, healthy donors were stimulated in vitro with A/California/04/09 (pH1N1 strain, egg-grown), A/New Caledonia/20/09 (sH1N1, egg-grown), X31 (A/Puerto Rico H1N1 internal proteins, A/Hong Kong. | |||||||||
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| DOI: | 10.21430/M3P9T1UFB9 | |||||||||
| Subjects: | 12 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY40: Delineate innate immune responses in populations at risk (the elderly and the immunosuppressed) that are different from the general population | |||||||||||||||||||||||
| Status: | Updated | ||||||||||||||||||||||
| Description: | We will recruit adult (21-49 years of age), elderly (>50 years), ages as outlined in the RFA, or non-elderly but immunosuppressed (defined as taking at least 10 mg of prednisone daily for at least one month) participants from the Greater New Haven area and rheumatology clinics in the Yale-New Haven Healthcare System. Individuals of either gender and all ethnic groups will be eligible to participate. We will stimulate monocytes and DCs in vitro with ligands of TLRs 1-9 and quantify the efficiency of stimulation by assessment of production of cytokines and inflammatory mediators. TLRs 10 and 11 will not be addressed at this time as ligands are not known. Lineage specific pro-inflammatory cytokines from PBMCs by FACs. We will quantify intracellular levels of TNFα and IL-6 by FACS from PBMCs in suspension on the day of isolation of the cells. This is essential to control for differences in cell composition in PBMCs isolated from different individuals, given the broad range of hematopoietic cells synthesizing TNFα and IL-6. By using multi-color staining of PBMCs with lineage-specific fluorescent antibodies, we will identify lineages positive for intracellular cytokine production at the single cell level, and track potential age-associated changes in cell lineages. Our experimental approach will be to obtain monocytes/macrophages cells from young adult and elderly subjects, define their Mif genotype, and analyze their baseline and stimulus-induced production of MIF. Patient samples for genotyping will be obtained from the pellet of the Ficoll-hypaque isolation of PBMCs and extracted DNA will be analyzed for Mif genotype by established, robotic methodology that requires <1 μg of DNA. Purified monocytes/macrophage will be studied for their baseline and stimulation-induced responses following protocols in place in our laboratory. |
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| Program/Contract: |
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| DOI: | 10.21430/M3EMF3OMS4 | ||||||||||||||||||||||
| Subjects: | 903 | ||||||||||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||||||||||||
| SDY60: Decay of Memory T cells In Old Population | |||||||
| Status: | Updated | ||||||
| Description: | To expand our study of T cell memory repertoires in an aging population for which the repertoires may be decaying. These studies will provide data about the aging-specific dynamics of memory repertoires. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M38OJI5XI0 | ||||||
| Subjects: | 70 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY61: Systems Biology of 2007 Influenza Vaccination in Humans (See companion studies SDY269 2008 / SDY270 2009 / SDY271 Role for CaMKIV in the Regulation of Antibody Responses to Influenza Vaccine) | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Using a systems biology approach to study innate and adaptive responses to influenza vaccination in humans during the 2007-2008 influenza season. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3FH0SA2W0 | ||||||||||
| Subjects: | 12 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY74: Systems Biology Approach to Analysis of 2010-11 TIV Fluzone Influenza Vaccine Response in Healthy Individuals (see companion studies SDY301, SDY296) | |||||||
| Status: | Updated | ||||||
| Description: | This study will measure the immune response to the influenza vaccine The long-term goal is to develop improved vaccines to infectious diseases such as influenza. Blood will be collected from patients at several visits before and after vaccination. The blood will be used in a series of immunological tests to measure the strength and breadth of immune response. These assays may include T cell and B cell activation assays, microarray testing, Epimax, Epigen, and flow cytometry. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3EJ72RVRG | ||||||
| Subjects: | 12 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY80: Cellular and molecular characterization of the immune response in healthy NIH employees at baseline and after immunization with the H1N1 or seasonal influenza vaccines | |||||||||||
| Status: | Updated | ||||||||||
| Description: | The Center for Human Immunology, Autoimmunity, and Inflammatory Diseases proposes this protocol designed to obtain blood from healthy adult subjects (NIH employees) prior to vaccination and then at various time points after receiving the FDA-licensed seasonal and H1N1 influenza vaccine. These samples will be used to perform a comprehensive and detailed analysis of the immune system at baseline and in response to vaccination. To our knowledge, this protocol will be the first study to characterize the human cellular and molecular immune system parameters, or immunome, in a large number of healthy adults (NIH employees). This information may be useful in designing newer, more effective vaccines to prevent the spread of H1N1 influenza. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3STAI2V6T | ||||||||||
| Subjects: | 64 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY87: In-Depth Characterization of Immune Responses to Pneumovax Vaccination in Healthy Subjects | |||||||
| Status: | Updated | ||||||
| Description: | This study will measure the immune response to the Pneumovax vaccine The long-term goal is to develop improved vaccines to infectious diseases such as influenza. Blood will be collected from patients at several visits before and after vaccination. The blood will be used in a series of immunological tests to measure the strength and breadth of immune response. These assays may include T cell and B cell activation assays, microarray testing, Epimax, Epigen, and flow cytometry. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3AA0XR32D | ||||||
| Subjects: | 5 | ||||||
| Study PI, contact: |
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| Publications: | None | ||||||
| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY91: Rituximab for the Treatment of Wegener's Granulomatosis and Microscopic Polyangiitis (RAVE ITN021AI) | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Current conventional therapies for ANCA-associated vasculitis (AAV) are associated with high incidences of treatment failure, disease relapse, substantial toxicity, and patient morbidity and mortality. Rituximab is a monoclonal antibody used to treat non-Hodgkin's lymphoma. This study will evaluate the efficacy of rituximab with glucocorticoids in inducing disease remission in patients with severe forms of AAV (WG and MPA). The study consists of two phases: a 6-month remission induction phase, followed by a 12-month remission maintenance phase. All participants will receive at least 1 g of pulse intravenous methylprednisolone or a dose-equivalent of another glucocorticoid preparation. Depending on the participant's condition, he or she may receive up to 3 days of intravenous methylprednisolone for a total of 3 g of methylprednisolone (or a dose-equivalent). During the remission induction phase, all participants will receive oral prednisone daily (1 mg/kg/day, not to exceed 80 mg/day). Prednisone tapering will be completed by the Month 6 study visit. Participants will then be randomly assigned to one of two arms. Arm 1 participants will receive rituximab (375 mg/m^2) infusions once weekly for 4 weeks and cyclophosphamide (CYC) placebo daily for 3 to 6 months. Arm 2 participants will receive rituximab placebo infusions once weekly for 4 weeks and CYC daily for 3 to 6 months. During the remission maintenance phase, participants in Arm 1 will discontinue CYC placebo and start oral azathioprine (AZA) placebo daily until Month 18. Participants in Arm 2 will discontinue CYC and start AZA daily until Month 18. Participants who fail treatment before Month 6 will be crossed over to the other treatment arm unless there are specific contraindications. Participants in either group who reach clinical remission before they complete 6 months of therapy may switch from CYC/placebo to AZA/placebo if directed by their physicians.All participants will be followed for at least 18 months. Initially, study visits are weekly, progressing to monthly and then quarterly visits as the study proceeds. Blood collection will occur at each study visit. |
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| Program/Contract: |
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| DOI: | 10.21430/M3TK42R0QR | ||||||||||
| Subjects: | 197 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY100: PPARG and microRNA-146 in mucosal immune responses to C. difficile | ||||||||||
| Status: | Updated | |||||||||
| Description: | Clostridium difficile is typically a harmless anaerobic bacterium but recently it has re-emerged as a facultative pathogen that can cause nosocomial diarrhea, colitis and even death. Peroxisome proliferator-activated receptor (PPAR) gamma has been implicated in the prevention of inflammation in autoimmune and infectious diseases; however, its role in the immunoregulatory mechanisms modulating host responses to C. difficile remains largely unknown. To characterize the role of PPAR gamma in C. difficile-associated disease (CDAD), immunity and gut pathology, we used a mouse model of C. difficile infection in wild-type and T cell-specific PPAR gamma null mice. The loss of PPAR gamma in T cells increased disease activity and colonic inflammatory lesions following C. difficile infection. Colonic expression of IL-17 was upregulated and IL-10 downregulated in colons of T cell-specific PPAR gamma null mice. Also, both the loss of PPAR gamma in T cells and C. difficile infection favored Th17 responses in spleen and colonic lamina propria of mice with CDAD. MicroRNA (miRNA)-sequencing analysis and RT-PCR validation indicated that miR-146b was significantly overexpressed in colons of C. difficile-infected mice. We next developed a computational model that predicts the upregulation of miR-146b, downregulation of the PPAR gamma co-activator NCOA4, and PPAR gamma, leading to upregulation of IL-17. Treatment of C. difficile-infected mice with the PPAR gamma agonist pioglitazone ameliorated colitis and suppressed pro-inflammatory gene expression. In conclusion, our data indicates that miRNA-146b and PPAR gamma may be implicated in the regulation of Th17 responses and colitis in C. difficile-infected mice. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3XUDZGCYI | |||||||||
| Subjects: | 98 | |||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | |||||||||
| SDY139: The peptide specificity of the endogenous T follicular helper cell repertoire generated after protein immunization | |||||||||
| Status: | Updated | ||||||||
| Description: | T follicular helper (Tfh) cells potentiate high-affinity, class-switched antibody responses, the predominant correlate of protection from vaccines. Despite intense interest in understanding both the generation and effector functions of this lineage, little is known about the epitope specificity of Tfh cells generated during polyclonal responses. To date, studies of peptide-specific Tfh cells have relied on either the transfer of TcR transgenic cells or use of peptide:MHC class II tetramers and antibodies to stain TcR and follow limited peptide specificities. In order to comprehensively evaluate polyclonal responses generated from the natural endogenous TcR repertoire, we developed a sorting strategy to separate Tfh cells from non-Tfh cells and found that their epitope-specific responses could be tracked with cytokine-specific ELISPOT assays. The immunodominance hierarchies of Tfh and non-Tfh cells generated in response to immunization with several unrelated protein antigens were remarkably similar. Additionally, increasing the kinetic stability of peptide-MHC class II complexes enhanced the priming of both Tfh and conventional CD4 T cells. These findings may provide us with a strategy to rationally and selectively modulate epitope-specific Tfh responses. By understanding the parameters that control epitope-specific priming, vaccines may be tailored to enhance or focus Tfh responses to facilitate optimal B cell responses. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3OM5T92K5 | ||||||||
| Subjects: | 62 | ||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||
| SDY144: Systems Biology Approach to Study Influenza Vaccine 2011-12 in Healthy Children (see companion studies SDY364, SDY368, SDY387, SDY522) | |||||||||||
| Status: | Updated | ||||||||||
| Description: | The treatment of pediatric immune system dysfunctions depends upon the basic understanding of its molecular and cellular components, as well as the inherent relationships between these components. Specifically, such knowledge requires an appreciation of B-Iymphocytes, T lymphocytes, natural killer cells and dendritic cells. Research investigating these cells and their functions necessitates the availability and acquisition of peripheral blood samples from healthy children to form control data groups against which various experimental conditions can be measured. Volunteers will be asked to donate blood samples to be used to further study the circulating dendritic cell subpopulations and establish their normal ranges. Blood samples will also be used to isolate antigen specific T lymphocytes, serve as a monocyte source and establish gene signatures. The assay results from SDY144's EXP13603, EXP11769, and EXP13604 are the same as for this study. The difference is how the floe cytometry results were analyzed in this study versus SDY144. |
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| Program/Contract: |
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| DOI: | 10.21430/M3ANETOJEC | ||||||||||
| Subjects: | 17 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY165: Characterization of in vitro Stimulated B Cells from Human Subjects | |||||||||||
| Status: | Updated | ||||||||||
| Description: | During the human B cell (Bc) recall response, rapid cell division results in multiple Bc subpopulations. RNA microarray and functional analyses showed that proliferating CD27lo cells are a transient pre-plasmablast population, expressing genes associated with Bc receptor editing. Undivided cells had an active transcriptional program of non-ASC B cell functions, including cytokine secretion and costimulation, suggesting a link between innate and adaptive Bc responses. Transcriptome analysis suggested a gene regulatory network for CD27lo and CD27hi Bc differentiation. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3GTK55VEV | ||||||||||
| Subjects: | 15 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY167: VRC304 - A Phase I Study of the Safety and Immunogenicity of a Recombinant DNA Plasmid Vaccine (VRC-AVIDNA036-00-VP) Encoding for the Influenza Virus H5 Hemagglutinin Protein in Healthy Adults | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | The primary objective was to evaluate the safety and tolerability of an investigational vaccine VRC-AVIDNA036-00-VP in humans at doses 1 mg and 4 mg administered intramuscularly using a needle-free injection system. The secondary objectives included evaluation of whether VRC-AVIDNA036-00-VP (at doses 1 mg and 4 mg) induced antibodies as assessed by an HAI assay at Day 0 and Week 12. Exploratory analyses included evaluation of the immunogenicity of VRC-AVIDNA036-00-VP at doses 1 mg and 4 mg using intracellular cytokine staining, ELISpot, neutralizing antibody assay, HAI assay to H1 or H3HA or other immunological assays at time intervals between Day 0 and Week 42. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3SGHW16WZ | ||||||||||||
