DR42 DataRelease

SDY1230: Immunization Via Mosquito Bite With Radiation-Attenuated Plasmodium Falciparum Sporozoites (IMRAS)
Status: New
Description: This is a Phase 1 open-labeled study. In addition to safety and tolerability of Plasmodium falciparum Sporozoites (PfRAS), this study is a comprehensive, systems biology-based effort to identify and validate biomarkers of protection with PfRAS immunization, comparing sterility protected to nonprotected study subjects. The goal of the trial design is to achieve approximately 50% sterile protection in order to facilitate the identification of biomarkers and correlates of protection.
Program/Contract:
ProgramContract
Human Immunology Project Consortium (HIPC) RFA-AI-15-041 Immune Responses To Malaria And HIV Infection And Immunization (Seattle Biomed)
DOI: 10.21430/M31PQIFA91
Subjects: 54
Study PI, contact:
NameOrganizationSite
Judith Epstein Naval Medical Research Center (NMRC) Naval Medical Research Center (NMRC)
Publications:
IMRAS-A clinical trial of mosquito-bite immunization with live, radiation-attenuated P. falciparum sporozoites: Impact of immunization parameters on protective efficacy and generation of a repository of immunologic reagents.. PloS one Jun 2020. doi: 10.1371/journal.pone.0233840 [Pubmed: 32555601]
Early whole blood transcriptional responses to radiation-attenuated Plasmodium falciparum sporozoite vaccination in malaria naive and malaria pre-exposed adult volunteers.. Malaria journal Jul 2021. doi: 10.1186/s12936-021-03839-3 [Pubmed: 34243763]
Resources:
ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01994525]
Assays:
Assay TypeNumber of Exp. Samples
RNA sequencing 45
Clinical Assessments:None

SDY1600: Mapping Immune Responses to CMV in Renal Transplantation
Status: New
Description: We propose to characterize in depth the relationship between CMV, the compromised host immune response and tissue injury using high-throughput technologies and novel statistical and computational approaches in the setting of solid organ transplant. This setting is unique as it provides the ability to understand viral infection and host tissue injury from the beginning, as the donor organ, when transplanted into a recipient, is generally pristine and without any substantive injury, and will experience exposure or reactivation of CMV only after engraftment. For the sake of homogeneity, we have elected to restrict these studies to kidney transplants, given that this is the most common organ transplanted, has a robust immune response profile that resembles most of the other organ transplants, and is the first organ system to be chosen for the conduct of all phase 1/2/3 pharmaceutical clinical trials. The primary goal of this proposal is to advance the field by creating a unique resource of highly annotated clinical phenotype and multidimensional omics data on the immune response to CMV during primary infection and reactivation. The secondary objective is to gain new insights into how CMV contributes to chronic allograft rejection and identify new approaches to patient management and therapy. These studies have broad applications to understanding the host:pathogen interactions in immunocompromised individuals and their downstream effects in other chronic disease states.
Program/Contract:
ProgramContract
Human Immunology Project Consortium (HIPC) RFA-AI-15-041 Mapping Immune Responses To CMV In Renal Transplant Recipients (UCLA)
DOI: 10.21430/M30V1NQBF0
Subjects: 61
Study PI, contact:
NameOrganizationSite
David Elashoff UCLA UCLA
Alexander Hoffman UCLA UCLA
Suphamai (Michael) Bunnapradist UCLA UCLA
Flavio Vincenti UCSF UCSF
Publications:
NK and CD8+ T cell phenotypes predict onset and control of CMV viremia after kidney transplant.. JCI insight Nov 2021. doi: 10.1172/jci.insight.153175 [Pubmed: 34609965]
Acute and Chronic Changes in Gene Expression After CMV DNAemia in Kidney Transplant Recipients.. Frontiers in immunology Nov 2021. doi: 10.3389/fimmu.2021.750659 [Pubmed: 34867983]
Resources:
Assays:
Assay TypeNumber of Exp. Samples
Flow Cytometry 431
Luminex xMAP 168
RNA sequencing 152
Clinical Assessments:None

