DR50.2 DataRelease
Release Date: February 2024
New Studies: 21
Updated Studies: 42
New Studies
| SDY1884: Biomarkers for PTLD in Children (CTOTC-06) | |||||||||||||||||||||||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||||||||||||||||||||||
| Description: | EBV-associated post-transplant lymphoproliferative disease (PTLD) is the most common malignancy in children after transplant. Diagnosis and effective treatment of the EBV-associated cancer is hampered by our inability to determine which children are at risk of developing these cancers and to detect the cancer at an early stage. In this study, we plan to test new "biomarkers" in the blood of children that will tell us very early on if the child is at risk of developing the EBV-associated cancer or if the cancer is present. These studies provide new opportunities for detection, diagnosis, and treatment of children with EBV-associated, post-transplant cancer. | ||||||||||||||||||||||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3E26QO4D7 | ||||||||||||||||||||||||||||||||||||||||||
| Subjects: | 944 | ||||||||||||||||||||||||||||||||||||||||||
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| Assays: | None | ||||||||||||||||||||||||||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||||||||||||||||||||||||||
| SDY1909: Study to Evaluate Safety, Immunogenicity and Efficacy of PfSPZ Vaccine in HIV Negative and HIV Positive Tanzanian Adults (BSPZV3a) | ||||||||||
| Status: | New | |||||||||
| Description: | This trial is a single center trial designed to assess the safety, tolerability, immunogenicity and efficacy of PfSPZ Vaccine (9.0x10^5 PfSPZ given at 0, +2, +4, +6 and +28 days (Group 1, HIV negative, and Group 2, HIV positive)). Controls will receive parallel injections with normal saline (NS). All administrations of PfSPZ or NS will be by direct venous inoculation (DVI). Twenty-one male and female adult volunteers, aged from 18 to 45 years, who live in and around the Bagamoyo township, will be enrolled based on pre-defined inclusion and exclusion criteria. 12/21 subjects will be HIV positive volunteers (who clinical stage 1) on stable anti-retroviral therapy (ART) for at least 3 months with a CD4+ cell count above 500 cells/_L at screening. The rest (9/21) will be healthy HIV negative adults. Treatment allocation will be double-blind within Group 1 and 2b but not between the groups or subgroups. Immunizations will begin with healthy HIV negative volunteers first (Group 1), before inoculation of HIV positive volunteers (Groups 2a and 2b). Transitioning from immunization of HIV negative to immunization of HIV positive will begin by immunizing a sentinel group of 3 HIV positive individuals with a reduced vaccine dose of 4.5x10^5 PfSPZ (Group 2a). This transition will be staggered by at least two (2) weeks, to allow for a safety data review. If the safety data do not meet pause criteria, this will signal a ""go"" for transitioning to immunizations of sentinel group of three (3) HIV positive volunteers. If pause criteria are met, there will be no immediate transition, and instead an ad-hoc meeting of the Safety Monitoring Committee (SMC) will be called for an independent review and recommendation. Transition from the unblinded HIV positive sentinel Group 2a to the full study cohort of double blinded placebo controlled HIV positive volunteers (Group 2b), will also be staggered for at least two (2) weeks. There will be a scheduled review by the SMC of safety data collected from the sentinel HIV positive group for up to 7 days after the fourth immunization. After the safety review, transition to the main HIV positive group (Group 2b) will take into account the SMC recommendation(s). | |||||||||
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| DOI: | 10.21430/M3D8HU5M98 | |||||||||
| Subjects: | 21 | |||||||||
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| Publications: | None | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2112: HTP proteomics, DIA | ||||||||||
| Status: | New | |||||||||
| 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 | |||||||||
| SDY2310: Immune characterization of lung tumors by flow cytometry | ||||||||||
| Status: | New | |||||||||
| Description: | Characterization of tumor immune compartment in an endogenous mouse model of lung adenocarcinoma after chronic bacterial instillation. Samples were obtained from Dr. Harris, Laboratory of Human Carcinogenesis, CCR-NCI; animals were housed and treated at the animal facility of the Laboratory of Animal Science Program - Leidos Biomedical Research of the Frederick National Laboratory for Cancer Research. | |||||||||
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| DOI: | 10.21430/M3EQNSM26N | |||||||||
| Subjects: | 83 | |||||||||
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| Publications: | None | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2468: Kinetics and durability of humoral responses to SARS-CoV-2 infection and vaccination | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description: | Using the PARIS longitudinal cohort, the authors determined the kinetics of antibody responses to spike protein after infections, during the primary immunization series, during monovalent and bivalent booster vaccination as well as during breakthrough infections. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| DOI: | 10.21430/M37GAKH32A | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Subjects: | 825 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Publications: | None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| SDY2483: Mycobacterium tuberculosis-specific antibodies detect progression to active tuberculosis in South African adolescents | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | Identifying and treating individuals destined to progress from asymptomatic infection to active tuberculosis (TB) is key to eradicating TB. Recent studies have begun to define transcriptomic, metabolomic, proteomic, and T cell receptor signatures of TB progression, but simple Mycobacterium tuberculosis (Mtb)-specific biomarkers that detect TB progression have yet to be defined. We used a high-throughput systems serology approach to profile Mtb-specific humoral responses in individuals who progressed to active TB and matched non-progressor controls from a longitudinal cohort of HIV-negative South African adolescents, the Adolescent Cohort Study (ACS). Compared with non-progressors, ACS progressors had altered Mtb-specific humoral responses that were longitudinally stable and did not correlate with RISK6, a six-gene transcriptomic signature of progression. An Mtb-specific serological signature of progression (SeroScore) was defined that stably differentiated progressors up to two years prior to TB diagnosis, and outperformed RISK6 at remote timepoints. However, both SeroScore and RISK6 had reduced performance among female participants. In a second, more heterogeneous cohort, Grand Challenges 6-74 (GC6), the SeroScore was able to detect progressors among adolescents, but not adults. A second SeroScore, defined in GC6, also identified progressors in both GC6 and ACS in an age-dependent manner. These data demonstrate that Mtb-specific antibody signatures can detect TB progression months to years prior to TB diagnosis, and that age and sex are critical variables modulating the Mtb-specific humoral phenotypes associated with TB progression. Antibody profiles may therefore help guide the development of novel clinical tools to improve TB management worldwide. | |||||||||||||||
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| DOI: | 10.21430/M37FGQMVH3 | |||||||||||||||
| Subjects: | 348 | |||||||||||||||
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| Publications: | None | |||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||
| SDY2516: A next-generation intranasal trivalent MMS vaccine induces durable and broad protection against SARS-CoV-2 variants of concern | |||||||||||||||||
| Status: | New | ||||||||||||||||
| Description: | As SARS-CoV-2 variants of concern (VoCs) that evade immunity continue to emerge, next-generation adaptable COVID-19 vaccines which protect the respiratory tract and provide broader, more effective, and durable protection are urgently needed. Here, we have developed one such approach, a highly efficacious, intranasally delivered, trivalent measles-mumps-SARS-CoV-2 spike (S) protein (MMS) vaccine candidate that induces robust systemic and mucosal immunity with broad protection. This vaccine candidate is based on three components of the MMR vaccine, a measles virus Edmonston and the two mumps virus strains [Jeryl Lynn 1 (JL1) and JL2] that are known to provide safe, effective, and long-lasting protective immunity. The six proline-stabilized prefusion S protein (preS-6P) genes for ancestral SARS-CoV-2 WA1 and two important SARS-CoV-2 VoCs (Delta and Omicron BA.1) were each inserted into one of these three viruses which were then combined into a trivalent “MMS” candidate vaccine. Intranasal immunization of MMS in IFNAR1−/− mice induced a strong SARS-CoV-2-specific serum IgG response, cross-variant neutralizing antibodies, mucosal IgA, and systemic and tissue-resident T cells. Immunization of golden Syrian hamsters with MMS vaccine induced similarly high levels of antibodies that efficiently neutralized SARS-CoV-2 VoCs and provided broad and complete protection against challenge with any of these VoCs. This MMS vaccine is an efficacious, broadly protective next-generation COVID-19 vaccine candidate, which is readily adaptable to new variants, built on a platform with a 50-y safety record that also protects against measles and mumps. | ||||||||||||||||