| Subjects: | 45 | ||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||
| SDY180: Systems scale interactive exploration reveals quantitative and qualitative differences in response to 2009-2010 Fluzone influenza vaccine and pneumococcal vaccine | |||||||||||||||||
| Status: | Updated | ||||||||||||||||
| Description: | Systems immunology approaches were employed to investigate innate and adaptive immune responses to influenza and pneumococcal vaccines. These two non-live vaccines show different magnitudes of transcriptional responses at different time points af- ter vaccination. Software solutions were developed to explore correlates of vaccine efficacy measured as antibody titers at day 28. These enabled a further dissection of transcriptional responses. Thus, the innate response, measured within hours in the peripheral blood, was dominated by an interferon transcriptional signature after influenza vaccination and by an inflammation signature after pneumo- coccal vaccination. Day 7 plasmablast responses induced by both vaccines was more pronounced after pneumococcal vaccination. Together, these results suggest that comparing global immune responses elicited by different vaccines will be critical to our understanding of the immune mechanisms underpinning successful vaccination. | ||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3I44H8R17 | ||||||||||||||||
| Subjects: | 46 | ||||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||||||
| SDY194: Innate Immune Pathways in Elderly and Immunosuppressed Populations 2011 | |||||||||
| Status: | Updated | ||||||||
| Description: | Innate Immune Pathways in Elderly and Immunosuppressed Populations | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M32GW683ZT | ||||||||
| Subjects: | 120 | ||||||||
| Study PI, contact: |
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| Publications: | None | ||||||||
| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||
| SDY196: Responses to Influenza Vaccination in Systemic Lupus Year 1 2005-2006 | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Influenza is an important pathogen in the United States, with approximately 20,000 deaths per year, mainly among elderly people or those with underlying medical conditions that increase susceptibility to complications from the disease. In addition, considerable morbidity is associated with influenza with a significant impact in productivity in the workplace and home. Influenza has the potential for much more serious consequences as demonstrated by the appearance of four world-wide pandemics in the last century. In principle, serious influenza outbreaks can be prevented by vaccination. However, vaccination is complicated by two features: First, the influenza virus undergoes frequent mutations in the genes encoding the surface proteins hemagglutinin (HA) and neuraminidase (NA), leading to the need to reformulate the vaccine every year. Second, the appearance of the rapidity with which influenza infections can spread. Thus, influenza holds significant potential as a bioterrorism agent. Lupus patients have an increased risk of infection and mount lower responses to vaccinations. The objectives of this study will use genetic, cellular and humoral techniques to identify and explain abnormalities in the immune response to influenza vaccination in lupus patients. The results will clarify vaccine effectiveness among affected patients, increase the understanding of immune dysregulation in lupus, and aid in establishing guidelines for the effective vaccination of lupus patients. The benefits to the subjects are not direct; however, information gained may improve responses of reducing or preventing influenza among the affected population. Additionally, with an increased understanding of the processes of lupus, targets for disease intervention or strategies for treatment may appear. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3ABJS44K6 | ||||||||||||
| Subjects: | 62 | ||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY197: Responses to Influenza Vaccination in Systemic Lupus Year 2 2006-2007 | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Influenza is an important pathogen in the United States, with approximately 20,000 deaths per year, mainly among elderly people or those with underlying medical conditions that increase susceptibility to complications from the disease. In addition, considerable morbidity is associated with influenza with a significant impact in productivity in the workplace and home. Influenza has the potential for much more serious consequences as demonstrated by the appearance of four world-wide pandemics in the last century. In principle, serious influenza outbreaks can be prevented by vaccination. However, vaccination is complicated by two features: First, the influenza virus undergoes frequent mutations in the genes encoding the surface proteins hemagglutinin (HA) and neuraminidase (NA), leading to the need to reformulate the vaccine every year. Second, the appearance of the rapidity with which influenza infections can spread. Thus, influenza holds significant potential as a bioterrorism agent. Lupus patients have an increased risk of infection and mount lower responses to vaccinations. The objectives of this study will use genetic, cellular and humoral techniques to identify and explain abnormalities in the immune response to influenza vaccination in lupus patients. The results will clarify vaccine effectiveness among affected patients, increase the understanding of immune dysregulation in lupus, and aid in establishing guidelines for the effective vaccination of lupus patients. The benefits to the subjects are not direct; however, information gained may improve responses of reducing or preventing influenza among the affected population. Additionally, with an increased understanding of the processes of lupus, targets for disease intervention or strategies for treatment may appear. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3FD1QTLQQ | ||||||||||||
| Subjects: | 63 | ||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY198: Responses to Influenza Vaccination in Systemic Lupus Year 3 2007-2008 | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Influenza is an important pathogen in the United States, with approximately 20,000 deaths per year, mainly among elderly people or those with underlying medical conditions that increase susceptibility to complications from the disease. In addition, considerable morbidity is associated with influenza with a significant impact in productivity in the workplace and home. Influenza has the potential for much more serious consequences as demonstrated by the appearance of four world-wide pandemics in the last century. In principle, serious influenza outbreaks can be prevented by vaccination. However, vaccination is complicated by two features: First, the influenza virus undergoes frequent mutations in the genes encoding the surface proteins hemagglutinin (HA) and neuraminidase (NA), leading to the need to reformulate the vaccine every year. Second, the appearance of the rapidity with which influenza infections can spread. Thus, influenza holds significant potential as a bioterrorism agent. Lupus patients have an increased risk of infection and mount lower responses to vaccinations. The objectives of this study will use genetic, cellular and humoral techniques to identify and explain abnormalities in the immune response to influenza vaccination in lupus patients. The results will clarify vaccine effectiveness among affected patients, increase the understanding of immune dysregulation in lupus, and aid in establishing guidelines for the effective vaccination of lupus patients. The benefits to the subjects are not direct; however, information gained may improve responses of reducing or preventing influenza among the affected population. Additionally, with an increased understanding of the processes of lupus, targets for disease intervention or strategies for treatment may appear. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3D393V41D | ||||||||||||
| Subjects: | 74 | ||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY199: Responses to Influenza Vaccination in Systemic Lupus Year 4 2008-2009 | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Influenza is an important pathogen in the United States, with approximately 20,000 deaths per year, mainly among elderly people or those with underlying medical conditions that increase susceptibility to complications from the disease. In addition, considerable morbidity is associated with influenza with a significant impact in productivity in the workplace and home. Influenza has the potential for much more serious consequences as demonstrated by the appearance of four world-wide pandemics in the last century. In principle, serious influenza outbreaks can be prevented by vaccination. However, vaccination is complicated by two features: First, the influenza virus undergoes frequent mutations in the genes encoding the surface proteins hemagglutinin (HA) and neuraminidase (NA), leading to the need to reformulate the vaccine every year. Second, the appearance of the rapidity with which influenza infections can spread. Thus, influenza holds significant potential as a bioterrorism agent. Lupus patients have an increased risk of infection and mount lower responses to vaccinations. The objectives of this study will use genetic, cellular and humoral techniques to identify and explain abnormalities in the immune response to influenza vaccination in lupus patients. The results will clarify vaccine effectiveness among affected patients, increase the understanding of immune dysregulation in lupus, and aid in establishing guidelines for the effective vaccination of lupus patients. The benefits to the subjects are not direct; however, information gained may improve responses of reducing or preventing influenza among the affected population. Additionally, with an increased understanding of the processes of lupus, targets for disease intervention or strategies for treatment may appear. | ||||||||||||
| Program/Contract: |
|
||||||||||||
| DOI: | 10.21430/M39YLN3479 | ||||||||||||
| Subjects: | 69 | ||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY200: Responses to Influenza Vaccination in Systemic Lupus Year 5 2009-2010 | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Influenza is an important pathogen in the United States, with approximately 20,000 deaths per year, mainly among elderly people or those with underlying medical conditions that increase susceptibility to complications from the disease. In addition, considerable morbidity is associated with influenza with a significant impact in productivity in the workplace and home. Influenza has the potential for much more serious consequences as demonstrated by the appearance of four world-wide pandemics in the last century. In principle, serious influenza outbreaks can be prevented by vaccination. However, vaccination is complicated by two features: First, the influenza virus undergoes frequent mutations in the genes encoding the surface proteins hemagglutinin (HA) and neuraminidase (NA), leading to the need to reformulate the vaccine every year. Second, the appearance of the rapidity with which influenza infections can spread. Thus, influenza holds significant potential as a bioterrorism agent. Lupus patients have an increased risk of infection and mount lower responses to vaccinations. The objectives of this study will use genetic, cellular and humoral techniques to identify and explain abnormalities in the immune response to influenza vaccination in lupus patients. The results will clarify vaccine effectiveness among affected patients, increase the understanding of immune dysregulation in lupus, and aid in establishing guidelines for the effective vaccination of lupus patients. The benefits to the subjects are not direct; however, information gained may improve responses of reducing or preventing influenza among the affected population. Additionally, with an increased understanding of the processes of lupus, targets for disease intervention or strategies for treatment may appear. | ||||||||||
| Program/Contract: |
|
||||||||||
| DOI: | 10.21430/M3ZR6IH181 | ||||||||||
| Subjects: | 73 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY201: Responses to Influenza Vaccination in Systemic Lupus Year 6 2010-2011 | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Influenza is an important pathogen in the United States, with approximately 20,000 deaths per year, mainly among elderly people or those with underlying medical conditions that increase susceptibility to complications from the disease. In addition, considerable morbidity is associated with influenza with a significant impact in productivity in the workplace and home. Influenza has the potential for much more serious consequences as demonstrated by the appearance of four world-wide pandemics in the last century. In principle, serious influenza outbreaks can be prevented by vaccination. However, vaccination is complicated by two features: First, the influenza virus undergoes frequent mutations in the genes encoding the surface proteins hemagglutinin (HA) and neuraminidase (NA), leading to the need to reformulate the vaccine every year. Second, the appearance of the rapidity with which influenza infections can spread. Thus, influenza holds significant potential as a bioterrorism agent. Lupus patients have an increased risk of infection and mount lower responses to vaccinations. The objectives of this study will use genetic, cellular and humoral techniques to identify and explain abnormalities in the immune response to influenza vaccination in lupus patients. The results will clarify vaccine effectiveness among affected patients, increase the understanding of immune dysregulation in lupus, and aid in establishing guidelines for the effective vaccination of lupus patients. The benefits to the subjects are not direct; however, information gained may improve responses of reducing or preventing influenza among the affected population. Additionally, with an increased understanding of the processes of lupus, targets for disease intervention or strategies for treatment may appear. | ||||||||||
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| DOI: | 10.21430/M35J0WA7CR | ||||||||||
| Subjects: | 34 | ||||||||||
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| SDY212: Apoptosis and other immune biomarkers predict influenza vaccine (TIV 2008) responsiveness SLVP015 | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Despite the importance of the immune system in many diseases, there are currently no objective benchmarks of immunological health. In an effort to indentify benchmarks of immunological health, influenza vaccination was used in 30 young (20-30 years) and 59 older subjects (60 to 89 years) as models for strong and weak immune responses, respectively. Serological responses to influenza strains as well as a wide variety of other parameters, including gene expression, antibodies to hemagglutinin peptides, serum cytokines, cell subset phenotypes and in vitro cytokine stimulation were measured. Using machine learning, nine variables predicting antibody response with 84% accuracy were identified. Two of these variables are involved in apoptosis, which positively associated with the response to vaccination and was confirmed to be a contributor to vaccine responsiveness in mice. The identification of these biomarkers provides new insights into what immune features may be most important for immune health. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M37NGTHMDS | ||||||||||||