SDY1742: Phase 1, dose escalation, randomized controlled trial to evaluate the safety, immunogenicity and efficacy of intravenously administered attenuated Plasmodium falciparum sporozoite vaccine (PfSPZ Vaccine) in Tanzanian adults
Status: New
Description: We are using controlled human malaria infection (CHMI) by direct venous inoculation (DVI) of cryopreserved, infectious Plasmodium falciparum (Pf) sporozoites (SPZ) (PfSPZ Challenge) to try to reduce time and costs of developing PfSPZ Vaccine to prevent malaria in Africa. Immunization with 5 doses at 0, 4, 8, 12 and 20 weeks of 2.7x10^5 PfSPZ of PfSPZ Vaccine gave 65% vaccine efficacy (VE) at 24 weeks against mosquito bite CHMI in United States (U.S.) adults and 52% (time-to-event) or 29% (proportional) VE over 24 weeks against naturally transmitted Pf in Malian adults. We assessed the identical regimen in Tanzanians for VE against PfSPZ Challenge. 20-30 year old men were randomized to receive 5 doses normal saline or PfSPZ Vaccine in a double blind trial. VE was assessed 3 and 24 weeks later. Adverse events were similar in vaccinees and controls. Antibody responses to Pf circumsporozoite protein were significantly lower than in malaria naive Americans, but significantly higher than in Malians. All 18 controls developed Pf parasitemia after CHMI. 4/20 (20%) vaccinees remained uninfected after 3 week CHMI (p=0.015 by time to event, p=0.543 by proportional analysis) and all four (100%) were uninfected after repeat 24 week CHMI (p=0.005 by proportional, p=0.004 by time to event analysis). PfSPZ Vaccine was safe, well tolerated, and induced durable VE in 4 subjects. CHMI by DVI of PfSPZ Challenge appeared more stringent over 24 weeks than mosquito bite CHMI in U.S or natural exposure in Malian adults, thereby providing a rigorous test of VE in Africa.
Program/Contract:
ProgramContract
DMID Sanaria Grant Program Genome-Wide Sieve Analysis And Immunological Validation To Identify Targets Of Protective Efficacy In Field Trials Of A Whole-Organism Malaria Vaccine
DOI: 10.21430/M36M272QBE
Subjects: 67
Study PI, contact:
NameOrganizationSite
Stephen Hoffman Sanaria Inc., Rockville, Maryland Ifakara Health Institute Bagamoyo, Tanzania
Publications:
Safety, Immunogenicity, and Protective Efficacy against Controlled Human Malaria Infection of Plasmodium falciparum Sporozoite Vaccine in Tanzanian Adults.. The American journal of tropical medicine and hygiene Aug 2018. doi: 10.4269/ajtmh.17-1014 [Pubmed: 29943719]
Resources:
clinicaltrials.gov https://clinicaltrials.gov/ct2/show/NCT02132299]
Assays:None
Clinical Assessments:None

SDY1809: Efficacy of clinical evaluations for COVID-19 on the front line
Status: New
Description: We conducted a retrospective review of patients assessed for possible COVID-19 illness at our urban medical center in Los Angeles, California. We carefully reviewed all clinical records to ascertain the provider's level of clinical suspicion for COVID-19 illness and compared these assessments with available results of SARS-CoV-2 testing, in addition to longitudinal data on clinical outcomes. We found that the vast majority of patients (96% of N = 25) clinically assessed to have a low probability of COVID-19 illness were subsequently confirmed to have either a negative SARS-CoV-2 test result or, in the absence of testing, clinical stability without any further concern for COVID-19 illness. All clinical assessments were performed by a physician, with some (16%) conducted by a nurse practitioner or physician assistant in conjunction with physician supervision.
Program/Contract:
ProgramContract
SeroNet Diversity and Determinants of the Immune-Inflammatory Response to SARS-CoV-2
DOI: 10.21430/M3V899V1LA
Subjects: 0
Study PI, contact:
NameOrganizationSite
Publications:
Efficacy of clinical evaluations for COVID-19 on the front line.. International journal of emergency medicine Nov 2020. doi: 10.1186/s12245-020-00313-w [Pubmed: 33160316]
Resources:
Assays:None
Clinical Assessments:None

SDY1810: Pseudo-safety in a cohort of patients with COVID-19 discharged home from the emergency department
Status: New
Description: Introduction: Emergency Departments (ED) are often the first line of contact with individuals infected with COVID-19 and play a key role in triage. However, there is currently little specific guidance for deciding when patients with COVID-19 require hospitalisation and when they may be safely observed as an outpatient. Methods: In this retrospective study, we characterised all patients with COVID-19 discharged home from EDs in our US multisite healthcare system from March 2020 to August 2020, focusing on individuals who returned within 2 weeks and required hospital admission. We restricted analyses to first-encounter data that do not depend on laboratory or imaging diagnostics in order to inform point-of-care assessments in resource-limited environments. Vitals and comorbidities were extracted from the electronic health record. We performed ordinal logistic regression analyses to identify predictors of inpatient admission, intensive care and intubation. Results: Of n=923 patients who were COVID-19 positive discharged from the ED, n=107 (11.6%) returned within 2 weeks and were admitted. In a multivariable-adjusted model including n=788 patients with complete risk factor information, history of hypertension increased odds of hospitalisation and severe illness by 1.92-fold (95% CI 1.07 to 3.41), diabetes by 2.20-fold (1.18 to 4.02), chronic lung disease by 2.21-fold (1.22 to 3.92) and fever by 2.89-fold (1.71 to 4.82). Having at least two of these risk factors increased the odds of future hospitalisation by 6.68-fold (3.54 to 12.70). Patients with hypertension, diabetes, chronic lung disease or fever had significantly longer hospital stays (median 5.92 days, 3.08-10.95 vs 3.21, 1.10-5.75, p<0.01) with numerically higher but not significantly different rates of intensive care unit admission (27.02% vs 14.30%, p=0.27) and intubation (12.16% vs 7.14%, p=0.71). Discussion: Patients infected with COVID-19 may appear clinically safe for home convalescence. However, those with hypertension, diabetes, chronic lung disease and fever may in fact be only 'pseudo-safe' and are most at risk for subsequent hospitalisation with more severe illness and longer hospital stays.
Program/Contract:
ProgramContract
SeroNet Diversity and Determinants of the Immune-Inflammatory Response to SARS-CoV-2
DOI: 10.21430/M398ES8RTH
Subjects: 0
Study PI, contact:
NameOrganizationSite
Publications:
Pseudo-safety in a cohort of patients with COVID-19 discharged home from the emergency department.. Emergency medicine journal : EMJ Feb 2021. doi: 10.1136/emermed-2020-210041 [Pubmed: 33602725]
Resources:
Assays:None
Clinical Assessments:None