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| DOI: | 10.21430/M3XCZXYJ29 | ||||||||||||||||
| Subjects: | 0 | ||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||
| SDY2517: Geographically skewed recruitment and COVID-19 seroprevalence estimates: a cross-sectional serosurveillance study and mathematical modelling analysis | ||||||||||
| Status: | New | |||||||||
| Description: | Objectives: Convenience sampling is an imperfect but important tool for seroprevalence studies. For COVID-19, local geographic variation in cases or vaccination can confound studies that rely on the geographically skewed recruitment inherent to convenience sampling. The objectives of this study were: (1) quantifying how geographically skewed recruitment influences SARS-CoV-2 seroprevalence estimates obtained via convenience sampling and (2) developing new methods that employ Global Positioning System (GPS)-derived foot traffic data to measure and minimise bias and uncertainty due to geographically skewed recruitment. Design: We used data from a local convenience-sampled seroprevalence study to map the geographic distribution of study participants' reported home locations and compared this to the geographic distribution of reported COVID-19 cases across the study catchment area. Using a numerical simulation, we quantified bias and uncertainty in SARS-CoV-2 seroprevalence estimates obtained using different geographically skewed recruitment scenarios. We employed GPS-derived foot traffic data to estimate the geographic distribution of participants for different recruitment locations and used this data to identify recruitment locations that minimise bias and uncertainty in resulting seroprevalence estimates. Results: The geographic distribution of participants in convenience-sampled seroprevalence surveys can be strongly skewed towards individuals living near the study recruitment location. Uncertainty in seroprevalence estimates increased when neighbourhoods with higher disease burden or larger populations were undersampled. Failure to account for undersampling or oversampling across neighbourhoods also resulted in biased seroprevalence estimates. GPS-derived foot traffic data correlated with the geographic distribution of serosurveillance study participants. Conclusions: Local geographic variation in seropositivity is an important concern in SARS-CoV-2 serosurveillance studies that rely on geographically skewed recruitment strategies. Using GPS-derived foot traffic data to select recruitment sites and recording participants' home locations can improve study design and interpretation. | |||||||||
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| DOI: | 10.21430/M3RQBC30KW | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2518: Differences in SARS-CoV-2 Vaccine Response Dynamics Between Class-I- and Class-II-Specific T-Cell Receptors in Inflammatory Bowel Disease | |||||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||||
| Description: | T-cells specifically bind antigens to induce adaptive immune responses using highly specific molecular recognition, and a diverse T-cell repertoire with expansion of antigen-specific clones can indicate robust immune responses after infection or vaccination. For patients with inflammatory bowel disease (IBD), a spectrum of chronic intestinal inflammatory diseases usually requiring immunomodulatory treatment, the T-cell response has not been well characterized. Understanding the patient factors that result in strong vaccination responses is critical to guiding vaccination schedules and identifying mechanisms of T-cell responses in IBD and other immune-mediated conditions. Here we used T-cell receptor sequencing to show that T-cell responses in an IBD cohort were influenced by demographic and immune factors, relative to a control cohort of health care workers (HCWs). Subjects were sampled at the time of SARS-CoV-2 vaccination, and longitudinally afterwards; TCR Vβ gene repertoires were sequenced and analyzed for COVID-19-specific clones. We observed significant differences in the overall strength of the T-cell response by age and vaccine type. We further stratified the T-cell response into Class-I- and Class-II-specific responses, showing that Ad26.COV2.S vector vaccine induced Class-I-biased T-cell responses, whereas mRNA vaccine types led to different responses, with mRNA-1273 vaccine inducing a more Class-I-deficient T-cell response compared to BNT162b2. Finally, we showed that these T-cell patterns were consistent with antibody levels from the same patients. Our results account for the surprising success of vaccination in nominally immuno-compromised IBD patients, while suggesting that a subset of IBD patients prone to deficiencies in T-cell response may warrant enhanced booster protocols. | ||||||||||||||||||||||||
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| DOI: | 10.21430/M3BGKXJRWY | ||||||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||||||||
| SDY2519: Temporal variations in the severity of COVID-19 illness by race and ethnicity | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | Introduction: Early reports highlighted racial/ethnic disparities in the severity of COVID-19 seen across the USA; the extent to which these disparities have persisted over time remains unclear. Our research objective was to understand temporal trends in racial/ethnic variation in severity of COVID-19 illness presenting over time. Methods: We conducted a retrospective cohort analysis using longitudinal data from Cedars-Sinai Medical Center, a high-volume health system in Southern California. We studied patients admitted to the hospital with COVID-19 illness from 4 March 2020 through 5 December 2020. Our primary outcome was COVID-19 severity of illness among hospitalised patients, assessed by racial/ethnic group status. We defined overall illness severity as an ordinal outcome: hospitalisation but no intensive care unit (ICU) admission; admission to the ICU but no intubation; and intubation or death. Results: A total of 1584 patients with COVID-19 with available demographic and clinical data were included. Hispanic/Latinx compared with non-Hispanic white patients had higher odds of experiencing more severe illness among hospitalised patients (OR 2.28, 95% CI 1.62 to 3.22) and this disparity persisted over time. During the initial 2 months of the pandemic, non-Hispanic blacks were more likely to suffer severe illness than non-Hispanic whites (OR 2.02, 95% CI 1.07 to 3.78); this disparity improved by May, only to return later in the pandemic. Conclusion: In our patient sample, the severity of observed COVID-19 illness declined steadily over time, but these clinical improvements were not seen evenly across racial/ethnic groups; greater illness severity continues to be experienced among Hispanic/Latinx patients. | |||||||||||||||
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| DOI: | 10.21430/M3U0J3FOKP | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
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| Assays: | None | |||||||||||||||
| Clinical Assessments: | None | |||||||||||||||
| SDY2520: Neutralization escape by SARS-CoV-2 Omicron subvariant BA.2.86 | ||||||||||
| Status: | New | |||||||||
| Description: | The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variant BA.2.86 has over 30 mutations in spike compared with BA.2 and XBB.1.5, which raised the possibility that BA.2.86 might evade neutralizing antibodies (NAbs) induced by vaccination or infection. In this study, we show that NAb titers are substantially lower to BA.2.86 compared with BA.2 but are similar or slightly higher than to other current circulating variants, including XBB.1.5, EG.5.1, and FL.1.5.1. Moreover, NAb titers against all these variants were higher in vaccinated individuals with a history of XBB.1.5 infection compared with vaccinated individuals with no history of XBB.1.5 infection, suggesting the potential utility of the monovalent XBB.1.5 mRNA boosters. | |||||||||