| Subjects: | 91 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY216: CD4+ T cell differentiation studies | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Differentiation of CD4+ T cells into effector or regulatory phenotypes is tightly controlled by the cytokine milieu, complex intracellular signaling networks and numerous transcriptional regulators. We combined experimental approaches and computational modeling to investigate the mechanisms controlling differentiation and plasticity of CD4+ T cells in the gut of mice. Our computational model encompasses the major intracellular pathways involved in CD4+ T cell differentiation into T helper 1 (Th1), Th2, Th17 and induced regulatory T cells (iTreg). Our modeling efforts predicted a critical role for peroxisome proliferator-activated receptor gamma (PPARg) in modulating plasticity between Th17 and iTreg cells. PPARg regulates differentiation, activation and cytokine production, thereby controlling the induction of effector and regulatory responses, and is a promising therapeutic target for dysregulated immune responses and inflammation. Our modeling efforts predict that following PPARg activation, Th17 cells undergo phenotype switch and become iTreg cells. This prediction was validated by results of adoptive transfer studies showing an increase of colonic iTreg and a decrease of Th17 cells in the gut mucosa of mice with colitis following pharmacological activation of PPAR?. Deletion of PPARg in CD4+ T cells impaired mucosal iTreg and enhanced colitogenic Th17 responses in mice with CD4+ T cell-induced colitis. Thus, for the first time we provide novel molecular evidence in vivo demonstrating that PPARg in addition to regulating CD4+ T cell differentiation also plays a major role controlling Th17 and iTreg plasticity in the gut mucosa. | ||||||||||||
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| DOI: | 10.21430/M36YGDV91N | ||||||||||||
| Subjects: | 91 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY217: Orchestration of CD4 T cell epitope preferences after multi-peptide immunization | |||||||
| Status: | Updated | ||||||
| Description: | A detailed understanding of the molecular and cellular mechanisms that underlie epitope preferences in T cell priming is important for vaccines designed to elicit a broad T cell response. Protein vaccinations generally elicit CD4 T cell responses that are skewed toward a small fraction of epitopes, a phenomenon known as immunodominance. This characteristic of T cell responses, that limits the diversity of CD4 T cell recognition, is generally attributed to intracellular antigen processing. However, we recently discovered that immunodominance hierarchies persist even after vaccination with synthetic peptides. In this study, we probed the regulatory mechanisms that cause diminished CD4 T cell responses to subdominant peptides after such multi-peptide immunization in mice. We have found that the delivery of subdominant and dominant epitopes on separate dendritic cells rescues expansion of less favored CD4 T cells. Furthermore, through the use of genetic models and inhibitors, we have found that selective losses in CD4 T cell responses are mediated by an IFN-gamma-induced pathway, involving indoleamine 2,3-dioxygenase (IDO), and that regulatory T cell (Treg) activities may also regulate preferences in CD4 T cell specificity. We propose that after multi-peptide immunization, the expansion and differentiation of dominant T cells initiate complex regulatory events that determine the final peptide specificity of the elicited CD4 T cell response. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M35YNXHF8K | ||||||
| Subjects: | 283 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY218: Oral Immunotherapy for Childhood Egg Allergy (CoFAR3) | ||||||||||
| Status: | Updated | |||||||||
| Description: | In the United States, as many as 6% to 8% of children are affected by food allergy. In young children, allergic reactions to egg can range from mild rash to systemic anaphylaxis. The usual standard of care for allergy is complete avoidance of this food allergen and treatment of accidental systemic reactions by access to self-injected epinephrine. However, accidental exposure to allergens in processed foods may be difficult to avoid. Currently, several therapeutic strategies are being investigated to prevent and treat food allergies. Since standard injection (under the skin) immunotherapy for food allergy is associated with a high rate of allergic reactions, a few studies have recently tried oral immunotherapy (OIT) in food allergy. The purpose of this study is to determine the safety and efficacy of the administration of OIT. The intent is to develop desensitization and eventually tolerance to egg allergen. This study will evaluate tolerance to egg white solid that may be gained by gradually increasing the amounts of egg white solid given to a child over a long period of time. This study will last up to 48 months. The participants will be randomly assigned to receive oral immunotherapy treatment with egg white solid or placebo. This study will include dose escalation and maintenance followed by oral food challenge (OFC). For participants receiving egg OIT, visit 1 consists of multiple small incremental doses of egg white solid. This is followed by 32-40 weeks of gradual dose escalation to a stable maintenance dose of egg white solid for at least 8 weeks. At approximately Week 44, participants are given an OFC using 5 grams of egg white solid to identify desensitized individuals. Participants and study staff are unblinded following this initial OFC. Maintenance egg OIT therapy is continued for an additional 1-3 years. Oral Food Challenges with 10 grams of egg white solid will be performed for participants on maintenance egg OIT at subsequent time points (approximately Week 96 and annually thereafter) to test for desensitization. If passed, a repeat OFC after being off therapy for 4-6 weeks will be performed to test for tolerance. An OFC to test for tolerance will use 10 grams of egg white solid and be followed by an open feeding of egg. Participants receiving placebo during dose escalation and maintenance are given an OFC using 5 grams of egg white solid to test for desensitization at approximately 44 weeks. They are unblinded at that time, continue on an egg-restricted diet, and are followed until up to 2 years. These participants will only receive an OFC at a subsequent time point if their egg Immunoglobulin E (IgE) declines to be less than 2 kilounits of antibody per liter; this OFC will use 10 grams of egg white solid and be followed by an open feeding of egg. At selected visits, blood and urine collection, physical examination, prick skin tests, and atopic dermatitis and asthma evaluations will occur. |
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| Program/Contract: |
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| DOI: | 10.21430/M3Q2O0X9Z5 | |||||||||
| Subjects: | 55 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY224: Immune Responses to Seasonal TIV 2010-2011 Influenza Vaccination in Humans (see companion study SDY396,SDY564) | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | High-frequency sampling combined with systems biology analysis of human peripheral blood cells following influenza vaccination was used to investigate T cell and B cell responses. Functional principal component analysis was used to examine time varying B cell vaccine response highlighting a single subject-specific mathematical pattern explaining ninety percent of the transcriptome variation. In addtition, daily sampling and monitoring of the proliferation marker Ki-67, revealed influenza-specific CD4 T cells do respond to vaccination. | ||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M37KMO7JLW | ||||||||||||||
| Subjects: | 14 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
| SDY230: Predictive computational modeling of the mucosal immune responses during Helicobacter pylori infection | ||||||||||
| Status: | Updated | |||||||||
| Description: | T helper (Th) cells play a major role in the modulation of immune responses at the gastric mucosa and lesion formation during Helicobacter pylori infection. The contributions of CD4+ T cell subsets to gastritis development and control of H. pylori colonization are not well understood. We used two computational approaches: ordinary differential equation (ODE)-based and agent-based modeling (ABM) to study the mechanisms underlying cellular immune responses to H. pylori and the influence of CD4+ T cell subsets in initiation, progression and outcome of disease. To calibrate the model, in vivo experimentation was performed by infecting C57BL/6 mice intragastrically with H. pylori and assaying immune cell subsets in the stomach and gastric lymph nodes (GLN) on days 0, 7, 14, 30 and 60 post-infection. Our computational model reproduced the dynamic behaviors of effector and regulatory pathways in the gastric lamina propria (LP) in silico. Simulation results show the induction of an initial Th17 response, followed by a dominant Th1 response, and a regulatory response characterized by high levels of mucosal iTreg cells. We also investigated the potential role of peroxisome proliferator-activated receptor + (PPAR+) activation in the modulation of host responses to H. pylori by using loss-of-function approaches. Specifically, in silico results showed a predominance of Th1 and Th17 cells in the stomach of the cell-specific PPARg knockout system when compared to the wild-type simulation. Our ABM suggested similar dynamics in the induction of host responses showing analogous T cell distributions to ODE modeling and facilitated tracking lesion formation. In addition, the myeloid cell-specific PPAR+ knockout model illustrated increased Th17 differentiation in the gastric LP. These integrated immunoinformatics approaches characterized the induction of mucosal immunoregulatory pathways controlled by PPAR+ during H. pylori infection that affect initiation, progression and outcome of disease. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M37ANCFRHF | |||||||||
| Subjects: | 53 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY241: Simulation and Prediction of the Adaptive Immune Response and Quantification of Early and Adaptive Immune Response Kinetics to Influenza A Virus Infection | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Seasonal and pandemic influenza A virus (IAV) continues to be a public health threat. Modeling approaches were used combined with experimental data to investigate innate and adaptive immune responses to IAV infection. Mathematical models developed describe the dynamic interactions between influenza virus, target cells, cytotoxic lymphocytes, and virus-specific IgG and IgM. A two-compartment model developed quantifies the effects of viral replication and adaptive immunity. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3ERWHDJEO | ||||||||||||
| Subjects: | 495 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY256: Cooperation between DCs and basophils in TH2 response to papain | |||||||
| Status: | Updated | ||||||
| Description: | To investigate the contribution of dendritic cells and basophils to TH2 differentiation, induction with OVA and papain was used to investigate signalling in both in vivo and in vitro systems. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3GCSV0KAE | ||||||
| Subjects: | 211 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY258: Dendritic cells and TH2 differentiation in vivo | |||||||
| Status: | Updated | ||||||
| Description: | TH2 cell differentiation was investigated by measuring IL-4 output after OVA plus papain challenge in normal and dendritic-cell depleted mice. The role of migrating dermal dendritic cells in OVA plus papain challenge by blocking migration and depleting dendritic cell subtypes. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3F0JEOKSX | ||||||
| Subjects: | 281 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY259: Reactive oxygen species and TH2 responses to papain | |||||||
| Status: | Updated | ||||||
| Description: | The role of reactive oxygen species in the TH2 response to papain was investigated. The production of ROS by dendritic cells both in vivo and in vitro was examined as an inducer of TH2 differentiation and suppressor of TH1 differentiation. CD70 and IL-12 as effectors of ROS-mediated suppression of TH1 differentiation were investigated as well as the effect of ROS on IL-4-mediated TH2 response. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3DWBGXETN | ||||||
| Subjects: | 212 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY260: The role of TLR4 and TRIF signaling in TH2 response to papain | |||||||
| Status: | Updated | ||||||
| Description: | The role of TLR4 signalling in TH2 response to papain was measured by IL-4 and antibody production. The involvement of MyD88, TRIF, and oxidized phospholipids in the TLR4 pathway was examined. Basophil recruitment to the draining lymph node through dendritic-cell-secreted CCL7 was investigated as a component of the TLR4/TRIF pathway. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3KIQA4LOV | ||||||
| Subjects: | 110 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY262: SWHP03 A novel pig model of Helicobacter pylori infection demonstrating Th1 and cytotoxic T cell responses | |||||||||||||||||||||||||||||||||||||||||||
| Status: | Updated | ||||||||||||||||||||||||||||||||||||||||||
| Description: | Pigs were divided into 4 groups of uninfected (n=9), infected with H. pylori strain J99 (n=9), strain SS1 (n=8) and SW-SS1 (n=9). Following a 12-hour fasting period, bacterial challenge was performed by orogastric gavage with 1x1010 CFU H. pylori live organisms (strains J99, SS1 or SW-SS1) resuspended in sterile brucella broth administered on days 0 and 2 of the study. As a control, the uninfected group received sterile brucella broth without any bacteria. A delay in gastric emptying was ensured by oral administration of brucella broth supplemented with fetal bovine serum (FBS) prior to the bacterial or mock challenges. To suppress gastric acidity and to increase the efficiency of H. pylori colonization, all pigs received Famotidine (1mg/kg) intramuscularly 90 minutes prior to each bacterial and control inoculation and 5% urea was added to drinking water for 4 days post-infection to provide sufficient substrate for H. pylori urease and to increase gastric pH. Pigs were monitored and scored for clinical signs of disease daily. Peripheral blood was collected from the vena cava weekly to study systemic immune responses by flow cytometry. Pigs were euthanized between day 51 and 60 post-infection to assess gastric colonization with H. pylori, to study lesions and local immune responses in the gastric mucosa and lymph node (GLN). Tissue was collected from 3 major regions of the stomach: fundus gland (F), pyloric gland (P), cardiac gland (C) and further subdivided in 2 sections (F-A, F-B, P-A, P-B, C-A, C-B) for specific applications. Furthermore, Spleen and GLN were collected for further analysis. | ||||||||||||||||||||||||||||||||||||||||||
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| DOI: | 10.21430/M3BAR04LX3 | ||||||||||||||||||||||||||||||||||||||||||
| Subjects: | 35 | ||||||||||||||||||||||||||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||||||||||||||||||||||||||