SDY1863: Safety and immunogenicity in age de-escalation of PfSPZ Vaccine in Tanzania
Status: New
Description: 93 healthy Tanzanian adults, adolescents, children, and infants were enrolled in this dose escalation, age de-escalation trial. Blinded study participants were randomized to receive 3 doses of 1.8x10^6, 9.0x10^5, 4.5x10^5 or 2.7x10^5 PfSPZ of PfSPZ Vaccine or a normal saline (NS) placebo administered 8 weeks apart by DVI. Adult participants underwent CHMI as a test of efficacy 3 to 11 weeks after the final vaccine dose; a second CHMI was performed in these participants 37 to 40 weeks after the 3rd dose. 12 additional adult participants were recruited to participate as infectivity controls for the CHMI. There were no significant differences in adverse events between vaccinees and controls or between dosage regimens. Since all age groups received 3 doses of 9.0x10^5 PfSPZ of PfSPZ Vaccine, immune responses were compared at this dosage. Median antibody responses against PfCSP and PfSPZ were highest in infants and lowest in adults. T cell responses were highest in 6-10-year-olds after one dose and 1-5-year-olds after 3 doses; infants had no significant positive T cell responses. In the vaccine efficacy (VE) evaluations, All 22 CHMIs in controls resulted in parasitemia by qPCR. For the 9x10^5 PfSPZ group, VE was 100% (5/5) at 3 or 11 weeks (p<0.000l, Barnard?s test, 2-tailed). For 1.8x10^6 PfSPZ, VE was 33% (2/6) at 7.5 weeks (p=0.028). VE of dosage groups (100% vs 33%) was significantly different (p=0.022). Volunteers underwent repeat CHMI at 37 to 40 weeks after last dose. 6/6 and 5/6 volunteers developed parasitemia, but time to first parasitemia was significantly longer than controls in the 9x105 PfSPZ group (10.89 vs 7.80 days) (p=0.039), indicating a significant reduction in parasites in the liver. Antibody and T cell responses were higher in the 1.8x106 PfSPZ group.
Program/Contract:
ProgramContract
DMID Sanaria Grant Program Genome-Wide Sieve Analysis And Immunological Validation To Identify Targets Of Protective Efficacy In Field Trials Of A Whole-Organism Malaria Vaccine
DOI: 10.21430/M383DYLCOE
Subjects: 105
Study PI, contact:
NameOrganizationSite
Said Jongo Ifakara Health Institute Ifakara Health Institute
Publications:
Increase of Dose Associated With Decrease in Protection Against Controlled Human Malaria Infection by PfSPZ Vaccine in Tanzanian Adults.. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Dec 2020. doi: 10.1093/cid/ciz1152 [Pubmed: 31782768]
Resources:
ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02613520]
Assays:None
Clinical Assessments:None

SDY1870: Kinetics of immunological memory to SARS-CoV-2
Status: New
Description: SARS-CoV-2-specific antibodies, CD4+ T cells, and CD8+ T cells are made in response to SARS-CoV-2 infection. Understanding the kinetics and durability of immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines and assessing the likely future course of the COVID-19 pandemic. We assessed the immune memory of all three branches of adaptive immunity (CD4+ T cell, CD8+ T cell, and humoral immunity) in a predominantly cross-sectional study, including a longitudinal subset, extending for up to eight months post-infection.
Program/Contract:
ProgramContract
Cooperative Centers on Human Immunology RFA-AI-17-040 Functional and Dysfunctional Human CD4 T cell and B cell Responses to Bacteria and Viruses (RFA-AI-17-040)
DOI: 10.21430/M3S4OZJRCN
Subjects: 264
Study PI, contact:
NameOrganizationSite
Shane Crotty La Jolla Institute for Immunology La Jolla Institute for Immunology
Alessandro Sette La Jolla Institute for Immunology La Jolla Institute for Immunology
Daniela Weiskopf La Jolla Institute for Immunology La Jolla Institute for Immunology
Publications:
Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.. Science (New York, N.Y.) Feb 2021. doi: 10.1126/science.abf4063 [Pubmed: 33408181]
Resources:
Assays:
Assay TypeNumber of Exp. Samples
ELISA 1375
Flow Cytometry 2269
Neutralizing Antibody Titer Assay 275
Clinical Assessments:None