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| DOI: | 10.21430/M38YJ0KH68 | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2521: Ethnoracial Disparities in SARS-CoV-2 Seroprevalence in a Large Cohort of Individuals in Central North Carolina from April to December 2020 | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of deaths around the world within the past 2 years. Transmission within the United States has been heterogeneously distributed by geography and social factors with little data from North Carolina. Here, we describe results from a weekly cross-sectional study of 12,471 unique hospital remnant samples from 19 April to 26 December 2020 collected by four clinical sites within the University of North Carolina Health system, with a majority of samples from urban, outpatient populations in central North Carolina. We employed a Bayesian inference model to calculate SARS-CoV-2 spike protein immunoglobulin prevalence estimates and conditional odds ratios for seropositivity. Furthermore, we analyzed a subset of these seropositive samples for neutralizing antibodies. We observed an increase in seroprevalence from 2.9 (95% confidence interval [CI], 1.8 to 4.5) to 12.8 (95% CI, 10.6 to 15.2) over the course of the study. Latinx individuals had the highest odds ratio of SARS-CoV-2 exposure at 6.56 (95% CI, 4.66 to 9.44). Our findings aid in quantifying the degree of asymmetric SARS-CoV-2 exposure by ethnoracial grouping. We also find that 49% of a subset of seropositive individuals had detectable neutralizing antibodies, which was skewed toward those with recent respiratory infection symptoms. IMPORTANCE PCR-confirmed SARS-CoV-2 cases underestimate true prevalence. Few robust community-level SARS-CoV-2 ethnoracial and overall prevalence estimates have been published for North Carolina in 2020. Mortality has been concentrated among ethnoracial minorities and may result from a high likelihood of SARS-CoV-2 exposure, which we observe was particularly high among Latinx individuals in North Carolina. Additionally, neutralizing antibody titers are a known correlate of protection. Our observation that development of SARS-CoV-2 neutralizing antibodies may be inconsistent and dependent on severity of symptoms makes vaccination a high priority despite prior exposure. | |||||||||||||||
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| DOI: | 10.21430/M3U4LBF0AQ | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
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| SDY2522: Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| 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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| SDY2523: Coronavirus-Specific Antibody Cross Reactivity in Rhesus Macaques Following SARS-CoV-2 Vaccination and Infection | |||||||||
| Status: | New | ||||||||
| Description: | Vaccines are being rapidly developed with the goal of ending the SARS-CoV-2 pandemic. However, the extent to which SARS-CoV-2 vaccination induces serum responses that cross-react with other coronaviruses remains poorly studied. Here we define serum profiles in rhesus macaques after vaccination with DNA or Ad26 based vaccines expressing SARS-CoV-2 Spike protein followed by SARS-CoV-2 challenge, or SARS-CoV-2 infection alone. Analysis of serum responses showed robust reactivity to the SARS-CoV-2 full-length Spike protein and receptor binding domain (RBD), both included in the vaccine. However, serum cross-reactivity to the closely related sarbecovirus SARS-CoV-1 Spike and RBD, was reduced. Reactivity was also measured to the distantly related common cold alpha-coronavirus, 229E and NL63, and beta-coronavirus, OC43 and HKU1, Spike proteins. Using SARS-COV-2 and SARS-CoV-1 lentivirus based pseudoviruses, we show that neutralizing antibody responses were predominantly SARS-CoV-2 specific. These data define patterns of cross-reactive binding and neutralizing serum responses induced by SARS-CoV-2 infection and vaccination in rhesus macaques. Our observations have important implications for understanding polyclonal responses to SARS-CoV-2 Spike, which will facilitate future CoV vaccine assessment and development.ImportanceThe rapid development and deployment of SARS-CoV-2 vaccines has been unprecedented. In this study, we explore the cross-reactivity of SARS-CoV-2 specific antibody responses to other coronaviruses. By analyzing responses from NHPs both before and after immunization with DNA or Ad26 vectored vaccines, we find patterns of cross reactivity that mirror those induced by SARS-CoV-2 infection. These data highlight the similarities between infection and vaccine induced humoral immunity for SARS-CoV-2 and cross-reactivity of these responses to other CoVs. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M36X7KDBP4 | ||||||||
| Subjects: | 0 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY2524: Enhanced evasion of neutralizing antibody response by Omicron XBB.1.5, CH.1.1, and CA.3.1 variants | |||||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||||
| Description: | Omicron subvariants continuingly challenge current vaccination strategies. Here, we demonstrate nearly complete escape of the XBB.1.5, CH.1.1, and CA.3.1 variants from neutralizing antibodies stimulated by three doses of mRNA vaccine or by BA.4/5 wave infection, but neutralization is rescued by a BA.5-containing bivalent booster. CH.1.1 and CA.3.1 show strong immune escape from monoclonal antibody S309. Additionally, XBB.1.5, CH.1.1, and CA.3.1 spike proteins exhibit increased fusogenicity and enhanced processing compared with BA.2. Homology modeling reveals the key roles of G252V and F486P in the neutralization resistance of XBB.1.5, with F486P also enhancing receptor binding. Further, K444T/M and L452R in CH.1.1 and CA.3.1 likely drive escape from class II neutralizing antibodies, whereas R346T and G339H mutations could confer the strong neutralization resistance of these two subvariants to S309-like antibodies. Overall, our results support the need for administration of the bivalent mRNA vaccine and continued surveillance of Omicron subvariants. | ||||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3SK8JOTUY | ||||||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||||||||
| SDY2525: Enhanced IgG immune response to COVID-19 vaccination in patients with sickle cell disease | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Patients with sickle cell disease (SCD) are considered to be immunocompromised, yet data on the antibody response to SARS-CoV-2 vaccination in SCD is limited. We investigated anti-SARS-CoV-2 IgG titres and overall neutralizing activity in 201 adults with SCD and demographically matched non-SCD controls. Unexpectedly, patients with SCD generate a more robust and durable COVID-19 vaccine IgG response compared to matched controls, though the neutralizing activity remained similar across both cohorts. These findings suggest that patients with SCD achieve a similar antibody response following COVID-19 vaccination compared to the general population, with implications for optimal vaccination strategies for patients with SCD. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3PHNVZFSL | ||||||||||||
| Subjects: | 0 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY2526: Host range, transmissibility and antigenicity of a pangolin coronavirus | |||||||||||||||||
| Status: | New | ||||||||||||||||
| Description: | The pathogenic and cross-species transmission potential of SARS-CoV-2-related coronaviruses (CoVs) remain poorly characterized. Here we recovered a wild-type pangolin (Pg) CoV GD strain including derivatives encoding reporter genes using reverse genetics. In primary human cells, PgCoV replicated efficiently but with reduced fitness and showed less efficient transmission via airborne route compared with SARS-CoV-2 in hamsters. PgCoV was potently inhibited by US Food and Drug Administration approved drugs, and neutralized by COVID-19 patient sera and SARS-CoV-2 therapeutic antibodies in vitro. A pan-Sarbecovirus antibody and SARS-CoV-2 S2P recombinant protein vaccine protected BALB/c mice from PgCoV infection. In K18-hACE2 mice, PgCoV infection caused severe clinical disease, but mice were protected by a SARS-CoV-2 human antibody. Efficient PgCoV replication in primary human cells and hACE2 mice, coupled with a capacity for airborne spread, highlights an emergence potential. However, low competitive fitness, pre-immune humans and the benefit of COVID-19 countermeasures should impede its ability to spread globally in human populations. | ||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3JI8V6AUI | ||||||||||||||||
| Subjects: | 0 | ||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||
| SDY2527: Signatures of AAV-2 immunity are enriched in children with severe acute hepatitis of unknown etiology | ||||||||||
| Status: | New | |||||||||
| Description: | Severe acute hepatitis of unknown etiology in children is under investigation in 35 countries. Although several potential etiologic agents have been investigated, a clear cause for the liver damage observed in these cases remains to be identified. Using VirScan, a high-throughput antibody profiling technology, we probed the antibody repertoires of nine cases of severe acute hepatitis of unknown etiology treated at Children's of Alabama and compared their antibody responses with 38 pediatric and 470 adult controls. We report increased adeno-associated dependoparvovirus A (AAV-A) breadth in cases relative to controls and adeno-associated virus 2 (AAV-2) peptide responses that were conserved in seven of nine cases but rarely observed in pediatric and adult controls. These findings suggest that AAV-2 is a likely etiologic agent of severe acute hepatitis of unknown etiology. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3WV6HXDPC | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2529: Antibody Response to Omicron BA.4-BA.5 Bivalent Booster | |||||||||||||||||||||
| Status: | New | ||||||||||||||||||||
| Description: | Here, the authors assess the effect of the new bivalent vaccines on the neutralizing-antibody response. | ||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3WFEVLU02 | ||||||||||||||||||||