| SDY269: Systems Biology of 2008 Influenza Vaccination in Humans (See companion studies SDY61 2007 / SDY270 2009 / SDY271 Role for CaMKIV in the Regulation of Antibody Responses to Influenza Vaccine) | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | Using a systems biology approach to study innate and adaptive responses to influenza vaccination in humans during the 2008-2009 influenza season. | ||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3CDX6TL4I | ||||||||||||||
| Subjects: | 63 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
| SDY272: Humoral responses to Influenza vaccination in aged populations - Year 1 2011 (See companion studies SDY622 2012, SDY648 2013, SDY739 2014, SDY819 2015) | ||||||||||
| Status: | Updated | |||||||||
| Description: | The purpose of this study was to measure the antibody responses to the Trivalent Inactivated influenza Vaccine(TIV) in young and aged subjects | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3T9X2TDBK | |||||||||
| Subjects: | 46 | |||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | |||||||||
| SDY278: Optimization FACS panels | |||||||
| Status: | Updated | ||||||
| Description: | Optimization of ICS and phenotyping panels for the Mal067 study using cryopreserved PBMC samples from the SAC cohort | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M392SKIDA9 | ||||||
| Subjects: | 1 | ||||||
| Study PI, contact: |
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| Publications: | None | ||||||
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| Clinical Assessments: | None | ||||||
| SDY281: Study responses of Adult and neonatal APCs to TLR ligands | ||||||||||||||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||||||||||||||
| Description: | The assays in this study entail stimulation of adult and neonatal blood cells with various concentrations of defined prototype ligands for TLRs 1-9. Multiparameter flow cytometry was used to detect intracellular cytokines (TNF, IL-6, IL-10, IL-12p40, IL-12p70, and IFN-alpha) in whole blood and PBMCs. | |||||||||||||||||||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M38S6PGG9Z | |||||||||||||||||||||||||||||||||||||||
| Subjects: | 80 | |||||||||||||||||||||||||||||||||||||||
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| Publications: | None | |||||||||||||||||||||||||||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||||||||||||||||||||||||||
| SDY284: Human TLR4/MD-2 knockin (KI) mice and comparison of TLR4 agonists ability to enhance innate immunity and development of adaptive immunity in mice | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | The study's aim is to generate knockin (KI) mice expressing human TLR4 (huTLR4KI mice), human MD-2 (huMD-2KI mice) and both human TLR4 and MD-2 (TLR4/MD-2 KI mice) rather than the endogenous murine gene(s). The rationale is that differences in responses to non-enteric (variant) LPSs between humans and mice may limit the applicability of murine models as a means to 1) assess host responses to infection with organisms like Y. pestis, from which LPS triggers little response via human compared to murine TLR4/MD-2. 2) evaluate the safety and efficacy of purified/synthetic TLR4 ligand immunotherapeutics. Initial characterization of KI mice was done to determination the safety of MPL, a purified TLR4 agonist, in TLR4/MD-2 KI mice compared to wildtype mice. The study generated data to evaluate the ability of MPL (and for comparison a CpG TLR9 agonist) to enhance antibody and T cell responses and thus protective immunity induced by immunization of wildtype and TLR4/MD-2 KI mice with F1 plus V antigen from Y. pestis. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M30ZC7U5IW | ||||||||||||||||||
| Subjects: | 5 | ||||||||||||||||||
| Study PI, contact: |
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| Publications: | None | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY286: Modeling Pulmonary Immunity: Evaluation of the Innate Immune Response to Pathogens 1) Francisella tularensis 2) Mycobacterium tuberculosis and 3) Influenza A virus in cynomolgus macaque | |||||||||
| Status: | Updated | ||||||||
| Description: | A greater understanding of how alveolar macrophages respond to pathogens is important for the design of novel therapeutic agents for treatment of potentially lethal pulmonary infections. To increase understanding of early pulmonary infection response of macaques following infection with viral and bacterial pathogen, alveolar macrophages were used to determine the similarities and differences between species to invading pulmonary pathogens | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3EAOXZB4O | ||||||||
| Subjects: | 24 | ||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||
| SDY288: Modeling Pulmonary Immunity: Evaluation of the Innate Immune Response to Pathogens 1) Francisella tularensis 2) Mycobacterium tuberculosis and 3) Influenza A virus in mice (C57BL/6 and BALB/c) | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | A greater understanding of how alveolar macrophages respond to pathogens is important for the design of novel therapeutic agents for treatment of potentially lethal pulmonary infections. To increase understanding of early pulmonary infection response of mice following infection with viral and bacterial pathogen, alveolar macrophages were used to determine the similarities and differences between species to invading pulmonary pathogens | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3H9VMI0DF | ||||||||||||
| Subjects: | 876 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY296: Systems Biology Approach to Analysis of 2011-12 TIV Fluzone Influenza Vaccine Response in Healthy Individuals (see companion studies SDY74, SDY301) | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | This project will contribute to the overall vision and goals of this U19 by analyzing the immune response to Flu vaccination in healthy individuals. The knowledge generated in this Project will be transferred to Projects 3-5 where immune effects of vaccination will be studied in patients with underlying immune system alterations. | ||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M300RMFHZQ | ||||||||||||||
| Subjects: | 45 | ||||||||||||||
| Study PI, contact: |
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| SDY301: Systems Biology Approach to Analysis of 2012-13 TIV Fluzone Influenza Vaccine Response in Healthy Individuals (see companion studies SDY74, SDY296) | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | This project will contribute to the overall vision and goals of this U19 by analyzing the immune response to Flu vaccination in healthy individuals. The knowledge generated in this Project will be transferred to Projects 3-5 where immune effects of vaccination will be studied in patients with underlying immune system alterations. | ||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3T0BGMGGC | ||||||||||||||
| Subjects: | 40 | ||||||||||||||
| Study PI, contact: |
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| Publications: | None | ||||||||||||||
| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY302: IL-21 expression during H. pylori infection | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | The development of gastritis during Helicobacter pylori infection is dependent on an activated adaptive immune response orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to gastritis and control of infection are still under investigation. To investigate the role of interleukin-21 (IL-21) in the gastric mucosa during H. pylori infection, we combined mathematical modeling of CD4(+) T cell differentiation with in vivo mechanistic studies. We infected IL-21-deficient and wild-type mice with H. pylori strain SS1 and assessed colonization, gastric inflammation, cellular infiltration, and cytokine profiles. Chronically H. pylori-infected IL-21-deficient mice had higher H. pylori colonization, significantly less gastritis, and reduced expression of proinflammatory cytokines and chemokines compared to these parameters in infected wild-type littermates. These in vivo data were used to calibrate an H. pylori infection-dependent, CD4(+) T cell-specific computational model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-g) and IL-17 during chronic H. pylori infection. The model predicted activated expression of T-bet and RORgt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of IL-21 in the modulation of IL-10. Driven by our modeling-derived predictions, we found reduced levels of CD4(+) splenocyte-specific tbx21 and rorc expression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4(+) T cell-specific IL-10 expression in H. pylori-infected IL-21-deficient mice. Our results indicate that IL-21 regulates Th1 and Th17 effector responses during chronic H. pylori infection in a STAT1- and STAT3-dependent manner, therefore playing a major role controlling H. pylori infection and gastritis. Importance: Helicobacter pylori is the dominant member of the gastric microbiota in more than 50% of the world's population. H. pylori colonization has been implicated in gastritis and gastric cancer, as infection with H. pylori is the single most common risk factor for gastric cancer. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization and chronic infection. This study uses a combined computational and experimental approach to investigate how IL-21, a proinflammatory T cell-derived cytokine, maintains the chronic proinflammatory T cell immune response driving chronic gastritis during H. pylori infection. This research will also provide insight into a myriad of other infectious and immune disorders in which IL-21 is increasingly recognized to play a central role. The use of IL-21-related therapies may provide treatment options for individuals chronically colonized with H. pylori as an alternative to aggressive antibiotics. | |||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3HIA408ZR | |||||||||||||||
| Subjects: | 36 | |||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | |||||||||||||||
| SDY305: Plasmablast response to inactivated and live attenuated influenza vaccines (TIV3/TIV3 ID) SLVP021 2012 | |||||||||||||||||
| Status: | Updated | ||||||||||||||||
| Description: | To study the plasmablast response to 2012 seasonal inactivated influenza vaccine | ||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3U2R9IV87 | ||||||||||||||||
| Subjects: | 25 | ||||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||||||
| SDY312: T cell responses to H1N1v and a longitudinal study of seasonal influenza vaccination (TIV) SLVP015 2009 (See companion studies SDY315 2012 / SDY314 2008 / SDY311 2010 / SDY112 2011) | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Systems biology approach to examine effects of seasonal flu vaccination in adults of different ages on gene expression, cytokine stimulation and serum cytokines with parameters such as immune senescence to uncover new markers and mechanisms behind failure of immune function in many older people. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3G230OYOM | ||||||||||||
| Subjects: | 84 | ||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||
| SDY314: T cell responses to H1N1v and a longitudinal study of seasonal influenza vaccination (TIV) SLVP015 2008 (See companion studies SDY315 2012 / SDY312 2009 / SDY311 2010 / SDY112 2011) | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Systems biology approach to examine effects of seasonal flu vaccination in adults of different ages on gene expression, cytokine stimulation and serum cytokines with parameters such as immune senescence to uncover new markers and mechanisms behind failure of immune function in many older people. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3WZ7XK2GG | ||||||||||||
| Subjects: | 92 | ||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||
| SDY364: Systems Biology Approach to Study Influenza Vaccine 2012-13 in Healthy Children (see companion studies SDY144, SDY368, SDY387, SDY522) | |||||||||||
| Status: | Updated | ||||||||||
| Description: | The treatment of pediatric immune system dysfunctions depends upon the basic understanding of its molecular and cellular components, as well as the inherent relationships between these components. Specifically, such knowledge requires an appreciation of B-Iymphocytes, T lymphocytes, natural killer cells and dendritic cells. Research investigating these cells and their functions necessitates the availability and acquisition of peripheral blood samples from healthy children to form control data groups against which various experimental conditions can be measured. Volunteers will be asked to donate blood samples to be used to further study the circulating dendritic cell subpopulations and establish their normal ranges. Blood samples will also be used to isolate antigen specific T lymphocytes, serve as a monocyte source and establish gene signatures. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3U11KLQFF | ||||||||||
| Subjects: | 23 | ||||||||||
| Study PI, contact: |
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| Publications: | None | ||||||||||
| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY368: Systems Biology Approach to Study Influenza Vaccine 2013-14 in Healthy Children (see companion studies SDY364, SDY144, SDY387, SDY522) | |||||||||||
| Status: | Updated | ||||||||||
| Description: | The treatment of pediatric immune system dysfunctions depends upon the basic understanding of its molecular and cellular components, as well as the inherent relationships between these components. Specifically, such knowledge requires an appreciation of B-Iymphocytes, T lymphocytes, natural killer cells and dendritic cells. Research investigating these cells and their functions necessitates the availability and acquisition of peripheral blood samples from healthy children to form control data groups against which various experimental conditions can be measured. Volunteers will be asked to donate blood samples to be used to further study the circulating dendritic cell subpopulations and establish their normal ranges. Blood samples will also be used to isolate antigen specific T lymphocytes, serve as a monocyte source and establish gene signatures. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3VUYLMJSR | ||||||||||
| Subjects: | 22 | ||||||||||
| Study PI, contact: |
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| Publications: | None | ||||||||||
| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY369: Systems Biology Approach to Study Influenza Vaccine in Children with Autoimmunity (Juvenile Dermatomyositis JDM) 2011/2012 Cohort (see companion studies SDY376, SDY372, SDY645) | |||||||||||
| Status: | Updated | ||||||||||
| Description: | This Project will study vaccine responses in healthy and sick children. It will address the following questions: 1) which are the best biomarkers of protective immune response to influenza vaccine in healthy children; 2) how unique autoimmune backgrounds set the stage for responsiveness/unresponsiveness to vaccines; 3) whether vaccination contributes to increase the breadth of autoimmunity in a disease-specific manner. Ultimately, we expect that these studies will shed light on basic aspects of humoral immune responses to vaccines and will permit us to discover biomarkers of response that can be applied to healthy children and to the general population. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M38SIW861C | ||||||||||
| Subjects: | 4 | ||||||||||
| Study PI, contact: |
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| Publications: | None | ||||||||||
| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY372: Systems Biology Approach to Study Influenza Vaccine in Children with Autoimmunity (Juvenile Dermatomyositis JDM) 2012/2013 Cohort (see companion studies (SDY369, SDY376, SDY645) | |||||||||||
| Status: | Updated | ||||||||||
| Description: | This Project will study vaccine responses in healthy and sick children. It will address the following questions: 1) which are the best biomarkers of protective immune response to influenza vaccine in healthy children; 2) how unique autoimmune backgrounds set the stage for responsiveness/unresponsiveness to vaccines; 3) whether vaccination contributes to increase the breadth of autoimmunity in a disease-specific manner. Ultimately, we expect that these studies will shed light on basic aspects of humoral immune responses to vaccines and will permit us to discover biomarkers of response that can be applied to healthy children and to the general population. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3NOD39G06 | ||||||||||
| Subjects: | 19 | ||||||||||
| Study PI, contact: |
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| Publications: | None | ||||||||||
| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY376: Systems Biology Approach to Study Influenza Vaccine in Children with Autoimmunity (Juvenile Dermatomyositis JDM) 2013/2014 Cohort (see companion studies SDY369, SDY372, SDY645) | |||||||||||
| Status: | Updated | ||||||||||
| Description: | This Project will study vaccine responses in healthy and sick children. It will address the following questions: 1) which are the best biomarkers of protective immune response to influenza vaccine in healthy children; 2) how unique autoimmune backgrounds set the stage for responsiveness/unresponsiveness to vaccines; 3) whether vaccination contributes to increase the breadth of autoimmunity in a disease-specific manner. Ultimately, we expect that these studies will shed light on basic aspects of humoral immune responses to vaccines and will permit us to discover biomarkers of response that can be applied to healthy children and to the general population. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M37IMDD0RO | ||||||||||
| Subjects: | 13 | ||||||||||
| Study PI, contact: |
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| Publications: | None | ||||||||||
| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY387: Systems Biology Approach to Study Influenza Vaccine 2010-11 in Healthy Children (see companion studies SDY144, SDY368, SDY387, SDY522) | |||||||||||
| Status: | Updated | ||||||||||
| Description: | The treatment of pediatric immune system dysfunctions depends upon the basic understanding of its molecular and cellular components, as well as the inherent relationships between these components. Specifically, such knowledge requires an appreciation of B-Iymphocytes, T lymphocytes, natural killer cells and dendritic cells. Research investigating these cells and their functions necessitates the availability and acquisition of peripheral blood samples from healthy children to form control data groups against which various experimental conditions can be measured. Volunteers will be asked to donate blood samples to be used to further study the circulating dendritic cell subpopulations and establish their normal ranges. Blood samples will also be used to isolate antigen specific T lymphocytes, serve as a monocyte source and establish gene signatures. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M34N2JOQQM | ||||||||||
| Subjects: | 22 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY396: Immune Responses to Seasonal LAIV 2011-2012 Influenza Vaccination in Humans (see companion study SDY224,SDY564) | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | To use system biology approaches to compare differences in immune responses to vaccine | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3S7UQFBVS | ||||||||||||
| Subjects: | 18 | ||||||||||||
| Study PI, contact: |
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| Publications: | None | ||||||||||||
| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||
| SDY406: Immune Responses to Influenza-Like Illness SLVP022 2013 through 2018 | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | To investigate the nasal transcriptional response and peripheral plasmablast response in acute influenza infection | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3U4SDFNWN | ||||||||||||
| Subjects: | 86 | ||||||||||||
| Study PI, contact: |
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| Publications: | None | ||||||||||||
| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||
| SDY416: Study to measure the immune response to the influenza vaccine in patients with chronic plaque psoriasis | |||||||
| Status: | Updated | ||||||
| Description: | Interleukin-12 (IL-12) and interleukin-23 are heterodimeric cytokines, with a common p40 subunit and a unique chain (IL-12p35 and IL-23p19). The p40 subunit of both interleukins binds to the transmembrane IL-12 receptor-beta1 (IL-12R ) on the surface of T lymphocytes and natural killer cells. Ustekinumab is a fully human monoclonal antibody, anti-IL12p40, which binds to the p40 subunit of IL-12 and IL-23 with high affinity and specificity, inhibiting the activity of both interleukins. Ustekinumab has proven to be highly effective in the treatment of chronic plaque psoriasis, with up to 76% of patients achieving a 75% reduction in their psoriasis area and severity index (PASI-75).1, It is routinely recommended that psoriasis patients treated with biologic therapies such as ustekinumab be vaccinated annually with the influenza vaccine. We can thus assess the importance of these cytokines in the immune response to vaccination by comparing the immune response to influenza vaccination of psoriasis patients treated with ustekinumab with that of patients who are not receiving this treatment. We will assess gene expression profiles and white blood cell subsets in the blood of psoriasis patients before vaccination and at multiple time-points after vaccination. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3KG2XM196 | ||||||
| Subjects: | 45 | ||||||
| Study PI, contact: |
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| Publications: | None | ||||||
| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY522: Differences in Antibody Responses Between Trivalent Inactivated Influenza Vaccine and Live Attenuated Influenza Vaccine (2011-12) Correlate With the Kinetics and Magnitude of Interferon Signaling in Children (see companion study SDY144) | |||||||||||
| Status: | Updated | ||||||||||
| Description: | The treatment of pediatric immune system dysfunctions depends upon the basic understanding of its molecular and cellular components, as well as the inherent relationships between these components. Specifically, such knowledge requires an appreciation of B-Iymphocytes, T lymphocytes, natural killer cells and dendritic cells. Research investigating these cells and their functions necessitates the availability and acquisition of peripheral blood samples from healthy children to form control data groups against which various experimental conditions can be measured. Volunteers will be asked to donate blood samples to be used to further study the circulating dendritic cell subpopulations and establish their normal ranges. Blood samples will also be used to isolate antigen specific T lymphocytes, serve as a monocyte source and establish gene signatures. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3XZMA3XL4 | ||||||||||
| Subjects: | 20 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY597: DC transcriptomics in response to vaccines | |||||||
| Status: | Updated | ||||||
| Description: | The mechanisms by which microbial vaccines interact with human APCs remain elusive. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3AC1WMBDO | ||||||
| Subjects: | 20 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY873: Modeling Viral Immunity and Antagonism in Dendritic Cells | |||||||
| Status: | Updated | ||||||
| Description: | A suite of ex vivo perturbations are applied to explore DC response | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3EXEMMV8M | ||||||
| Subjects: | 93 | ||||||
| Study PI, contact: |
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| Publications: | None | ||||||
| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY887: Defective signaling in aging, influenza vaccination 2007 SLVP015 | |||||||||
| Status: | Updated | ||||||||
| Description: | Pilot year. Despite the importance of the immune system in many diseases, there are currently no objective benchmarks of immunological health. In an effort to indentify benchmarks of immunological health, influenza vaccination was used in 10 young (20-30 years) and 19 older subjects (60 to 89 years) as models for strong and weak immune responses, respectively. Serological responses to influenza strains as well as a wide variety of other parameters, including gene expression, antibodies to hemagglutinin peptides, serum cytokines, cell subset phenotypes and in vitro cytokine stimulation were measured. Using machine learning, nine variables predicting antibody response with 84% accuracy were identified. Two of these variables are involved in apoptosis, which positively associated with the response to vaccination and was confirmed to be a contributor to vaccine responsiveness in mice. The identification of these biomarkers provides new insights into what immune features may be most important for immune health. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M33JMYFLF1 | ||||||||
| Subjects: | 29 | ||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||
| SDY901: Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors | |||||||
| Status: | Updated | ||||||
| Description: | The success in lung cancer therapy with Programmed Death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased cytotoxic T cells and increased markers of T cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T cell function and lowering the levels of tumor promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape, and mechanistically link treatment response to PD-1 inhibition. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3VRA7INN8 | ||||||
| Subjects: | 8 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY997: AMP Lupus Network Project: Molecular Characterization of Lupus Nephritis and Correlation with Response to Therapy | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description: | Phase I will be devoted to the study of at least 45 subjects with lupus nephritis and 25 controls with the intent of achieving the following goals: (i) to assess feasibility of obtaining a sufficient yield of high quality data based on current and refined AMP SOPs, (ii) to assess recruitment rates and the number of sites necessary to effectively recruit for Phase II, (iii) to ensure that the technologies developed in Phase 0 are working well, especially with regard to transport and scaling up to handle specimens from multiple sites; (iv) to demonstrate that the selected technologies can be used for the purpose of reliably differentiating lupus nephritis kidneys from kidney tissue without lupus nephritis, (v) where necessary, to further refine the technologies before embarking on a large-scale project; and most importantly (vi) to provide critical data upon which to make rational decisions about key elements of the Phase II study design (e.g., eligibility criteria, estimates of variation for power calculations, and site-specific capability regarding patient recruitment, specimen handling, etc.). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M35FLWNXH1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Subjects: | 118 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY998: AMP Rheumatoid Arthritis Phase 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description: | The primary goal for RA arthroplasty P1 studies are: To establish if molecular signatures and pathways identified using core AMP technologies differ between OA and RA in 20 RA surgical samples and 10 OA arthroplasty samples. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3KXJHSP4T | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Subjects: | 62 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY1086: Responses to Inactivated Influenza Vaccine (IIV) in adults with or without antibiotics | ||||||||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||||||||
| Description: | Single center, open mechanistic study in which subjects will be randomized to receive IIV per label at day 4 of a 5 day course of a specific antibiotic regimen (Group A) or IIV alone (Group B). Blood samples for immunologic testing will be collected at screening (from D -21 to D -1), on D0 (at vaccination), D1, D3, D7 (+/- 1 day), D30 (+/- 5 days), D90 (+/-14 days), D180 (+-/14 days), D365 (+/-28 days) post vaccination for both groups to study innate and/or adaptive immune responses. Stool samples will be collected in both groups at screening (from D - 21 to D -1), on vaccination (D0), D1, D3, D7 (+/- 1 day) and D30 (+/- 5 days), D90 (+/-14 days), D180 (+/-14 days), D365 (+/- 28 days) to study the gut microbiome in both groups. For Group A, additional visit on D-6 to D-3 will occur with stool and blood samples collection. Study will be conducted outside the 2014-2015 and 2015-2016 influenza seasons.Antibiotics received by Group A will be started 3 days prior to vaccination (D-3) and continued on day of vaccination (D0) and for one day after vaccination (D1) for a total of 5 days a) Flagyl 500 mg po tid b) Vancocin 125 mg po qid c) Neomycin sulfate 500mg po tid. The dosage of each antibiotic is taken from their respective package inserts and does not exceed the maximum dose allowed for each antibiotic. The antibiotic regimen is a broad spectrum regimen covering all types of fecal flora (anaerobes, gram positive, and gram negative bacteria); has a good safety record; has poor systemic absorption for part of the regimen (Vancocin and Neomycin sulfate ); and part of the regimen is used to treat Clostridium difficile infections (Vancocin and Flagyl). Subjects in Group A are asked to avoid all ethanol and any ethanol- containing drugs while taking antibiotics and for 48h before and after taking the antibiotics. | |||||||||||||||||||||||||||||||||
| Program/Contract: |
|
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| DOI: | 10.21430/M3GEIUPY7R | |||||||||||||||||||||||||||||||||
| Subjects: | 34 | |||||||||||||||||||||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | |||||||||||||||||||||||||||||||||
| SDY1097: Early-life compartmentalization of human T cells | |||||||
| Status: | Updated | ||||||
| Description: | Knowledge of human immune responses during early life remains sparse, owing to the difficulty and impracticality of obtaining blood and tissue samples from infants. Our current view of normal infant immune responses, including T cell differentiation and function, is based mainly on the sampling of umbilical cord blood or fetal tissue, which reflect immune responses in utero but not responses to the diverse antigens encountered in early life. Fundamental information about the establishment of adaptive immunity during infancy, including how T cells respond, differentiate and populate tissue sites, remains undefined. Through collaboration with organ procurement agencies, we have established protocols for obtaining lymphoid and mucosal tissues from individual organ donors for whom consent has been given for the use of tissues for research. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M35HJN0H16 | ||||||
| Subjects: | 43 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY1290: Dendritic Cell Maturation Dynamics | |||||||
| Status: | Updated | ||||||