SDY1881: Safety and immunogenicity of PfSPZ Vaccine in Equatorial Guinea (EGSPZV1)
Status: New
Description: Thirty adult males were randomized in the ratio 2:1 to receive three doses of 2.7 ? 105 PfSPZ of PfSPZ Vaccine (N = 20) or normal saline placebo (N = 10) by direct venous inoculation at 8-week intervals. The vaccine was safe and well tolerated. Seventy percent, 65%, and 45% of vaccinees developed antibodies to Plasmodium falciparum (Pf ) circumsporozoite protein (PfCSP) by enzyme-linked immunosorbent assay, PfSPZ by automated immunofluorescence assay, and PfSPZ by inhibition of sporozoite invasion assay, respectively. Antibody responses were significantly lower than responses in U.S. adults who received the same dosage regimen, but not significantly different than responses in young adult Malians.
Program/Contract:
ProgramContract
DMID Sanaria Grant Program Genome-Wide Sieve Analysis And Immunological Validation To Identify Targets Of Protective Efficacy In Field Trials Of A Whole-Organism Malaria Vaccine
DOI: 10.21430/M3FDQR1MGL
Subjects: 33
Study PI, contact:
NameOrganizationSite
Salim Abdulla Ifakara Health Institute Ifakara Health Institute
Publications:
Advancing Global Health through Development and Clinical Trials Partnerships: A Randomized, Placebo-Controlled, Double-Blind Assessment of Safety, Tolerability, and Immunogenicity of PfSPZ Vaccine for Malaria in Healthy Equatoguinean Men.. The American journal of tropical medicine and hygiene Jan 2018. doi: 10.4269/ajtmh.17-0449 [Pubmed: 29141739]
Resources:
ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/record/NCT02418962]
Assays:None
Clinical Assessments:None

SDY1883: 35th Multicenter Airway Research Collaboration (MARC-35): dual transcriptomic profile of nasopharyngeal aspirates
Status: New
Description: Among infants (age <1 year) hospitalized for bronchiolitis, we used dual transcriptomic profiling of the nasopharyngeal aspirates to identify an endotype with a higher risk for developing asthma. For enrolled infants, hospital site teams collected nasopharyngeal aspirates (NPAs) within 24 hours of the bronchiolitis hospitalization. Total RNA was isolated from the NPA samples using Trizol LS reagent in combination with the Direct-zol RNA Miniprep Kit. RNA was prepared for sequencing using the NEBNext Ultra II Directional RNA Library Prep Kit (New England Biolabs, Ipswich, MA) and sequenced on an Illumina NovaSeq6000 using a S4 100PE Flowcell (Illumina, San Diego, CA).
Program/Contract:
ProgramContract
NIAID Program Research Project Grant (Parent R01) Prospective Cohort Study Of Severe Bronchiolitis And Risk Of Recurrent Wheezing (MARC-35 WIND)
DOI: 10.21430/M3YR3W2EBA
Subjects: 1
Study PI, contact:
NameOrganizationSite
Carlos A. Camargo Massachusetts General Hospital Massachusetts General Hospital
Publications:
Integrated omics endotyping of infants with respiratory syncytial virus bronchiolitis and risk of childhood asthma.. Nature communications Jun 2021. doi: 10.1038/s41467-021-23859-6 [Pubmed: 34127671]
Resources:
The WIND Study www.windstudy.org]
Assays:None
Clinical Assessments:None