| Subjects: | 74 | ||||||||||||||||||||
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| SDY2530: Antigenic Landscape Analysis of Individuals Vaccinated with a Universal Influenza Virus Vaccine Candidate Reveals Induction of Cross-Subtype Immunity | |||||||
| Status: | New | ||||||
| Description: | Here, serum samples from a phase I clinical trial (CVIA057, NCT03300050) were analyzed using an influenza virus protein microarray | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M35VAODAQ2 | ||||||
| Subjects: | 61 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY2531: Engineered Influenza Virus Virions Reveal the Contributions of Non-hemagglutinin Structural Proteins to Vaccine-Mediated Protection | |||||||||
| Status: | New | ||||||||
| Description: | The development of improved and universal anti-influenza vaccines would represent a major advance in the protection of human health. In order to facilitate the development of such vaccines, understanding how viral proteins can contribute to protection from disease is critical. Much of the previous work to address these questions relied on reductionist systems (i.e., vaccination with individual proteins or virus- like particles [VLPs] that contain only a few viral proteins); thus, we have an incomplete understanding of how immunity to different subsets of viral proteins contributes to protection. Here, we report the development of a platform in which a single viral protein can be deleted from an authentic viral particle that retains the remaining full complement of structural proteins and viral RNA. As a first study with this system, we chose to delete the major influenza A virus (IAV) antigen, the hemagglutinin (HA) protein, to evaluate how the other components of the viral particle contribute en masse to protection from influenza disease. Our results show that while anti-HA immunity plays a major role in protection from challenge with a vaccine-matched strain, the contributions from other structural proteins were the major drivers of protection against highly antigenically drifted, homosubtypic strains. This work highlights the importance of evaluating the inclusion of non-HA viral proteins in the development of broadly efficacious and long-lasting influenza vaccines. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3TX82XYNN | ||||||||
| Subjects: | 90 | ||||||||
| Study PI, contact: |
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Updated Studies
| SDY78: Antigenic and immunogenic properties of recombinant hemagglutinin proteins when produced in various protein expression systems | |||||||||
| Status: | Updated | ||||||||
| Description: | Assess the immunogenicity and antigenicity of recombinant hemagglutinin proteins produced and purified by various methods | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3EER1F151 | ||||||||
| Subjects: | 178 | ||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||
| SDY112: T cell responses to H1N1v and a longitudinal study of seasonal influenza vaccination (TIV) SLVP015 2011 (See companion studies SDY311 2010 / SDY312 2009 / SDY314 2008 / SDY315 2012) | |||||||||||||
| 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/M320H8XYFG | ||||||||||||
| Subjects: | 93 | ||||||||||||
| Study PI, contact: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||
| SDY113: Plasmablast response to inactivated and live attenuated influenza vaccines (TIV3/TIV3 ID/LAIV) SLVP021 2011 | |||||||||||||||||
| Status: | Updated | ||||||||||||||||
| Description: | To study the plasmablast response to influenza vaccines | ||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3KPFS7KXI | ||||||||||||||||
| Subjects: | 70 | ||||||||||||||||
| Study PI, contact: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||||||
| SDY202: Heterovariant cross-reactive B-cell responses induced by the 2009 pandemic influenza virus A subtype H1N1 vaccine SLVP021 | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | To study the plasmablast response to monovalent inactivated 2009 pandemic pH1N1 vaccine | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3LS2SRM8M | ||||||||||||
| Subjects: | 79 | ||||||||||||
| Study PI, contact: |
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| Publications: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||
| SDY215: TIV 2008 vaccination of CD95-/- mice and ELISA for detection of influenza-specific antibodies | |||||||
| Status: | Updated | ||||||
| Description: | Evaluation of the mouse immune response to influenza vaccination. ELISA was used to examine the immune response of mutant mice (MRL/Mpj-Faslpr/J (Mpj/lpr), B6.MRL-Faslpr/J (B6/lpr), MRL/MpJ (Mpj) and C57BL/6L (B6)) to a single dose of the trivalent 2008 seasonal influenza vaccine | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M38JPMTP8S | ||||||
| Subjects: | 17 | ||||||
| Study PI, contact: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY232: Determinants of human NK cell diversity by mass cytometry | |||||||
| Status: | Updated | ||||||
| Description: | Natural Killer (NK) cells play critical roles in immune defense and reproduction, yet remain the most poorly understood lymphocyte population. Because their activation is controlled by a variety of combinatorially expressed activating and inhibitory receptors, NK cell diversity and function are closely linked. To provide an unprecedented understanding of NK cell repertoire diversity, we used mass cytometry to simultaneously analyze 35 parameters, including 28 NK cell receptors, on peripheral blood NK cells from five sets of monozygotic twins and twelve unrelated donors of defined HLA and killer cell immunoglobulin-like receptor (KIR) genotype. This analysis revealed a remarkable degree of NK cell diversity, with an estimated 6,000-30,000 phenotypic populations within an individual and >100,000 phenotypes in this population. Genetics largely determined inhibitory receptor expression, whereas activation receptor expression was heavily environmentally influenced. Therefore, NK cells may maintain self-tolerance through strictly regulated expression of inhibitory receptors, while using adaptable expression patterns of activating and costimulatory receptors to respond to pathogens and tumors. These findings further suggest the possibility that discrete NK cell subpopulations could be harnessed for immunotherapeutic strategies in the settings of infection, reproduction, and transplantation | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3J7Z67HEA | ||||||
| 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: | 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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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||||||
| SDY311: T cell responses to H1N1v and a longitudinal study of seasonal influenza vaccination (TIV) SLVP015 2010 (See companion studies SDY315 2012 / SDY312 2009 / SDY314 2008 / 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/M33MSDRJ55 | ||||||||||||||
| Subjects: | 76 | ||||||||||||||
| 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 | ||||||||||||
| SDY478: T cell responses to H1N1v and a longitudinal study of seasonal influenza vaccination SLVP015 2013 | |||||||||||
| 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/M3YEJTSS29 | ||||||||||
| Subjects: | 71 | ||||||||||
| 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 | ||||||||||
| SDY514: Monozygotic and Dizygotic Twin Pair T-Cell Responses to Influenza Vaccination SLVP018 2009 | |||||||||||
| 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/M3M6BADC48 | ||||||||||
| 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: | None | ||||||||||
| SDY515: Monozygotic and Dizygotic Twin Pair T-Cell Responses to Influenza Vaccination SLVP018 2010 | |||||||||||||
| 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/M3RDGZH60O | ||||||||||||
| 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 | ||||||||||||
| SDY519: Monozygotic and Dizygotic Twin Pair T-Cell Responses to Influenza Vaccination SLVP018 2011 | |||||||||||
| 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/M3TI6PGH9Q | ||||||||||
| 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: | None | ||||||||||
| SDY675: Heritable influence on the B and T cell receptor repertoire | |||||||
| Status: | Updated | ||||||
| Description: | The adaptive immune systems capability to protect the body requires a highly diverse lymphocyte antigen receptor repertoire. However, the influence of individual genetic and epigenetic differences on these repertoires is frequently underestimated. By leveraging the unique characteristics of B, CD4+ T, and CD8+ T lymphocyte subsets isolated from monozygotic twins, we have elucidated the impact of heritable factors on the V(D)J recombination process and have shown that the repertoires of both naive and antigen experienced cells are subject to biases resulting from initial recombination differences. Moreover, we show that the relative usage of V and J gene segments is chromosomally biased, with approximately 1.5 times as many rearrangements originating from a single chromosome. These data refine our understanding of the heritable mechanisms affecting the repertoire, and show that bias exists on a chromosome-wide level. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3XMYVQI9X | ||||||