| Description: | Maturation and migration to lymph nodes (LNs) constitutes a central paradigm in conventional dendritic cell (cDC) biology but remains poorly defined in humans. Using our organ donor tissue resource, we analyzed cDC subset distribution, maturation, and migration in mucosal tissues (lungs, intestines), associated lymph nodes (LNs), and other lymphoid sites from 78 individuals ranging from less than 1 year to 93 years of age. The distribution of cDC1 (CD141hiCD13hi) and cDC2 (Sirp-?+CD1c+) subsets was a function of tissue site and was conserved between donors. We identified cDC2 as the major mature (HLA-DRhi) subset in LNs with the highest frequency in lung-draining LNs. Mature cDC2 in mucosal-draining LNs expressed tissue-specific markers derived from the paired mucosal site, reflecting their tissue-migratory origin. These distribution and maturation patterns were largely maintained throughout life, with site-specific variations. Our findings provide evidence for localized DC tissue surveillance and reveal a lifelong division of labor between DC subsets, with cDC2 functioning as guardians of the mucosa. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3T9R8JS6G | ||||||
| Subjects: | 77 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY1335: Immune Profiling Assay Development for Pertussis vaccines | |||||||
| Status: | Updated | ||||||
| Description: | Enrollment min/max Age Unit is years old | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3T5G6GG5X | ||||||
| Subjects: | 72 | ||||||
| Study PI, contact: |
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| Publications: | None | ||||||
| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY1389: Lymph node reservoirs for long-lived memory T cells | |||||||||
| Status: | Updated | ||||||||
| Description: | Translating studies on T cell function and modulation from mouse models to humans requires extrapolating in vivo results on mouse T cell responses in lymphoid organs (spleen and lymph nodes) to human peripheral blood T cells. However, our understanding of T cell responses in human lymphoid sites and their relation to peripheral blood remains sparse. Here, we used a unique human tissue resource to study human T cells in different anatomical compartments within individual donors, and identify a subset of memory CD8+T cells in LN which maintain a distinct differentiation and functional profile compared to memory CD8+T cells in blood, spleen, bone marrow (BM), and lungs. Whole transcriptome and high dimensional CyTOF profiling reveals that LN memory CD8+T cells express signatures of quiescence and self-renewal compared to corresponding populations in blood, spleen, BM and lung. LN memory T cells exhibit a distinct transcriptional signature including expression of stem cell-associated transcription factors TCF-1, LEF-1, T-follicular helper cell markers CXCR5, and CXCR4, and reduced expression of effector molecules. LN memory T cells display high homology to a subset of mouse CD8+T cells identified in chronic infection models which responds to checkpoint blockade immunotherapy. Functionally, human LN memory T cells exhibit increased proliferation to T cell receptor (TCR)-mediated stimulation and maintain higher TCR clonal diversity compared to memory T cells from blood and other sites. These findings establish human LN as reservoirs for memory T cells with high capacities for expansion and diverse recognition and important targets for immunotherapies. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3NBGEA98C | ||||||||
| Subjects: | 51 | ||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||
| SDY1393: Toll-like Receptors in Older Adults and Response to Vaccination - Year2 | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | We will identify how age and frailty affect gene expression signatures of vaccine response. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3TW6SIAIL | ||||||||||||
| Subjects: | 65 | ||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||
| SDY1465: Monozygotic and Dizygotic Twin Pair T-Cell Responses to Influenza Vaccination SLVP018 2012 | |||||||||
| Status: | Updated | ||||||||
| Description: | Evaluate the variation in immune response between individuals and assess whether it changes as a function of age and similarity in genetic and environmental background (by comparing differences between monozygotic and dizygotic twin pairs of different ages). | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3EPDNX0XF | ||||||||
| Subjects: | 23 | ||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||
| SDY1479: Plasmablast response to inactivated and live attenuated influenza vaccines (TIV3/TIV3 ID) in 2014 | |||||||||||
| Status: | Updated | ||||||||||
| Description: | The aim of this study is to compare the response to different formulations of licensed influenza vaccines. The type of seasonal influenza vaccination(s) received independently by volunteers in the year(s) since their last study visit will not impact eligibility. Volunteers will be assigned into one of three vaccine groups (intramuscular trivalent inactivated influenza vaccine (TIV); live attenuated influenza vaccine (LAIV- given year 1 only) or intradermal TIV, based on the type of study vaccine they received in 2010, 2011, 2012, or 2013. All participants will receive a single dose of their assigned seasonal influenza vaccine. Volunteers will complete 3 study visits at Day 0, Day 6-8 and Day 24-32. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3PHCIW62R | ||||||||||
| Subjects: | 19 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY1480: Genetic and Environmental Factors in the Response to Influenza Vaccination 2014 | |||||||||||
| Status: | Updated | ||||||||||
| Description: | This is a phase IV study of 120 healthy 12-49 year old adolescents and adult volunteers who are given licensed seasonal influenza vaccine. There are no exclusions for gender, ethnicity or race. The volunteers will be enrolled into one of 3 groups: Group A: Up to 40 healthy monozygotic (MZ) twin volunteers, 12-49 years old, will be given inactivated influenza vaccine quadrivalent (IIV4). Each volunteer will complete a total of 3 visits: Day 0 (pre-immunization), Day 6-8 and Day 28+ 7 post-immunization. All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). Group B: Up to 40 healthy dizygotic (DZ) twin volunteers, 12-49 years old, will be given inactivated influenza vaccine quadrivalent (IIV4). Each volunteer will complete a total of 3 visits: Day 0 (pre-immunization), Day 6-8 and Day 28+7 post-immunization. All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). Group C: Up to 40 healthy monozygotic (MZ) twin volunteers, 12-49 years old, will be randomized within the twin pair to receive either inactivated influenza vaccine quadrivalent (IIV4) or live, attenuated influenza vaccine quadrivalent (LAIV4). Each volunteer will complete a total of 3 visits: Day 0 (pre-immunization), Day 6-8 and Day 28+7 post-immunization. All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). This group was discontinued in 2016 due to ACIP recommendations against the use of LAIV but may be reopened in 2018 pending LAIV4 availability. Each twin is counted as a single participant. All reporting numbers reflect the number of participants, not the number of twin pairs. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3E3KCYPU4 | ||||||||||
| Subjects: | 54 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY1482: Innate and Acquired Immunity to Influenza Infection and Immunization (SLVP029) | |||||||||||
| Status: | Updated | ||||||||||
| Description: | This is a study of healthy children and adults receive the current seasonal influenza vaccine. The volunteers were enrolled into one of 7 groups over a 5-year period. Immunization is administered; blood samples and NP swabs are collected at various time points based on groups assigned. Group A (LAIV4/annual return), Group B (LAIV4/ single year), Group C (LAIV4/NP swab group), Group D (IIV4/annual return), Group E (IIV4/single year), Group F (LAIV4/single year), Group G (IIV4/single year) | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3O4HKKCJR | ||||||||||
| Subjects: | 53 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY1484: Role of CD4+ Memory Phenotype, Memory, and Effector T Cells in Vaccination and Infection (SLVP030) | |||||||||||
| Status: | Updated | ||||||||||
| Description: | This is a Phase IV study of up to 100 healthy children, ages 6 months to 10 years of age, who will receive either Flumist live, attenuated influenza virus vaccine, quadrivalent (LAIV4) or the current Fluzone inactivated influenza vaccine, quadrivalent (IIV4). The volunteers will be enrolled into one of 3 Groups (A, B, C). Volunteers will return each year until 2018-2019 for annual flu immunizations and study visits. Questionnaires will be administered annually to record demographic characteristics, vaccination history, exposure to animals, day care and medically attended illness. There are no exclusions for gender, ethnicity or race. Volunteers in Group C will also receive the measles, mumps, rubella and varicella (MMRV) vaccine at approximately 12-15 months of age (to be administered by the volunteers' personal pediatrician, not as a study vaccine). They will then come for a study visit to collect blood 60 days later. Each twin is counted as a single participant. All reporting numbers reflect the number of participants, not the number of twin pairs. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3VRIZVVE5 | ||||||||||
| Subjects: | 81 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY1502: Platelets attach to lung ILC2 expressing PSGL-1 and influence ILC2 function | |||||||
| Status: | Updated | ||||||
| Description: | Electron microscopy demonstrates that mouse lung ILC2 expressing PSGL-1 have platelets attached to their surface and that platelet depletion reduces lung ILC2 proliferation and Th2 cytokines suggesting ILC2 function is influenced by attachment to platelets | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3208RB6VB | ||||||
| Subjects: | 26 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY1503: Transcriptomes From Human Tissue Biopsies During Pregnancy | |||||||
| Status: | Updated | ||||||
| Description: | Spontaneous preterm labor is one of the leading causes of preterm birth and is associated with pathological changes in both the uterine myometrium and cervix The aim of this study was to understand how these changes occur at a cellular level. Samples of 310 single cell transcriptomes were derived from biopsies of tissues obtained from 4 pregnant women in their third trimester that underwent planned cesarean hysterectomies because of suspected morbidly adherent placentas. Using single cell transcriptomic analyses, different cell types obtained from cervical and uterine biopsies during late pregnancy were delineated using marker genes. Expressed genes were cross validated using the Human Protein Atlas. The cells were separated into 5 major groups using unbiased clustering of marker genes: endothelial, leukocytes, epithelial, smooth muscle, and stromal cells. Genes that separated the different cell types were observed to be genes whose coordinated expression drives that cell types specific biological function. In addition to cell type specific genes, enriched expression of genes implicated in active inflammatory processes were also observed. The single cell catalogue created during this study gives a deeper understanding of pathologies that occur during childbirth, including preterm births. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3XNT9FCYT | ||||||
| Subjects: | 0 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1536: Unconventional ST2- and CD127-negative lung ILC2 populations are induced by the fungal allergen Alternaria | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Group 2 innate lymphoid cells (ILC2s) have been recognized for their ability to drive type 2 responses in experimental animal models in the absence of T cells. Mice intranasally challenged with Alternaria alternata, a fungal allergen associated with severe asthma and fatal exacerbations in humans, potently activates ILC2s via the IL-33/ST2 (IL-33R) axis to robustly secrete type 2 cytokines. Animal models, including Alternaria-induced lung inflammation in mice, have given us critical insight into pathways of ILC2 regulation that appear to apply to ILC2 responses in human disease.7 Thus, accurate identification of ILC2s in the lungs of mice is critical to future understanding of their biology and contribution to allergic disease. We assessed whether the conventional ILC2 identification markers ST2 and CD127. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3SMNPG422 | ||||||||||
| Subjects: | 6 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY1555: Allele-specific expression changes dynamically during T cell activation in HLA and other autoimmune loci | |||||||
| Status: | Updated | ||||||
| Description: | Here we characterized the dynamics of genetic regulatory effects at eight time points during memory CD4+ T cell activation with high depth RNA-seq in healthy individuals. We discovered widespread dynamic allele-specific expression across the genome, where the balance of alleles changes over time, in 356 SNPs spanning 186 genes. These genes were four fold enriched in autoimmune loci. We found pervasive dynamic regulatory effects within six HLA genes, particularly for a major autoimmune risk gene, HLA-DQB1. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M379ZLATI0 | ||||||
| Subjects: | 10 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY1618: Superior mouse eosinophil depletion in vivo targeting transgenic Siglec-8 instead of endogenous Siglec-F: mechanisms and pitfalls | |||||||
| Status: | Updated | ||||||
| Description: | We uncovered shortcomings when using certain antibodies that target Siglec-F to deplete mouse eosinophils, while administration of anti-Siglec-8 antibody to Siglec-8 transgenic mice works well. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M348T28T35 | ||||||
| Subjects: | 12 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY1630: Effects of tissue localization on Natural Killer (NK) cell phenotypic and functional diversity | |||||||
| Status: | Updated | ||||||
| Description: | Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigated how tissue localization regulates the development and function of human Natural Killer (NK) cells, innate lymphocytes important for anti-viral and tumor immunity. Integrating high-dimensional analysis of NK cells from blood, lymphoid organs, and mucosal tissue sites from 59 individuals, we identify tissue-specific patterns of NK cell subset distribution, maturation and function across age and between diverse individuals. Mature and terminally differentiated NK cells with enhanced effector function predominate in blood, bone marrow, spleen and lungs, exhibiting shared transcriptional programs across sites. By contrast, precursor and immature NK cells with reduced effector capacity prevail in lymph nodes and intestines, exhibiting tissue-resident signatures and site-specific adaptations. Together, our results reveal anatomic control of NK cell development and maintenance as tissue-resident populations, while mature, terminally differentiated subsets mediate immunosurveillance through diverse peripheral sites. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M38FVNPEZC | ||||||
| Subjects: | 78 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY1644: Urban Environmental Factors and Childhood Asthma (URECA) (ICAC-07) | ||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||