SDY1885: Heterogeneity of human anti-viral immunity shaped by virus, tissue, age, and sex
Status: New
Description: The persistence of anti-viral immunity throughout the human body is essential for protection, and exhibits profound heterogeneity across individuals. Here, we elucidate the factors that shape maintenance and function of anti-viral T cell immunity by comprehensive profiling of virus-specific T cells across blood, lymphoid organs, and mucosal tissues of organ donors. We used flow cytometry, T cell receptor analysis, single-cell transcriptomics, and cytokine analysis to profile virus-specific CD8+ T cells recognizing ubiquitous pathogens influenza and cytomegalovirus. Our results reveal that virus specificity determines overall magnitude, tissue distribution, differentiation, and clonal repertoire of virus-specific T cells. Age and sex influence T cell differentiation and dissemination in tissues, while T cell tissue residence and functionality is highly correlated with the site. Together, our results demonstrate how the covariates of virus, tissue, age, and sex impact the anti-viral immune response, important for targeting, monitoring, and predicting immune responses to existing and emerging viruses.
Program/Contract:
ProgramContract
Human Immunology Project Consortium (HIPC) RFA-AI-15-041 Human Anti-Viral Immune Responses In Tissues And Circulation (Columbia)
DOI: 10.21430/M3Z6V3I3QM
Subjects: 59
Study PI, contact:
NameOrganizationSite
Donna Farber Columbia University Columbia University Medical Center
Publications:
Heterogeneity of human anti-viral immunity shaped by virus, tissue, age, and sex.. Cell reports Nov 2021. doi: 10.1016/j.celrep.2021.110071 [Pubmed: 34852222]
Resources:
Assays:
Assay TypeNumber of Exp. Samples
Flow Cytometry 641
Luminex xMAP 8850
RNA sequencing 47
Clinical Assessments:None

SDY1887: Safety, tolerability and immunogenicity in age de-escalation of PfSPZ Vaccine in Equatorial Guinea (EGSPZV2)
Status: New
Description: EGSPZV2 is a single center, double-blind, placebo-controlled trial. The study is to take place at the Baney Temporary Research Facility (BTRF) located in Baney City. One hundred and thirty-five healthy male and female; adults, adolescents, children and infant volunteers, aged from 6 months to 65 years who live in the Baney district and Malabo city on Bioko Island will be enrolled based on pre-defined inclusion and exclusion criteria implemented according to international ethical standards. The trial will consist of seven groups (Group 1a: younger adults, ages 18-35; Group 2: older adults, ages 36-65; Group 3: adolescents, ages 11-17; Group 4: older children, ages 6-10; Group 5: younger children, ages 1-5; Groups 6a/b: infants, ages 6 months - 11 months) of volunteers. Vaccination will begin in Group 1a (younger adults), with three doses of 2.7x10^6 PfSPZ Vaccine given eight weeks apart by DVI. An eighth group (Group 1b: younger adults, ages 18- 35), will be uniquely immunized with the comparator vaccine PfSPZ Challenge given under chloroquine prophylaxis (PfSPZ-CVac approach), rather than with PfSPZ Vaccine. A single PfSPZ-CVac younger adult group (group 1b) is included to provide a direct comparison with PfSPZ Vaccine (group 1a) for the ability to protect against CHMI. Each of the first two groups (1a and 1b) will have 20 participants receiving either PfSPZ Vaccine or PfSPZ Challenge and 6 participants receiving NS placebo by DVI, with treatment allocation randomized and double-blind. Volunteers in Group 1b will receive vaccinations 8 weeks after the initial vaccination of Group 1a. Volunteers in Group 1 (younger adults) will receive CHMI between 10 and 14 weeks post last vaccination (with a window of +/- 7 days on each side) and will be followed for 8 weeks following CHMI. Group 2 (older adults) will receive three doses of 2.7x10^6 PfSPZ Vaccine. Group 2 will consist of 12 participants receiving PfSPZ Vaccine and 4 participants receiving NS placebo by DVI, given eight weeks apart. Group 3, 4, 5 and 6b will each have 12 participants receiving three doses of 1.8x10^6 PfSPZ Vaccine and 4 participants receiving NS, also given eight weeks apart. Group 6a will consist of 3 volunteers who will receive a single dose of 9.0 x10^5 PfSPZ Vaccine. Sequential age groups will be staggered to allow assessment of safety and tolerability before further age de-escalation. To assure safety, vaccinations will start in younger adults and will progress to younger and older age groups using staggered start dates at approximately weekly intervals. Age escalation and initial age de-escalation will take place at the same time, hence Group 2 and 3 will be vaccinated at the same time. Progressively younger age groups will then be immunized after a review of safety data from the previously vaccinated group(s). There were no significant differences in solicited adverse events (AEs) between vaccinees and NS controls in any age group (p>0.17 for all comparisons). Two important SAEs were observed that were considered possibly related to vaccine - a generalized seizure and a spontaneous abortion. Comprehensive evaluation of both events indicated PfSPZ Vaccine was not a unique cause of either event. Seroconversion after PfSPZ Vaccine occurred in 68/69 (98.6%) of participants. Median PfCSP antibody levels were highest in participants ages 6 months to 10 years, declining with successively increasing age group. In the 18 to 35-year-old age groups (1a and 1b) There were no differences in solicited adverse events (AEs) between vaccinees and NS controls, or between PfSPZ Vaccine and PfSPZ-CVac recipients during the 6 days after administration of investigational product. However, from days 7-13 PfSPZ-CVac recipients had significantly more AEs, probably due to Pf parasitemia. Antibody responses were 2.9 times higher in PfSPZ Vaccine recipients as compared to PfSPZ-CVac recipients at time of CHMI. VE at a median of 14 weeks after last PfSPZ-CVac dose was 55% (8 of 13, p=0.051) and at a median of 15 weeks after last PfSPZ Vaccine dose was 27% (5 of 15, p=0.32).
Program/Contract:
ProgramContract
DMID Sanaria Grant Program Genome-Wide Sieve Analysis And Immunological Validation To Identify Targets Of Protective Efficacy In Field Trials Of A Whole-Organism Malaria Vaccine
DOI: 10.21430/M3XLUFOMXU
Subjects: 130
Study PI, contact:
NameOrganizationSite
Ali Mtoro Ifakara Health Institute Ifakara Health Institute
Publications:None
Resources:
ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/study/NCT02859350]
Assays:None
Clinical Assessments:None