| 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 | ||||||
| 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 | ||||||||
| SDY1464: T cell responses to H1N1v and a longitudinal study of seasonal influenza vaccination SLVP015 2014 | |||||||||||
| 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/M3AUKDIXFI | ||||||||||
| Subjects: | 101 | ||||||||||
| 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 | ||||||||||
| SDY1466: Monozygotic and Dizygotic Twin Pair T-Cell Responses to Influenza Vaccination SLVP018 2013 | |||||||||||
| 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/M33B64BQUE | ||||||||||
| Subjects: | 22 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Clinical Assessments: | None | ||||||||||
| SDY1467: B-cell Immunity to Influenza SLVP017 2009 | |||||||
| 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/M3BNBGK39S | ||||||
| Subjects: | 51 | ||||||
| Study PI, contact: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY1468: B-cell Immunity to Influenza (SLVP017) 2010 | |||||||||||
| 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/M30IB1ZZDJ | ||||||||||
| Subjects: | 71 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY1471: B-cell Immunity to Influenza (SLVP017) 2013 | |||||||||||
| 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/M3WEPI1HA3 | ||||||||||
| Subjects: | 10 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY2116: Inflammasome activation in infected macrophages drives COVID-19 pathology | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA, and sustained interferon (IFN) response all of which are recapitulated and required for pathology in the SARS-CoV-2 infected MISTRG6-hACE2 humanized mouse model of COVID-19 with a human immune system. Blocking either viral replication with Remdesivir or the downstream IFN stimulated cascade with anti-IFNAR2 in vivo in the chronic stages of disease attenuated the overactive immune-inflammatory response, especially inflammatory macrophages. Here, we show SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release IL-1 and IL-18 and undergo pyroptosis thereby contributing to the hyperinflammatory state of the lungs. Inflammasome activation and its accompanying inflammatory response is necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. Remarkably, this same blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Thus, inflammasomes oppose host infection by SARS-CoV-2 by production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3UICFULPO | ||||||||||||
| Subjects: | 0 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY2170: C57BL/6J Mice Are Not Suitable for Modeling Severe SARS-CoV-2 Beta and Gamma Variant Infection | |||||||
| Status: | Updated | ||||||
| Description: | SARS-CoV-2 variants, including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) variants, have displayed increased transmissibility and, therefore, have been categorized as variants of concern (VOCs). The pervasiveness of VOCs suggests a high probability of future mutations that may lead to increased virulence. Prior reports have shown that VOC infection without expression of human angiotensin converting enzyme-2 receptor (hACE2) in mice is possible. We sought to understand if the increased transmissibility of VOCs can infect C57BL/6 mice without expression of hACE2 receptor required for entry of SARS-CoV-2 normally. We examined the ability of infection with Beta and Gamma variants to infect and cause both pathological and clinical changes consistent with severe COVID-19, including body weight changes, survival, subgenomic viral titer, lung histology on Hematoxylin and Eosin (H&E) staining, and viral protein expression as measured by immunohistochemistry staining of viral antigen (IHC). These methods were used to examine three groups of mice: C57BL6, Rag2-/-, and Ccr2-/- mice. We observed that these mice, infected with Beta and Gamma variants of SARS-CoV-2, did not show pathological changes as indicated by weight loss, altered survival, or significant lung pathology on H&E staining. Subgenomic qPCR and IHC staining for viral protein indicated that there was some evidence of infection but far below ACE2 transgenic mice, which showed clinical disease and pathologic changes consistent with ARDS. These data suggest that these variants replicate poorly even in the setting of profound immune deficiency | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3URLEFSYD | ||||||
| Subjects: | 0 | ||||||
| Study PI, contact: |
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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. | |||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3JMMPMLSP | |||||||||||||
| Subjects: | 764 | |||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: | None | |||||||||||||
| Clinical Assessments: | None | |||||||||||||
| SDY2193: MoTrPAC 6-month rat endurance training | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | The MoTrPAC program is supported by the NIH Common Fund and is managed by a trans-agency working group representing multiple NIH institutes and centers, led by the NIH Office of Strategic Coordination, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, and National Institute of Biomedical Imaging and Bioengineering. | ||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3XZN09QFF | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
| Study PI, contact: |
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| Publications: | None | ||||||||||||||
| Resources: |
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| Assays: | None | ||||||||||||||
| Clinical Assessments: | None | ||||||||||||||
| SDY2250: Cas13d knockdown of lung protease Ctsl prevents and treats SARS-CoV-2 infection | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | SARS-CoV-2 entry into cells requires specific host proteases; however, no successful in vivo applications of host protease inhibitors have yet been reported for treatment of SARS-CoV-2 pathogenesis. Here we describe a chemically engineered nanosystem encapsulating CRISPR–Cas13d, developed to specifically target lung protease cathepsin L (Ctsl) messenger RNA to block SARS-CoV-2 infection in mice. We show that this nanosystem decreases lung Ctsl expression in normal mice efficiently, specifically and safely. We further show that this approach extends survival of mice lethally infected with SARS-CoV-2, correlating with decreased lung virus burden, reduced expression of proinflammatory cytokines/chemokines and diminished severity of pulmonary interstitial inflammation. Postinfection treatment by this nanosystem dramatically lowers the lung virus burden and alleviates virus-induced pathological changes. Our results indicate that targeting lung protease mRNA by Cas13d nanosystem represents a unique strategy for controlling SARS-CoV-2 infection and demonstrate that CRISPR can be used as a potential treatment for SARS-CoV-2 infection. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3SYJZ2G47 | ||||||||||||
| Subjects: | 0 | ||||||||||||
| Study PI, contact: |
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| Publications: |
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| Clinical Assessments: | None | ||||||||||||
| SDY2252: Reduced pathogenicity of the SARS-CoV-2 omicron variant in hamsters | ||||||||||
| Status: | Updated | |||||||||
| Description: | Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron (B.1.1.529) variant has proven to be highly transmissible and has outcompeted the Delta variant in many regions of the world. Early reports have also suggested that Omicron may result in less severe clinical disease in humans. Here, we show that Omicron is less pathogenic than prior SARS-CoV-2 variants in Syrian golden hamsters. Methods: Hamsters were inoculated with either SARS-CoV-2 Omicron or other SARS-CoV-2 variants. Animals were followed for weight loss, and upper and lower respiratory tract tissues were assessed for viral loads and histopathology. Findings: Infection of hamsters with the SARS-CoV-2 WA1/2020, Alpha, Beta, or Delta strains led to 4%-10% weight loss by day 4 and 10%-17% weight loss by day 6. In contrast, infection of hamsters with two different Omicron challenge stocks did not result in any detectable weight loss, even at high challenge doses. Omicron infection led to substantial viral replication in both the upper and lower respiratory tracts but demonstrated lower viral loads in lung parenchyma and reduced pulmonary pathology compared with WA1/2020 infection. Conclusions: These data suggest that the SARS-CoV-2 Omicron variant may result in robust upper respiratory tract infection, but less severe lower respiratory tract clinical disease, compared with prior SARS-CoV-2 variants. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3M5BTSAJ7 | |||||||||
| Subjects: | 0 | |||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | |||||||||
| SDY2255: Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses | |||||||||||||||||||||||
| Status: | Updated | ||||||||||||||||||||||