| Description: | The purpose of this study is to determine the way environmental factors (like the components of inner-city household dust) affect immune system development and symptoms of asthma in inner city children. The study is divided into three periods, as the subjects age from birth to 10 years old. Each age bracket will explore different objectives and endpoints. Study Objectives/Hypotheses: Subjects age 0 to 3 years old: Environmental factors in the inner city adversely influence the development of the immune system to promote cytokine dysregulation, allergy, and recurrent wheezing by age 3. Children who have had a viral lower respiratory infection and have developed cytokine dysregulation by age 3 are at increased risk for the development of asthma by age 6. Subjects age 4 to 7 years old: There is a unique pattern of immune development that is driven by specific urban exposures in early life, and this pattern of immune development is characterized by: 1) impairment of antiviral responses and 2) accentuation of Th2-like responses (e.g. cockroach-specific Interleukin-13(IL-13)). The clinical effects of these changes in immune development are frequent virus-induced wheezing and allergic sensitization by 3-4 years of age, and these characteristics synergistically increase the risk of asthma at age 7 years. Subjects age 7 to 10 years old: There are unique combinations of environmental exposures (cockroach allergens, indoor pollutants [Environmental Tobacco Smoke (ETS) and Nitrogen Dioxide (NO2)], lack of microbial exposure), and family characteristics (stress, genetic factors related to innate immunity) that synergistically promote asthma onset, persistence, and morbidity in urban neighborhoods. These exposures and characteristics influence immune expression and lung development during critical periods of growth, resulting in specific asthma phenotypes. Subjects age 10 to 16 years old: To determine the wheezing, asthma and atopy phenotypes in minority children growing up in poor urban neighborhoods as they develop from birth through adolescence. | |||||||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3H1YHLR5Z | |||||||||||||||||||||||||||
| Subjects: | 1218 | |||||||||||||||||||||||||||
| Study PI, contact: |
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| SDY1662: An Inflammatory Cytokine Signature Predicts Covid-19 Severity And Survival | |||||||
| Status: | Updated | ||||||
| Description: | Several studies have revealed that the hyper-inflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in infected patients. However, predictive biomarkers of pathogenic inflammation to help guide targetable immune pathways are critically lacking. We implemented a rapid multiplex cytokine assay to measure serum IL-6, IL-8, TNF-a, and IL-1b in hospitalized COVID-19 patients upon admission to the Mount Sinai Health System in New York. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3ODKGM8O5 | ||||||
| Subjects: | 2340 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: |
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| SDY1752: Quantitative chest CT combined with plasma cytokines predicts outcomes in COVID-19 patients | ||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||
| Description: | 152 patients with a positive PCR for COVID-19, complete plasma cytokine assessment, and a chest-CT upon 5 days from hospital admission were included. Demographics, clinical and laboratory variables, including plasma cytokines (IL-6, IL-8, and TNF-a) were collected. CT qualitative score for each patient, based on the degree of involvement of the five pulmonary lobes (score from 0 to 20), was obtained by two independent radiologists. CT quantitative analysis was performed using a segmentation open-software, supervised by one reader, to calculate the total lung volume (ml), well aerated lung volume (ml), ground-glass opacities (GGO) volume (ml), consolidation volume (ml), and GGO/well aerated lung ratio. The primary endpoints were survival and maximum severity degree according to the WHO scale). A elastic net regression was used to build five models (cytokines, CT qualitative, CT quantitative, combined and optimized models) to predict outcomes after cross-fold validation. Model performance was evaluated using a receiving operating characteristic (ROC) analysis. Interobserver agreement between different CT methods was also calculated using the intraclass correlation coefficient (ICC). | |||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3ZK51U9TH | |||||||||||||||||||||
| Subjects: | 152 | |||||||||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: | None | |||||||||||||||||||||
| Clinical Assessments: |
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| SDY1760: Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) A Prospective Cohort Study to Assess Longitudinal Immune Responses in Hospitalized Patients with COVID-19 | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | This is a prospective observational cohort of adult participants hospitalized with known or presumptive COVID-19. | |||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3FCC2J1RF | |||||||||||||||
| Subjects: | 1169 | |||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: | None | |||||||||||||||
| Clinical Assessments: | None | |||||||||||||||
| SDY1767: Longitudinal profiling of respiratory and systemic immune responses in severe COVID-19 | |||||||
| Status: | Updated | ||||||
| Description: | Immune response dynamics in coronavirus disease 2019 (COVID-19) and their severe manifestations have largely been studied in circulation. Here, we examined the relationship between immune processes in the respiratory tract and circulation through longitudinal phenotypic, transcriptomic, and cytokine profiling of paired airway and blood samples from patients with severe COVID-19 relative to heathy controls. In COVID-19 airways, T cells exhibited activated, tissue-resident, and protective profiles; higher T cell frequencies correlated with survival and younger age. Myeloid cells in COVID-19 airways featured hyperinflammatory signatures, and higher frequencies of these cells correlated with mortality and older age. In COVID-19 blood, aberrant CD163+ monocytes predominated over conventional monocytes, and were found in corresponding airway samples and in damaged alveoli. High levels of myeloid chemoattractants in airways suggest recruitment of these cells through a CCL2-CCR2 chemokine axis. Our findings provide insights into immune processes driving COVID-19 lung pathology with therapeutic implications for targeting inflammation in the respiratory tract. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3BZB4P8CI | ||||||
| Subjects: | 38 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY1876: Large-scale placenta DNA methylation mega-analysis on fetal sex | |||||||
| Status: | Updated | ||||||
| Description: | Although male-female differences in placental structure and function have been observed, little is understood about their molecular underpinnings. Here, we present a mega-analysis of 14 publicly available placenta DNA methylation (DNAm) microarray datasets to identify individual CpGs and regions associated with fetal sex. In the discovery dataset of placentas fromFull term pregnancies (N = 532 samples), 5,212 CpGs met genome-wide significance (p < 1E-8) and were enriched in pathways such as keratinization (FDR p-value = 7.37E-14), chemokine activity (FDR p-value = 1.56E-2), and eosinophil migration (FDR p-value = 1.83E-2). Nine DMRs were identified (fwerArea < 0.1) including a region in the promoter of ZNF300 that showed consistent differential DNAm in samples from earlier timepoints in pregnancy and appeared to be driven predominately by effects in the trophoblast cell type. We describe the largest study of fetal sex differences in placenta DNAm performed to date, revealing genes and pathways characterizing sex-specific placenta function and health outcomes later in life. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3HD6FG5E9 | ||||||
| Subjects: | 0 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: | |||||||
| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1890: SARS-CoV-2 Spreads through Cell-to-Cell Transmission | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible coronavirus responsible for the global COVID-19 pandemic. Herein we provide evidence that SARS-CoV-2 spreads through cell-cell contact in cultures, mediated by the spike glycoprotein. SARS-CoV-2 spike is more efficient in facilitating cell-to-cell transmission than SARS-CoV spike, which reflects, in part, their differential cell-cell fusion activity. Interestingly, treatment of cocultured cells with endosomal entry inhibitors impairs cell-to-cell transmission, implicating endosomal membrane fusion as an underlying mechanism. Compared with cell-free infection, cell-to-cell transmission of SARS-CoV-2 is refractory to inhibition by neutralizing antibody or convalescent sera of COVID-19 patients. While ACE2 enhances cell-to-cell transmission, we find that it is not absolutely required. Notably, despite differences in cell-free infectivity, the variants of concern (VOC) B.1.1.7 and B.1.351 have similar cell-to-cell transmission capability. Moreover, B.1.351 is more resistant to neutralization by vaccinee sera in cell-free infection, whereas B.1.1.7 is more resistant to inhibition by vaccine sera in cell-to-cell transmission. Overall, our study reveals critical features of SARS-CoV-2 spike-mediated cell-to-cell transmission, with important implications for a better understanding of SARS-CoV-2 spread and pathogenesis. | ||||||||||||
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| DOI: | 10.21430/M3GSKYH5JH | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2053: Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including third-dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is lower after infection compared with all vaccines evaluated but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks postvaccination in some cases. SARS-CoV-2 antibody specificity, breadth, and maturation are affected by imprinting from exposure history and distinct histological and antigenic contexts in infection compared with vaccination. | ||||||||||||
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| DOI: | 10.21430/M36A5Z1XU9 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2112: HTP proteomics, DIA | ||||||||||
| Status: | Updated | |||||||||
| Description: | We introduce a cost-effective, robust high throughput-compatible plasma depletion method enabling in-depth profiling of plasma, that detects >1,300 proteins per run with a throughput of 60 samples per day. | |||||||||
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| DOI: | 10.21430/M3BFTN6RVW | |||||||||
| Subjects: | 0 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2113: Augmentation of humoral and cellular immune responses after third-dose SARS-CoV-2 vaccination and viral neutralization in myeloma patients | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | Despite the efficacy of COVID-19 vaccines in healthy individuals, multiple myeloma (MM) patients are immunocompromised and mount suboptimal humoral and cellular responses after two doses of mRNA vaccine (Addeo et al., 2021; Aleman et al., 2021; Van Oekelen et al., 2021). A broader observation of limited vaccine responses in cancer patients, particularly those with hematologic malignancies (Thakkar et al., 2021), has led to the implementation of additional (i.e., third dose) vaccine administration as a way to increase protection for patients with immune suppression. A third dose of BNT162b2 (Pfizer-BioNTech) COVID19 vaccine has shown to be effective in preventing severe COVID-19 caused by the SARS-CoV-2 B.1.617.2 (Delta) variant in the general population (Bar-On et al., 2021; Barda et al., 2021). Furthermore, third-dose administration of either the BNT162b2 (Pfizer-BioNTech) or mRNA1273 (Moderna) COVID-19 vaccine was associated with augmented immune responses in a diverse cohort of cancer patients (Shapiro et al., 2022). However, the real-world effectiveness of additional dosing in myeloma patients and viral neutralization have not been reported. Additionally, the impact of the currently dominant SARS-CoV-2 B.1.1.529 (Omicron) variant on efficacy of the third dose is largely unknown in patients with hematologic malignancies (Zeng et al., 2022). | |||||||||||||||
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| DOI: | 10.21430/M3EEDBBP9C | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||
| SDY2187: Microbiome Preterm Birth DREAM Challenge | ||||||||||||||
| Status: | Updated | |||||||||||||
| Description: | Globally, every year about 11% of infants are born preterm, defined as a birth prior to 37 weeks of gestation, with significant and lingering health consequences. Multiple studies have related the vaginal microbiome to preterm birth. We present a crowdsourcing approach to predict: (a) preterm or (b) early preterm birth from 9 publicly available vaginal microbiome studies representing 3,578 samples from 1,268 pregnant individuals, aggregated from raw sequences via an open-source tool, MaLiAmPi. We validated the crowdsourced models on novel datasets representing 331 samples from 148 pregnant individuals. From 318 DREAM challenge participants we received 148 and 121 submissions for our two separate prediction sub-challenges with top-ranking submissions achieving bootstrapped AUROC scores of 0.69 and 0.87, respectively. Alpha diversity, VALENCIA community state types, and composition (via phylotype relative abundance) were important features in the top performing models, most of which were tree based methods. This work serves as the foundation for subsequent efforts to translate predictive tests into clinical practice, and to better understand and prevent preterm birth. | |||||||||||||
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| DOI: | 10.21430/M3JMMPMLSP | |||||||||||||
| Subjects: | 764 | |||||||||||||
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| Assays: | None | |||||||||||||
| Clinical Assessments: | None | |||||||||||||
| SDY2216: Waning and boosting of antibody Fc-effector functions upon SARS-CoV-2 vaccination | |||||||
| Status: | Updated | ||||||
| Description: | Since the emergence of SARS-CoV-2, vaccines targeting COVID-19 have been developed with unprecedented speed and efficiency. CoronaVac, utilising an inactivated form of the COVID-19 virus and the mRNA26 based Pfizer/BNT162b2 vaccines are widely distributed. Beyond the ability of vaccines to induce production of neutralizing antibodies, they might lead to the generation of antibodies attenuating the disease by recruiting cytotoxic and opsonophagocytic functions. However, the Fc-effector functions of vaccine induced antibodies are much less studied than virus neutralization. Here, using systems serology, we follow the longitudinal Fc-effector profiles induced by CoronaVac and BNT162b2 up until five months following the two-dose vaccine regimen. Compared to BNT162b2, CoronaVac responses wane more slowly, albeit the levels remain lower than that of BNT162b2 recipients throughout the entire observation period. However, mRNA vaccine boosting of CoronaVac responses, including response to the Omicron variant, induce significantly higher peak of antibody functional responses with increased humoral breadth. In summary, we show that vaccine platform-induced humoral responses are not limited to virus neutralization but rather utilise antibody dependent effector functions. We demonstrate that this functionality wanes with different kinetics and can be rescued and expanded via boosting with subsequent homologous and heterologous vaccination. | ||||||