SDY1890: SARS-CoV-2 Spreads through Cell-to-Cell Transmission
Status: New
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.
Program/Contract:
ProgramContract
SeroNet Center for Serological Testing to Improve Outcomes from Pandemic COVID-19 (STOP-COVID)
DOI: 10.21430/M34H0WAOXB
Subjects: 0
Study PI, contact:
NameOrganizationSite
Publications:
SARS-CoV-2 Spreads through Cell-to-Cell Transmission.. bioRxiv : the preprint server for biology Jun 2021. doi: 10.1101/2021.06.01.446579 [Pubmed: 34100011]
Resources:
Assays:None
Clinical Assessments:None

SDY1898: Early-pregnancy prediction of risk for pre-eclampsia using maternal blood leptin/ceramide ratio
Status: New
Description: OBJECTIVE: This study aimed to develop a blood test for the prediction of pre-eclampsia (PE) early in gestation. We hypothesised that the longitudinal measurements of circulating adipokines and sphingolipids in maternal serum over the course of pregnancy could identify novel prognostic biomarkers that are predictive of impending event of PE early in gestation. STUDY DESIGN: Retrospective discovery and longitudinal confirmation. SETTING: Maternity units from two US hospitals. PARTICIPANTS: Six previously published studies of placental tissue (78 PE and 95 non-PE) were compiled for genomic discovery, maternal sera from 15 women (7 non-PE and 8 PE) enrolled at ProMDxed were used for sphingolipidomic discovery, and maternal sera from 40 women (20 non-PE and 20 PE) enrolled at Stanford University were used for longitudinal observation. OUTCOME MEASURE: Biomarker candidates from discovery were longitudinally confirmed and compared in parallel to the ratio of placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) using the same cohort. The datasets were generated by enzyme-linked immunosorbent and liquid chromatography-tandem mass spectrometric assays. RESULTS: Our discovery integrating genomic and sphingolipidomic analysis identified leptin (Lep) and ceramide (Cer) (d18:1/25:0) as novel biomarkers for early gestational assessment of PE. Our longitudinal observation revealed a marked elevation of Lep/Cer (d18:1/25:0) ratio in maternal serum at a median of 23 weeks? gestation among women with impending PE as compared with women with uncomplicated pregnancy. The Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting impending event of PE with superior sensitivity (85% vs 20%) and area under curve (0.92 vs 0.52) from 5 to 25 weeks of gestation. CONCLUTION: Our study demonstrated the longitudinal measurement of maternal Lep/Cer (d18:1/25:0) ratio allows the non-invasive assessment of PE to identify pregnancy at high risk in early gestation, outperforming the established sFlt-1/PlGF ratio test. KEYWORDS: obstetrics, gynaecology, public health
Program/Contract:
ProgramContract
March of Dimes March of Dimes
DOI: 10.21430/M38OOTQNCC
Subjects: 0
Study PI, contact:
NameOrganizationSite
Ling Xuefeng Stanford University School of Medicine Clinical and Translational Research Program
Publications:
Early-pregnancy prediction of risk for pre-eclampsia using maternal blood leptin/ceramide ratio: discovery and confirmation.. BMJ open Nov 2021. doi: 10.1136/bmjopen-2021-050963 [Pubmed: 34824115]
Resources:
paper_link https://bmjopen.bmj.com/content/11/11/e050963.long]
GSE4707 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE4707]
GSE10588 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE10588]
GSE24129 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE24129]
GSE25906 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE25906]
GSE44711 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE44711]
GSE54618 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE54618]
Assays:None
Clinical Assessments:None