| Description: | Betacoronaviruses caused the outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome, as well as the current pandemic of SARS coronavirus 2 (SARS-CoV-2)1-4. Vaccines that elicit protective immunity against SARS-CoV-2 and betacoronaviruses that circulate in animals have the potential to prevent future pandemics. Here we show that the immunization of macaques with nanoparticles conjugated with the receptor-binding domain of SARS-CoV-2, and adjuvanted with 3M-052 and alum, elicits cross-neutralizing antibody responses against bat coronaviruses, SARS-CoV and SARS-CoV-2 (including the B.1.1.7, P.1 and B.1.351 variants). Vaccination of macaques with these nanoparticles resulted in a 50% inhibitory reciprocal serum dilution (ID50) neutralization titre of 47,216 (geometric mean) for SARS-CoV-2, as well as in protection against SARS-CoV-2 in the upper and lower respiratory tracts. Nucleoside-modified mRNAs that encode a stabilized transmembrane spike or monomeric receptor-binding domain also induced cross-neutralizing antibody responses against SARS-CoV and bat coronaviruses, albeit at lower titres than achieved with the nanoparticles. These results demonstrate that current mRNA-based vaccines may provide some protection from future outbreaks of zoonotic betacoronaviruses, and provide a multimeric protein platform for the further development of vaccines against multiple (or all) betacoronaviruses. | ||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3XFKMUMIV | ||||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||||||||||||
| SDY2257: COVID-19 vaccine mRNA-1273 elicits a protective immune profile in mice that is not associated with vaccine-enhanced disease upon SARS-CoV-2 challenge | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Vaccine-associated enhanced respiratory disease (VAERD) was previously observed in some preclinical models of severe acute respiratory syndrome (SARS) and MERS coronavirus vaccines. We used the SARS coronavirus 2 (SARS-CoV-2) mouse-adapted, passage 10, lethal challenge virus (MA10) mouse model of acute lung injury to evaluate the immune response and potential for immunopathology in animals vaccinated with research-grade mRNA-1273. Whole-inactivated virus or heat-denatured spike protein subunit vaccines with alum designed to elicit low-potency antibodies and Th2-skewed CD4+ T cells resulted in reduced viral titers and weight loss post challenge but more severe pathological changes in the lung compared to saline-immunized animals. In contrast, a protective dose of mRNA-1273 induced favorable humoral and cellular immune responses that protected from viral replication in the upper and lower respiratory tract upon challenge. A subprotective dose of mRNA-1273 reduced viral replication and limited histopathological manifestations compared to animals given saline. Overall, our findings demonstrate an immunological signature associated with antiviral protection without disease enhancement following vaccination with mRNA-1273. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3QM7OZTAC | ||||||||||||
| Subjects: | 0 | ||||||||||||
| Study PI, contact: |
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| Publications: |
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| Clinical Assessments: | None | ||||||||||||
| SDY2263: In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies | |||||||||||||||||||||||
| Status: | Updated | ||||||||||||||||||||||
| Description: | SARS-CoV-2-neutralizing antibodies (NAbs) protect against COVID-19. A concern regarding SARS-CoV-2 antibodies is whether they mediate disease enhancement. Here, we isolated NAbs against the receptor-binding domain (RBD) or the N-terminal domain (NTD) of SARS-CoV-2 spike from individuals with acute or convalescent SARS-CoV-2 or a history of SARS-CoV infection. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific modes of binding. Select RBD NAbs also demonstrated Fc receptor-γ (FcγR)-mediated enhancement of virus infection in vitro, while five non-neutralizing NTD antibodies mediated FcγR-independent in vitro infection enhancement. However, both types of infection-enhancing antibodies protected from SARS-CoV-2 replication in monkeys and mice. Three of 46 monkeys infused with enhancing antibodies had higher lung inflammation scores compared to controls. One monkey had alveolar edema and elevated bronchoalveolar lavage inflammatory cytokines. Thus, while in vitro antibody-enhanced infection does not necessarily herald enhanced infection in vivo, increased lung inflammation can rarely occur in SARS-CoV-2 antibody-infused macaques. | ||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M34KTYKX2D | ||||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||||||||||||
| SDY2321: Humoral profiling of pediatric patients with cancer reveals robust immunity following anti-SARS-CoV-2 vaccination superior to natural infection | |||||||
| Status: | Updated | ||||||
| Description: | Background: Pediatric patients with cancer infected with COVID-19 may be at higher risk of severe disease and may be unable to mount an adequate response to the virus due to compromised immunity secondary to their cancer therapy. Procedure: This study presents immunologic analyses of 20 pediatric patients with cancer, on active chemotherapy or having previously received chemotherapy, and measures their immunoglobulin titers and activation of cellular immunity response to acute SARS-CoV-2 infection and COVID-19 vaccination compared with healthy pediatric controls. Results: Forty-three patients were enrolled, of which 10 were actively receiving chemotherapy, 10 had previously received chemotherapy, and 23 were healthy controls. Pediatric patients with cancer had similar immunoglobulin titers, antibody binding capacity, and effector function assay activity after vaccination against COVID-19 compared with healthy controls, though more variability in response was noted in the cohort actively receiving chemotherapy. Compared with acute infection, vaccination against COVID-19 produced superior immunoglobulin responses, particularly IgA1, IgG1, and IgG3, and elicited superior binding capacity and effector function in children with cancer and healthy controls. Conclusions: Pediatric patients receiving chemotherapy and those who had previously received chemotherapy had adequate immune activation after both vaccination and acute infection compared to healthy pediatric controls, although there was a demonstrated variability in response for the patients on active chemotherapy. Vaccination against COVID-19 produced superior immune responses compared to acute SARS-CoV-2 infection in pediatric patients with cancer and healthy children, underscoring the importance of vaccination even in previously infected individuals. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M33P8B9NUW | ||||||
| Subjects: | 0 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2338: Mouse Adapted SARS-CoV-2 (MA10) Viral Infection Induces Neuroinflammation in Standard Laboratory Mice | ||||||||||
| Status: | Updated | |||||||||
| Description: | Increasing evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection impacts neurological function both acutely and chronically, even in the absence of pronounced respiratory distress. Developing clinically relevant laboratory mouse models of the neuropathogenesis of SARS-CoV-2 infection is an important step toward elucidating the underlying mechanisms of SARS-CoV-2-induced neurological dysfunction. Although various transgenic models and viral delivery methods have been used to study the infection potential of SARS-CoV-2 in mice, the use of commonly available laboratory mice would facilitate the study of SARS-CoV-2 neuropathology. Herein we show neuroinflammatory profiles of immunologically intact mice, C57BL/6J and BALB/c, as well as immunodeficient (Rag2−/−) mice, to a mouse-adapted strain of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 (MA10)). Our findings indicate that brain IL-6 levels are significantly higher in BALB/c male mice infected with SARS-CoV-2 MA10. Additionally, blood-brain barrier integrity, as measured by the vascular tight junction protein claudin-5, was reduced by SARS-CoV-2 MA10 infection in all three strains. Brain glial fibrillary acidic protein (GFAP) mRNA was also elevated in male C57BL/6J infected mice compared with the mock group. Lastly, immune-vascular effects of SARS-CoV-2 (MA10), as measured by H&E scores, demonstrate an increase in perivascular lymphocyte cuffing (PLC) at 30 days post-infection among infected female BALB/c mice with a significant increase in PLC over time only in SARS-CoV-2 MA10) infected mice. Our study is the first to demonstrate that SARS-CoV-2 (MA10) infection induces neuroinflammation in laboratory mice and could be used as a novel model to study SARS-CoV-2-mediated cerebrovascular pathology. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3MGIPQRJW | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2355: Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling | |||||||||||||||||
| Status: | Updated | ||||||||||||||||