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| DOI: | 10.21430/M365O4LM7J | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2282: JAX CCHI-Modulation of Lung Responses to Viral Infection- ALI SARS-CoV-2 | ||||||||||
| Status: | Updated | |||||||||
| Description: | Epithelial barriers lie at the interface between host and environment, where they sense invading pathogen. Dendritic cells (DCs) present pathogen-derived antigens to T and B cells to induce immune responses. However, the impact of the human lung tissue environment on DC and other cells, such as the newly identified innate lymphoid cell (ILC) family, as well as bacteria-reactive MAIT cells, is not completely understood. An understudied environmental factor is the lung microbiome. The JAX CCHI seeks to address these critical questions using a multi-disciplinary experimental approach that will integrate immunology with epithelial cell biology along with genomic, cellular, functional and microbiome parameters identified in human lung tissues. Our overarching hypothesis is that the quality and magnitude of mucosal T cell responses to respiratory viral infections are determined by the cross- talk between microbiota, epithelial cells and leukocytes. To address this hypothesis, we structured the JAX CCHI around two integrated research projects focused on basic immunological mechanisms of lung antiviral immunity; a technology development project that will create sophisticated cellular models leveraging 3D bioprinting, gene editing tools and microbiome-immune assays to support project objectives; a sample core for storage and distribution of human tissues; and a microbiome core for specialized microbiome profiling, cultivation, and computational analysis. Our Center will bring together clinicians with experts in lung immunology, the microbiome, bioengineering, genomics and computational biology to achieve our goals and maximize the potential of this research. The goals of this CCHI are to: 1) Understand how the networks of epithelial cells and immune cells in the human lung regulate innate and adaptive immunity to respiratory viruses; 2) Define how inflammation driven by the microbiome dictates the steady state of tissue, i.e., immune set-point; 3) Determine if and how this immune set-point is altered in two pulmonary diseases, childhood asthma and adult lung cancer, which have a major impact on public health; and 4) Develop innovative technologies to model human lung-immune dynamics and elucidate molecular mechanisms, cell types and pathways key to lung antiviral responses. Impact: Through studies focused on the sensors, inducers and modulators of antiviral immunity in the human lung, our CCHI will contribute insights that could help improve outcomes for infectious and other immune diseases that originate in or secondarily impact the lung. | |||||||||
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| DOI: | 10.21430/M32KGRDM51 | |||||||||
| Subjects: | 8 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2399: Preconception Genetic Carrier Screening for Miscarriage Risk Assessment: A Bioinformatic Approach to Identifying Candidate Lethal Genes and Variants | |||||||
| Status: | Updated | ||||||
| Description: | Purpose: Miscarriage, due to genetically heterogeneous etiology, is a common outcome of pregnancy. Preconception genetic carrier screening (PGCS) currently identifies at-risk partners for newborn genetic disorders; however, miscarriage-related genes are currently not part of the PGCS panels. Here we assessed the theoretical impact of known and candidate genes on prenatal lethality and the PGCS among diverse populations. Methods: We used a bioinformatic approach to define genes essential for human fetal survival (lethal genes), identify variants that are absent in a homozygous state in healthy human population, and to estimate heterozygous carrier rates for known recessive lethal Mendelian conditions and candidate lethal genes. Results: A total of 3080 known and candidate lethal genes were identified. Allele carrier frequencies were evaluated for 20398 pathogenic/likely pathogenic and loss-of-function (LoF) variants in 468 known human lethal genes, and 62815 LoF variants in 2612 candidate genes. In 163 genes, potential lethal variants are present in the general population with high frequency of at least 0.1%. Conclusion: This study identified a set of genes and variants potentially associated with lethality across different ethnic backgrounds. The diversity of these genes amongst the various ethnic groups underscores the importance of designing a pan-ethnic PGCS panel comprising miscarriage-related genes. Keywords: population carrier screening, lethal genes, intolerome, pregnancy loss, miscarriage. | ||||||
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| DOI: | 10.21430/M32PG4UUJV | ||||||
| Subjects: | 0 | ||||||
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| SDY2491: SARS-CoV-2 serosurvey across multiple waves of the COVID-19 pandemic in New York City between 2020-2023 | ||||||||||
| Status: | Updated | |||||||||
| Description: | Here, the authors describe results of a cross-sectional hospital-based study of anti-spike seroprevalence in New York City (NYC) from February 2020 to July 2022, and a follow-up period from August 2023 to October 2023. | |||||||||
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| DOI: | 10.21430/M3X08KNYJ3 | |||||||||
| Subjects: | 55092 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2522: Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | While immunologic correlates of COVID-19 have been widely reported, their associations with post-acute sequelae of COVID-19 (PASC) remain less clear. Due to the wide array of PASC presentations, understanding if specific disease features associate with discrete immune processes and therapeutic opportunities is important. Here we profile patients in the recovery phase of COVID-19 via proteomics screening and machine learning to find signatures of ongoing antiviral B cell development, immune-mediated fibrosis, and markers of cell death in PASC patients but not in controls with uncomplicated recovery. Plasma and immune cell profiling further allow the stratification of PASC into inflammatory and non-inflammatory types. Inflammatory PASC, identifiable through a refined set of 12 blood markers, displays evidence of ongoing neutrophil activity, B cell memory alterations, and building autoreactivity more than a year post COVID-19. Our work thus helps refine PASC categorization to aid in both therapeutic targeting and epidemiological investigation of PASC. | ||||||||||||||||||
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| DOI: | 10.21430/M3CZV2762J | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2607: Humoral immunity to an endemic coronavirus is associated with postacute sequelae of COVID-19 in individuals with rheumatic diseases | ||||||||||
| Status: | Updated | |||||||||
| Description: | Beyond the acute illness caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) infection, about one-fifth of infections result in long-term persistence of symptoms despite the apparent clearance of infection. Insights into the mechanisms that underlie postacute sequelae of COVID-19 (PASC) will be critical for the prevention and clinical management of long-term complications of COVID-19. Several hypotheses have been proposed that may account for the development of PASC, including persistence of virus and dysregulation of immune responses. Among the immunological changes noted in PASC, alterations in humoral immunity have been observed in some patient subsets. To begin to determine whether SARS-CoV-2- or other pathogen-specific humoral immune responses evolve uniquely in PASC, we performed comprehensive antibody profiling against SARS-CoV-2, a panel of endemic pathogens, and a panel of routine vaccine antigens using systems serology in two cohorts of patients with preexisting systemic autoimmune rheumatic disease (SARD) who either developed or did not develop PASC. A distinct qualitative shift observed in Fcγ receptor (FcγR) binding was observed in individuals with PASC. Specifically, individuals with PASC harbored weaker FcγR-binding anti-SARS-CoV-2 antibodies and stronger FcγR-binding antibody responses against the endemic coronavirus OC43. Individuals with PASC developed an OC43 S2-specific antibody response with stronger FcγR binding, linked to cross-reactivity across SARS-CoV-2 and common coronaviruses. These findings identify previous coronavirus imprinting as a potential marker for the development of PASC in individuals with SARDs. | |||||||||
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| DOI: | 10.21430/M32BIF6Z4Z | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2658: Dysregulated naive B cells and de novo autoreactivity in severe COVID-19 | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | Severe SARS-CoV-2 infection1 has been associated with highly inflammatory immune activation since the earliest days of the COVID-19 pandemic2–5. More recently, these responses have been associated with the emergence of self-reactive antibodies with pathologic potential6–10, although their origins and resolution have remained unclear11. Previously, we and others have identified extrafollicular B cell activation, a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity12,13, as a dominant feature of severe and critical COVID-19. Here, using single-cell B cell repertoire analysis of patients with mild and severe disease, we identify the expansion of a naive-derived, low-mutation IgG1 population of antibody-secreting cells (ASCs) reflecting features of low selective pressure. These features correlate with progressive, broad, clinically relevant autoreactivity, particularly directed against nuclear antigens and carbamylated proteins, emerging 10–15 days after the onset of symptoms. Detailed analysis of the low-selection compartment shows a high frequency of clonotypes specific for both SARS-CoV-2 and autoantigens, including pathogenic autoantibodies against the glomerular basement membrane. We further identify the contraction of this pathway on recovery, re-establishment of tolerance standards and concomitant loss of acute-derived ASCs irrespective of antigen specificity. However, serological autoreactivity persists in a subset of patients with postacute sequelae, raising important questions as to the contribution of emerging autoreactivity to continuing symptomology on recovery. In summary, this study demonstrates the origins, breadth and resolution of autoreactivity in severe COVID-19, with implications for early intervention and the treatment of patients with post-COVID sequelae. | ||||||||||||||||||
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| DOI: | 10.21430/M3BG5XDB1N | ||||||||||||||||||
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| SDY2673: Next Generation Methodology for Updating Computationally Optimized Broadly Reactive Antigen (COBRA) HA Vaccines Against Emerging Human Seasonal Influenza A(H3N2) Viruses | ||||||||||
| Status: | Updated | |||||||||
| Description: | Seasonal influenza vaccines typically consist of wild-type influenza A and B viruses that are limited in their ability to elicit protective immune responses against co-circulating influenza virus variant strains. Improved influenza virus vaccines need to elicit protective immune responses against multiple influenza virus drift variants within each season. Broadly reactive vaccine candidates potentially provide a solution to this problem, but their efficacy may begin to wane as influenza viruses naturally mutate through processes that mediates drift. Thus, it is necessary to develop a method that commercial vaccine manufacturers can use to update broadly reactive vaccine antigens to better protect against future and currently circulating viral variants. Building upon the COBRA technology, nine next-generation H3N2 influenza hemagglutinin (HA) vaccines were designed using a next generation algorithm and design methodology. These next-generation broadly reactive COBRA H3 HA vaccines were superior to wild-type HA vaccines at eliciting antibodies with high HAI activity against a panel of historical and co-circulating H3N2 influenza viruses isolated over the last 15 years, as well as the ability to neutralize future emerging H3N2 isolates. | |||||||||
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| DOI: | 10.21430/M388O87C8Y | |||||||||
| Subjects: | 135 | |||||||||
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| SDY2688: Neurologic sequelae of COVID-19 are determined by immunologic imprinting from previous coronaviruses | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health emergency. Although SARS-CoV-2 is primarily a respiratory pathogen, extra-respiratory organs, including the CNS, can also be affected. Neurologic symptoms have been observed not only during acute SARS-CoV-2 infection, but also at distance from respiratory disease, also known as long-COVID or neurological post-acute sequelae of COVID-19 (neuroPASC). The pathogenesis of neuroPASC is not well understood, but hypotheses include SARS-CoV-2-induced immune dysfunctions, hormonal dysregulations and persistence of SARS-CoV-2 reservoirs. In this prospective cohort study, we used a high throughput systems serology approach to dissect the humoral response to SARS-CoV-2 (and other common coronaviruses: 229E, HKU1, NL63 and OC43) in the serum and CSF from 112 infected individuals who developed (n = 18) or did not develop (n = 94) neuroPASC. Unique SARS-CoV-2 humoral profiles were observed in the CSF of neuroPASC compared with serum responses. All antibody isotypes (IgG, IgM, IgA) and subclasses (IgA1-2, IgG1-4) were detected in serum, whereas CSF was characterized by focused IgG1 (and absence of IgM). These data argue in favour of compartmentalized brain-specific responses against SARS-CoV-2 through selective transfer of antibodies from the serum to the CSF across the blood-brain barrier, rather than intrathecal synthesis, where more diversity in antibody classes/subclasses would be expected. Compared to individuals who did not develop post-acute complications following infection, individuals with neuroPASC had similar demographic features (median age 65 versus 66.5 years, respectively, P = 0.55; females 33% versus 44%, P = 0.52) but exhibited attenuated systemic antibody responses against SARS-CoV-2, characterized by decreased capacity to activate antibody-dependent complement deposition (ADCD), NK cell activation (ADNKA) and to bind Fcγ receptors. However, surprisingly, neuroPASC individuals showed significantly expanded antibody responses to other common coronaviruses, including 229E, HKU1, NL63 and OC43. This biased humoral activation across coronaviruses was particularly enriched in neuroPASC individuals with poor outcome, suggesting an 'original antigenic sin' (or immunologic imprinting), where pre-existing immune responses against related viruses shape the response to the current infection, as a key prognostic marker of neuroPASC disease. Overall, these findings point to a pathogenic role for compromised anti-SARS-CoV-2 responses in the CSF, likely resulting in incomplete virus clearance from the brain and persistent neuroinflammation, in the development of post-acute neurologic complications of SARS-CoV-2 infection. | ||||||||||||
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| DOI: | 10.21430/M3DJDSD6BI | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2703: Assessment of Human Cohort | |||||||
| Status: | Updated | ||||||
| Description: | Computationally assessing Human Antibody Responses following Fluzone Vaccination of UGA cohort | ||||||
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| DOI: | 10.21430/M3I0V8ASVT | ||||||
| Subjects: | 0 | ||||||
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