SDY1899: Human Placental Transcriptome and fetal sex differences in SPTB
Status: New
Description: A well-functioning placenta is crucial for normal gestation and regulates the nutrient, gas, and waste exchanges between the maternal and fetal circulations and is an important endocrine organ producing hormones that regulate both the maternal and fetal physiologies during pregnancy. Placental insufficiency is implicated in spontaneous preterm birth (SPTB). We proposed that deficits in the capacity of the placenta to maintain bioenergetic and metabolic stability during pregnancy may ultimately result in SPTB. To explore our hypothesis, we performed a RNA-seq study in male and female placentas from women with SPTB (<36 weeks gestation) compared to normal pregnancies (?38 weeks gestation) to assess the alterations in the gene expression profiles. We focused exclusively on Black women (cases and controls), who are at the highest risk of SPTB. Six hundred and seventy differentially expressed genes were identified in male SPTB placentas. Among them, 313 and 357 transcripts were increased and decreased, respectively. In contrast, only 61 differentially expressed genes were identified in female SPTB placenta. The ingenuity pathway analysis showed alterations in the genes and canonical pathways critical for regulating inflammation, oxidative stress, detoxification, mitochondrial function, energy metabolism, and the extracellular matrix. Many upstream regulators and master regulators important for nutrient-sensing and metabolism were also altered in SPTB placentas, including the PI3K complex, TGFB1/SMADs, SMARCA4, TP63, CDKN2A, BRCA1, and NFAT. The transcriptome was integrated with published human placental metabolome to assess the interactions of altered genes and metabolites. Collectively, significant and biologically relevant alterations in the transcriptome were identified in SPTB placentas with fetal sex disparities. Altered energy metabolism, mitochondrial function, inflammation, and detoxification may underly the mechanisms of placental dysfunction in SPTB
Program/Contract:
ProgramContract
March of Dimes March of Dimes
DOI: 10.21430/M3QPEJCGY4
Subjects: 0
Study PI, contact:
NameOrganizationSite
Rebecca Simmons Perelman School of Medicine, University of Pennsylvania Center for Research on Reproduction and Women's Health, Department of Obstetrics and Gynecology
Publications:
Human Placental Transcriptome Reveals Critical Alterations in Inflammation and Energy Metabolism with Fetal Sex Differences in Spontaneous Preterm Birth.. International journal of molecular sciences Jul 2021. doi: 10.3390/ijms22157899 [Pubmed: 34360662]
Resources:
paper_link https://www.mdpi.com/1422-0067/22/15/7899]
PRJNA729769 https://www.ncbi.nlm.nih.gov/bioproject/PRJNA729769]
GSE174415 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE174415]
Assays:None
Clinical Assessments:None

SDY1900: A Peripheral Immune Signature of Labor Induction
Status: New
Description: Approximately 1 in 4 pregnant women in the United States undergo labor induction. The onset and establishment of labor, particularly induced labor, is a complex and dynamic process influenced by multiple endocrine, inflammatory, and mechanical factors as well as obstetric and pharmacological interventions. The duration from labor induction to the onset of active labor remains unpredictable. Moreover, prolonged labor is associated with severe complications for the mother and her offspring, most importantly chorioamnionitis, uterine atony, and postpartum hemorrhage. While maternal immune system adaptations that are critical for the maintenance of a healthy pregnancy have been previously characterized, the role of the immune system during the establishment of labor is poorly understood. Understanding maternal immune adaptations during labor initiation can have important ramifications for predicting successful labor induction and labor complications in both induced and spontaneous types of labor. The aim of this study was to characterize labor-associated maternal immune system dynamics from labor induction to the start of active labor. Serial blood samples from fifteen participants were collected immediately prior to labor induction (baseline) and during the latent phase until the start of active labor. Using high-dimensional mass cytometry, a total of 1,059 single-cell immune features were extracted from each sample. A multivariate machine-learning method was employed to characterize the dynamic changes of the maternal immune system after labor induction until the establishment of active labor. A cross-validated linear sparse regression model (least absolute shrinkage and selection operator, LASSO) predicted the minutes since induction of labor with high accuracy (R = 0.86, p = 6.7e-15, RMSE = 277 min). Immune features most informative for the model included STAT5 signaling in central memory CD8+ T cells and pro-inflammatory STAT3 signaling responses across multiple adaptive and innate immune cell subsets. Our study reports a peripheral immune signature of labor induction, and provides important insights into biological mechanisms that may ultimately predict labor induction success as well as complications, thereby facilitating clinical decision-making to improve maternal and fetal well-being
Program/Contract:
ProgramContract
March of Dimes March of Dimes
DOI: 10.21430/M319OCI0WS
Subjects: 0
Study PI, contact:
NameOrganizationSite
Brice Gaudilliere Stanford University School of Medicine Division of Neonatal and Developmental Medicine, Department of Pediatrics
Publications:
A Peripheral Immune Signature of Labor Induction.. Frontiers in immunology Sep 2021. doi: 10.3389/fimmu.2021.725989 [Pubmed: 34566984]
Resources:
paper_link https://www.frontiersin.org/articles/10.3389/fimmu.2021.725989/full]
Data_link https://datadryad.org/stash/dataset/doi:10.5061/dryad.80gb5mkrg]
Assays:None
Clinical Assessments:None