| Description: | Mitochondrial DNA (mtDNA) escaping stressed mitochondria provokes inflammation via cGAS-STING pathway activation and, when oxidized (Ox-mtDNA), it binds cytosolic NLRP3, thereby triggering inflammasome activation. However, it is unknown how and in which form Ox-mtDNA exits stressed mitochondria in non-apoptotic macrophages. We found that diverse NLRP3 inflammasome activators rapidly stimulated uniporter-mediated calcium uptake to open mitochondrial permeability transition pores (mPTP) and trigger VDAC oligomerization. This occurred independently of mtDNA or reactive oxygen species, which induce Ox-mtDNA generation. Within mitochondria, Ox-mtDNA was either repaired by DNA glycosylase OGG1 or cleaved by the endonuclease FEN1 to 500-650 bp fragments that exited mitochondria via mPTP- and VDAC-dependent channels to initiate cytosolic NLRP3 inflammasome activation. Ox-mtDNA fragments also activated cGAS-STING signaling and gave rise to pro-inflammatory extracellular DNA. Understanding this process will advance the development of potential treatments for chronic inflammatory diseases, exemplified by FEN1 inhibitors that suppressed interleukin-1β (IL-1β) production and mtDNA release in mice. | ||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M35CKYIPBS | ||||||||||||||||
| Subjects: | 0 | ||||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||||||
| SDY2383: Methodological approaches to optimize multiplex oral fluid SARS-CoV-2 IgG assay performance and correlation with serologic and neutralizing antibody responses | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Background: Oral fluid (hereafter, saliva) is a non-invasive and attractive alternative to blood for SARS-CoV-2 IgG testing; however, the heterogeneity of saliva as a matrix poses challenges for immunoassay performance. Objectives: To optimize performance of a magnetic microparticle-based multiplex immunoassay (MIA) for SARS-CoV-2 IgG measurement in saliva, with consideration of: i) threshold setting and validation across different MIA bead batches; ii) sample qualification based on salivary total IgG concentration; iii) calibration to U.S. SARS-CoV-2 serological standard binding antibody units (BAU); and iv) correlations with blood-based SARS-CoV-2 serological and neutralizing antibody (nAb) assays. Methods: The salivary SARS-CoV-2 IgG MIA included 2 nucleocapsid (N), 3 receptor-binding domain (RBD), and 2 spike protein (S) antigens. Gingival crevicular fluid (GCF) swab saliva samples were collected before December 2019 (n = 555) and after molecular test-confirmed SARS-CoV-2 infection from 113 individuals (providing up to 5 repeated-measures; n = 398) and used to optimize and validate MIA performance (total n = 953). Combinations of IgG responses to N, RBD and S and total salivary IgG concentration (μg/mL) as a qualifier of nonreactive samples were optimized and validated, calibrated to the U.S. SARS-CoV-2 serological standard, and correlated with blood-based SARS-CoV-2 IgG ELISA and nAb assays. Results: The sum of signal to cutoff (S/Co) to all seven MIA SARS-CoV-2 antigens and disqualification of nonreactive saliva samples with ≤15 μg/mL total IgG led to correct classification of 62/62 positives (sensitivity [Se] = 100.0%; 95% confidence interval [CI] = 94.8%, 100.0%) and 108/109 negatives (specificity [Sp] = 99.1%; 95% CI = 97.3%, 100.0%) at 8-million beads coupling scale and 80/81 positives (Se = 98.8%; 95% CI = 93.3%, 100.0%] and 127/127 negatives (Sp = 100%; 95% CI = 97.1%, 100.0%) at 20-million beads coupling scale. Salivary SARS-CoV-2 IgG crossed the MIA cutoff of 0.1 BAU/mL on average 9 days post-COVID-19 symptom onset and peaked around day 30. Among n = 30 matched saliva and plasma samples, salivary SARS-CoV-2 MIA IgG levels correlated with corresponding-antigen plasma ELISA IgG (N: ρ = 0.76, RBD: ρ = 0.83, S: ρ = 0.82; all p < 0.001). Correlations of plasma SARS-CoV-2 nAb assay area under the curve (AUC) with salivary MIA IgG (N: ρ = 0.68, RBD: ρ = 0.78, S: ρ = 0.79; all p < 0.001) and with plasma ELISA IgG (N: ρ = 0.76, RBD: ρ = 0.79, S: ρ = 0.76; p < 0.001) were similar. Conclusions: A salivary SARS-CoV-2 IgG MIA produced consistently high Se (> 98.8%) and Sp (> 99.1%) across two bead coupling scales and correlations with nAb responses that were similar to blood-based SARS-CoV-2 IgG ELISA data. This non-invasive salivary SARS-CoV-2 IgG MIA could increase engagement of vulnerable populations and improve broad understanding of humoral immunity (kinetics and gaps) within the evolving context of booster vaccination, viral variants and waning immunity. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M369ETTADW | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2387: Progression and Resolution of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Golden Syrian Hamsters | |||||||||||
| Status: | Updated | ||||||||||
| Description: | To catalyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research, including development of novel interventive and preventive strategies, the progression of disease was characterized in a robust coronavirus disease 2019 (COVID-19) animal model. In this model, male and female golden Syrian hamsters were inoculated intranasally with SARS-CoV-2 USA-WA1/2020. Groups of inoculated and mock-inoculated uninfected control animals were euthanized at 2, 4, 7, 14, and 28 days after inoculation to track multiple clinical, pathology, virology, and immunology outcomes. SARS-CoV-2-inoculated animals consistently lost body weight during the first week of infection, had higher lung weights at terminal time points, and developed lung consolidation per histopathology and quantitative image analysis measurements. High levels of infectious virus and viral RNA were reliably present in the respiratory tract at days 2 and 4 after inoculation, corresponding with widespread necrosis and inflammation. At day 7, when the presence of infectious virus was rare, interstitial and alveolar macrophage infiltrates and marked reparative epithelial responses (type II hyperplasia) dominated in the lung. These lesions resolved over time, with only residual epithelial repair evident by day 28 after inoculation. The use of quantitative approaches to measure cellular and morphologic alterations in the lung provides valuable outcome measures for developing therapeutic and preventive interventions for COVID-19 using the hamster COVID-19 model. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3P39UDC8C | ||||||||||
| Subjects: | 0 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2389: Exposure of progressive immune dysfunction by SARS-CoV-2 mRNA vaccination in patients with chronic lymphocytic leukemia: A prospective cohort study | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Patients with chronic lymphocytic leukemia (CLL) have reduced seroconversion rates and lower binding antibody (Ab) and neutralizing antibody (NAb) titers than healthy individuals following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccination. Here, we dissected vaccine-mediated humoral and cellular responses to understand the mechanisms underlying CLL-induced immune dysfunction. We performed a prospective observational study in SARS-CoV-2 infection-naïve CLL patients (n = 95) and healthy controls (n = 30) who were vaccinated between December 2020 and June 2021. Sixty-one CLL patients and 27 healthy controls received 2 doses of the Pfizer-BioNTech BNT162b2 vaccine, while 34 CLL patients and 3 healthy controls received 2 doses of the Moderna mRNA-1273 vaccine. The median time to analysis was 38 days (IQR, 27 to 83) for CLL patients and 36 days (IQR, 28 to 57) for healthy controls. Testing plasma samples for SARS-CoV-2 anti-spike and receptor-binding domain Abs by enzyme-linked immunosorbent assay (ELISA), we found that all healthy controls seroconverted to both antigens, while CLL patients had lower response rates (68% and 54%) as well as lower median titers (23-fold and 30-fold; both p < 0.001). Similarly, NAb responses against the then prevalent D614G and Delta SARS-CoV-2 variants were detected in 97% and 93% of controls, respectively, but in only 42% and 38% of CLL patients, who also exhibited >23-fold and >17-fold lower median NAb titers (both p < 0.001). Interestingly, 26% of CLL patients failed to develop NAbs but had high-titer binding Abs that preferentially reacted with the S2 subunit of the SARS-CoV-2 spike. Since these patients were also seropositive for endemic human coronaviruses (HCoVs), these responses likely reflect cross-reactive HCoV Abs rather than vaccine-induced de novo responses. CLL disease status, advanced Rai stage (III-IV), elevated serum beta-2 microglobulin levels (β2m >2.4 mg/L), prior therapy, anti-CD20 immunotherapy (<12 months), and intravenous immunoglobulin (IVIg) prophylaxis were all predictive of an inability to mount SARS-CoV-2 NAbs (all p ≤ 0.03). T cell response rates determined for a subset of participants were 2.8-fold lower for CLL patients compared to healthy controls (0.05, 95% CI 0.01 to 0.27, p < 0.001), with reduced intracellular IFNγ staining (p = 0.03) and effector polyfunctionality (p < 0.001) observed in CD4+ but not in CD8+ T cells. Surprisingly, in treatment-naïve CLL patients, BNT162b2 vaccination was identified as an independent negative risk factor for NAb generation (5.8, 95% CI 1.6 to 27, p = 0.006). CLL patients who received mRNA-1273 had 12-fold higher (p < 0.001) NAb titers and 1.7-fold higher (6.5, 95% CI 1.3 to 32, p = 0.02) response rates than BNT162b2 vaccinees despite similar disease characteristics. The absence of detectable NAbs in CLL patients was associated with reduced naïve CD4+ T cells (p = 0.03) and increased CD8+ effector memory T cells (p = 0.006). Limitations of the study were that not all participants were subjected to the same immune analyses and that pre-vaccination samples were not available. CLL pathogenesis is characterized by a progressive loss of adaptive immune functions, including in most treatment-naïve patients, with preexisting memory being preserved longer than the capacity to mount responses to new antigens. In addition, higher NAb titers and response rates identify mRNA-1273 as a superior vaccine for CLL patients. | ||||||||||
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| DOI: | 10.21430/M3PV8VPKP0 | ||||||||||
| Subjects: | 0 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2402: Nucleocapsid-specific antibody function is associated with therapeutic benefits from COVID-19 convalescent plasma therapy | ||||||||||
| Status: | Updated | |||||||||
| Description: | Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP), a passive polyclonal antibody therapeutic agent, has had mixed clinical results. Although antibody neutralization is the predominant approach to benchmarking CCP efficacy, CCP may also influence the evolution of the endogenous antibody response. Using systems serology to comprehensively profile severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) functional antibodies of hospitalized people with COVID-19 enrolled in a randomized controlled trial of CCP (ClinicalTrials.gov: NCT04397757), we find that the clinical benefits of CCP are associated with a shift toward reduced inflammatory Spike (S) responses and enhanced nucleocapsid (N) humoral responses. We find that CCP has the greatest clinical benefit in participants with low pre-existing anti-SARS-CoV-2 antibody function and that CCP-induced immunomodulatory Fc glycan profiles and N immunodominant profiles persist for at least 2 months. We highlight a potential mechanism of action of CCP associated with durable immunomodulation, outline optimal patient characteristics for CCP treatment, and provide guidance for development of a different class of COVID-19 hyperinflammation-targeting antibody therapeutic agents. | |||||||||
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| DOI: | 10.21430/M3W35WN8AN | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2406: Maternal SARS-CoV-2 infection elicits sexually dimorphic placental immune responses | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | There is a persistent bias toward higher prevalence and increased severity of coronavirus disease 2019 (COVID-19) in males. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of COVID-19 disease in adults and play a key role in the placental antiviral response. Moreover, the interferon response has been shown to alter Fc receptor expression and therefore may affect placental antibody transfer. Here, we examined the intersection of maternal-fetal antibody transfer, viral-induced placental interferon responses, and fetal sex in pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Placental Fc receptor abundance, interferon-stimulated gene (ISG) expression, and SARS-CoV-2 antibody transfer were interrogated in 68 human pregnancies. Sexually dimorphic expression of placental Fc receptors, ISGs and proteins, and interleukin-10 was observed after maternal SARS-CoV-2 infection, with up-regulation of these features in placental tissue of pregnant individuals with male fetuses. Reduced maternal SARS-CoV-2–specific antibody titers and impaired placental antibody transfer were also observed in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2. | ||||||||||||
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| DOI: | 10.21430/M3T7A0KV72 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2407: Infant rhesus macaques immunized against SARS-CoV-2 are protected against heterologous virus challenge 1 year later | |||||||||||||||||
| Status: | Updated | ||||||||||||||||
| Description: | The U.S. Food and Drug Administration only gave emergency use authorization of the BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines for infants 6 months and older in June 2022. Yet questions regarding the durability of vaccine efficacy, especially against emerging variants, in this age group remain. We demonstrated previously that a two-dose regimen of stabilized prefusion Washington SARS-CoV-2 S-2P spike (S) protein encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or purified S-2P mixed with 3M-052, a synthetic Toll-like receptor (TLR) 7/8 agonist, in a squalene emulsion (Protein+3M-052-SE) was safe and immunogenic in infant rhesus macaques. Here, we demonstrate that broadly neutralizing and spike-binding antibodies against variants of concern (VOCs), as well as T cell responses, persisted for 12 months. At 1 year, corresponding to human toddler age, we challenged vaccinated rhesus macaques and age-matched nonvaccinated controls intranasally and intratracheally with a high dose of heterologous SARS-CoV-2 B.1.617.2 (Delta). Seven of eight control rhesus macaques exhibited severe interstitial pneumonia and high virus replication in the upper and lower respiratory tract. In contrast, vaccinated rhesus macaques had faster viral clearance with mild to no pneumonia. Neutralizing and binding antibody responses to the B.1.617.2 variant at the day of challenge correlated with lung pathology and reduced virus replication. Overall, the Protein+3M-052-SE vaccine provided superior protection to the mRNA-LNP vaccine, emphasizing opportunities for optimization of current vaccine platforms. The observed efficacy of both vaccines 1 year after vaccination supports the implementation of an early-life SARS-CoV-2 vaccine. | ||||||||||||||||
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| DOI: | 10.21430/M346BQS8LQ | ||||||||||||||||
| Subjects: | 0 | ||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||
| SDY2411: SARS-CoV-2 infection produces chronic pulmonary epithelial and immune cell dysfunction with fibrosis in mice | |||||||||||
| Status: | Updated | ||||||||||
| Description: | A subset of individuals who recover from coronavirus disease 2019 (COVID-19) develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal tissue samples. The mouse-adapted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days post-virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC. | ||||||||||
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| DOI: | 10.21430/M3YGG0HFGE | ||||||||||
| Subjects: | 0 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2432: Ad26 vaccine protects against SARS-CoV-2 severe clinical disease in hamsters | |||||||||||||||||
| Status: | Updated | ||||||||||||||||
| Description: | Coronavirus disease 2019 (COVID-19) in humans is often a clinically mild illness, but some individuals develop severe pneumonia, respiratory failure and death1-4. Studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hamsters5-7 and nonhuman primates8-10 have generally reported mild clinical disease, and preclinical SARS-CoV-2 vaccine studies have demonstrated reduction of viral replication in the upper and lower respiratory tracts in nonhuman primates11-13. Here we show that high-dose intranasal SARS-CoV-2 infection in hamsters results in severe clinical disease, including high levels of virus replication in tissues, extensive pneumonia, weight loss and mortality in a subset of animals. A single immunization with an adenovirus serotype 26 vector-based vaccine expressing a stabilized SARS-CoV-2 spike protein elicited binding and neutralizing antibody responses and protected against SARS-CoV-2-induced weight loss, pneumonia and mortality. These data demonstrate vaccine protection against SARS-CoV-2 clinical disease. This model should prove useful for preclinical studies of SARS-CoV-2 vaccines, therapeutics and pathogenesis. | ||||||||||||||||
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| DOI: | 10.21430/M3P4ALD7A6 | ||||||||||||||||
| Subjects: | 0 | ||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||
| SDY2453: B cell-specific XIST complex enforces X-inactivation and restrains atypical B cells | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | The long non-coding RNA (lncRNA) XIST establishes X chromosome inactivation (XCI) in female cells in early development and thereafter is thought to be largely dispensable. Here, we show XIST is continually required in adult human B cells to silence a subset of X-linked immune genes such as TLR7. XIST-dependent genes lack promoter DNA methylation and require continual XIST-dependent histone deacetylation. XIST RNA-directed proteomics and CRISPRi screen reveal distinctive somatic cell-type-specific XIST complexes and identify TRIM28 that mediates Pol II pausing at promoters of X-linked genes in B cells. Single-cell transcriptome data of female patients with either systemic lupus erythematosus or COVID-19 infection revealed XIST dysregulation, reflected by escape of XIST-dependent genes, in CD11c+ atypical memory B cells (ABCs). XIST inactivation with TLR7 agonism suffices to promote isotype-switched ABCs. These results indicate cell-type-specific diversification and function for lncRNA-protein complexes and suggest expanded roles for XIST in sex-differences in biology and medicine. | ||||||||||||||
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| DOI: | 10.21430/M3WU4T0N60 | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
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