SDY1902: Association of maternal prenatal selenium concentration and PTB
Status: New
Description: BACKGROUND: Selenium (Se), an essential trace mineral, has been implicated in preterm birth (PTB). We aimed to determine the association of maternal Se concentrations during pregnancy with PTB risk and gestational duration in a large number of samples collected from diverse populations. METHODS: Gestational duration data and maternal plasma or serum samples of 9946 singleton live births were obtained from 17 geographically diverse study cohorts. Maternal Se concentrations were determined by inductively coupled plasma mass spectrometry analysis. The associations between maternal Se with PTB and gestational duration were analysed using logistic and linear regressions. The results were then combined using fixed-effect and random-effect meta-analysis. FINDINGs: In all study samples, the Se concentrations followed a normal distribution with a mean of 93.8 ng/mL (SD: 28.5 ng/mL) but varied substantially across different sites. The fixed-effect meta-analysis across the 17 cohorts showed that Se was significantly associated with PTB and gestational duration with effect size estimates of an OR=0.95 (95% CI: 0.9 to 1.00) for PTB and 0.66 days (95% CI: 0.38 to 0.94) longer gestation per 15 ng/mL increase in Se concentration. However, there was a substantial heterogeneity among study cohorts and the random-effect meta-analysis did not achieve statistical significance. The largest effect sizes were observed in UK (Liverpool) cohort, and most significant associations were observed in samples from Malawi. INTERPRETATION: While our study observed statistically significant associations between maternal Se concentration and PTB at some sites, this did not generalise across the entire cohort. Whether population-specific factors explain the heterogeneity of our findings warrants further investigation. Further evidence is needed to understand the biologic pathways, clinical efficacy and safety, before changes to antenatal nutritional recommendations for Se supplementation are considered. KEYWORDS: child health, environmental health, epidemiology, maternal health, nutrition
Program/Contract:
ProgramContract
March of Dimes March of Dimes
DOI: 10.21430/M3BCC13TUN
Subjects: 0
Study PI, contact:
NameOrganizationSite
Nagendra Monangi Cincinnati Children's Hospital Medical Center Center for Prevention of Preterm Birth, Perinatal Institute
Ge Zhang Cincinnati Children's Hospital Medical Center Center for Prevention of Preterm Birth, Perinatal Institute
Publications:
Association of maternal prenatal selenium concentration and preterm birth: a multicountry meta-analysis.. BMJ global health Sep 2021. doi: 10.1136/bmjgh-2021-005856 [Pubmed: 34518202]
Resources:
paper_link https://gh.bmj.com/content/6/9/e005856.long]
Assays:None
Clinical Assessments:None

SDY1773: Human plasmacytoid dendritic cells mount a distinct antiviral response to virus-infected cells
Status: Updated
Description: Plasmacytoid dendritic cells (pDCs) can rapidly produce interferons and other soluble factors in response to extracellular viruses or virus mimics such as CpG-containing DNA. pDCs can also recognize live cells infected with certain RNA viruses, but the relevance and functional consequences of such recognition remain unclear. We studied the response of primary DCs to the prototypical persistent DNA virus, human cytomegalovirus (CMV). Human pDCs produced high amounts of type I interferon (IFN-I) when incubated with live CMV-infected fibroblasts but not with free CMV; the response involved integrin-mediated adhesion, transfer of DNA-containing virions to pDCs, and the recognition of DNA through TLR9. Compared with transient polyfunctional responses to CpG or free influenza virus, pDC response to CMV-infected cells was long-lasting, dominated by the production of IFN-I and IFN-III, and lacked diversification into functionally distinct populations. Similarly, pDC activation by influenza-infected lung epithelial cells was highly efficient, prolonged, and dominated by interferon production. Prolonged pDC activation by CMV-infected cells facilitated the activation of natural killer cells critical for CMV control. Last, patients with CMV viremia harbored phenotypically activated pDCs and increased circulating IFN-I and IFN-III. Thus, recognition of live infected cells is a mechanism of virus detection by pDCs that elicits a unique antiviral immune response.
Program/Contract:
ProgramContract
Human Immunology Project Consortium (HIPC) RFA-AI-15-041 Human Anti-Viral Immune Responses In Tissues And Circulation (Columbia)
DOI: 10.21430/M3LQG9JFFS
Subjects: 85
Study PI, contact:
NameOrganizationSite
Donna Farber Columbia University Columbia University Medical Center
Publications:
Human plasmacytoid dendritic cells mount a distinct antiviral response to virus-infected cells.. Science immunology Apr 2021. doi: 10.1126/sciimmunol.abc7302 [Pubmed: 33811059]
Resources:
Assays:
Assay TypeNumber of Exp. Samples
CyTOF 9
Flow Cytometry 665
RNA sequencing 84
Clinical Assessments:None
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