DR49.2 DataRelease
Release Date: October 2023
New Studies: 19
Updated Studies: 26
New Studies
| SDY1393: Toll-like Receptors in Older Adults and Response to Vaccination - Year2 | |||||||||||||
| Status: | New | ||||||||||||
| Description: | We will identify how age and frailty affect gene expression signatures of vaccine response. | ||||||||||||
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| DOI: | 10.21430/M3TW6SIAIL | ||||||||||||
| Subjects: | 65 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2282: JAX CCHI-Modulation of Lung Responses to Viral Infection- ALI SARS-CoV2 | ||||||||||
| Status: | New | |||||||||
| Description: | Epithelial barriers lie at the interface between host and environment, where they sense invading pathogen. Dendritic cells (DCs) present pathogen-derived antigens to T and B cells to induce immune responses. However, the impact of the human lung tissue environment on DC and other cells, such as the newly identified innate lymphoid cell (ILC) family, as well as bacteria-reactive MAIT cells, is not completely understood. An understudied environmental factor is the lung microbiome. The JAX CCHI seeks to address these critical questions using a multi-disciplinary experimental approach that will integrate immunology with epithelial cell biology along with genomic, cellular, functional and microbiome parameters identified in human lung tissues. Our overarching hypothesis is that the quality and magnitude of mucosal T cell responses to respiratory viral infections are determined by the cross- talk between microbiota, epithelial cells and leukocytes. To address this hypothesis, we structured the JAX CCHI around two integrated research projects focused on basic immunological mechanisms of lung antiviral immunity; a technology development project that will create sophisticated cellular models leveraging 3D bioprinting, gene editing tools and microbiome-immune assays to support project objectives; a sample core for storage and distribution of human tissues; and a microbiome core for specialized microbiome profiling, cultivation, and computational analysis. Our Center will bring together clinicians with experts in lung immunology, the microbiome, bioengineering, genomics and computational biology to achieve our goals and maximize the potential of this research. The goals of this CCHI are to: 1) Understand how the networks of epithelial cells and immune cells in the human lung regulate innate and adaptive immunity to respiratory viruses; 2) Define how inflammation driven by the microbiome dictates the steady state of tissue, i.e., immune set-point; 3) Determine if and how this immune set-point is altered in two pulmonary diseases, childhood asthma and adult lung cancer, which have a major impact on public health; and 4) Develop innovative technologies to model human lung-immune dynamics and elucidate molecular mechanisms, cell types and pathways key to lung antiviral responses. Impact: Through studies focused on the sensors, inducers and modulators of antiviral immunity in the human lung, our CCHI will contribute insights that could help improve outcomes for infectious and other immune diseases that originate in or secondarily impact the lung. | |||||||||
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| DOI: | 10.21430/M32KGRDM51 | |||||||||
| Subjects: | 8 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2306: 35th Multicenter Airway Research Collaboration (MARC-35): EWAS analysis of infants | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | In a multicenter prospective cohort study of infants (age <1 year) hospitalized with bronchiolitis, we profiled their epigenome-wide blood DNA methylation level from blood samples collected during hospitalization to examine the relationship with bronchiolitis severity. Extracted DNA was used to perform DNA methylation profiling using the Illumina Infinium MethylationEPIC BeadChip (Illumina, San Diego, CA). We investigated differentially methylated CpGs (DMCs) for the risk of treatment with positive pressure ventilation (PPV) during the bronchiolitis hospitalization. We identified that blood DNA methylation signatures were associated with bronchiolitis severity and played important roles in tissues, cells, and pathways. | ||||||||||||||||||
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| DOI: | 10.21430/M3265DVD4I | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Assays: | None | ||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||
| SDY2339: Nplate PK/PD Study with or without Neulasta in Rhesus Macaque | |||||||
| Status: | New | ||||||
| Description: | Vehicle, Nplate, and/or Neulasta was administered by subcutaneous injection to Co-60 irradiated animals (target LD30/45). Animals received either a single dose of Nplate at 2.5 mg/kg or 5 mg/kg, two doses of Nplate at 5 mg/kg 7 days apart, a single dose of Neulasta at 0.3 mg/kg 7 days apart, a single dose of Nplate at 5 mg/kg and two doses of Neulasta at 0.3 mg/kg 7 days apart, or vehicle. Administration of Nplate, Neulasta and/or vehicle began 24 hours ? 2 hours post irradiation. Hematology was compared among the groups and to vehicle control. Secondary endpoints, such as survival and clinical signs, were included. Pharmacokinetics of Nplate in the various Nplate-treated groups was studies. The vehicle control group contained 5 males and 5 females. All other groups contained 4 males and 4 females. Note: Day 1 is 24 hours after the day of irradiation, which is designated in the data files as Day -1. There is no Day 0. | ||||||
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| DOI: | 10.21430/M3Z6JX4CZ3 | ||||||
| Subjects: | 50 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2365: Interactions between Siglec-8 and endogenous sialylated cis ligands restrain cell death induction in human eosinophils and mast cells | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is a sialoside-binding receptor expressed on the surface of eosinophils and mast cells that bears an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an ITIM-like motif in its cytoplasmic domain. On eosinophils that have been primed with IL-5, GM-CSF, or IL-33, antibody ligation of Siglec-8 leads to cell death through a pathway involving the ?2 integrin-dependent generation of reactive oxygen species (ROS) via NADPH oxidase. In contrast, engagement of Siglec-8 on mast cells has been described to inhibit mast cell activation and mediator release but not impact cell viability. The differences in responses between cytokine-primed and unprimed eosinophils, and between eosinophils and mast cells, to Siglec-8 ligation are not understood. In addition, we have previously found that Siglec-8 binds to sialylated ligands on the surface of the same cell (so-called cis ligands) on eosinophils, preventing interaction with a Siglec-8 ligand in trans. However, these cis ligands have not been characterized and their functional relevance has not been elucidated. We therefore explored the potential influence of cis ligands of Siglec-8 on the surfaces of both eosinophils and mast cells. Sialidase from V. cholerae was used to cleave cell-surface sialic acid from human peripheral blood eosinophils and skin-derived mast cells. The lectins MAL-II and SNA were used to assess cell-surface levels of ?2,3- and ?2,6-linked sialic acid by flow cytometry, and, following an 18-24-hour incubation with anti-Siglec-8 mAb, cell viability was determined by annexin V and DAPI staining. Removal of sialic acid using exogenous sialidase had profound effects on the consequences of Siglec-8 antibody engagement on both cell types, eliminating the need for cytokine priming of eosinophils to facilitate cell death and enabling Siglec-8-dependent mast cell death without impacting anti-Siglec-8 antibody binding. This effect was dose dependent and blocked by inhibition of the enzymatic activity of the exogenous sialidase. The cell death process licensed by incubation with sialidase resembled that characterized in IL-5-primed eosinophils, including the upregulation of CD11b, production of ROS, and requirement for the signaling activities of Syk, PI3K, and PLC. However, priming of eosinophils with IL-5 did not alter overall levels of sialic acid on the cell surface, suggesting that cytokine priming may disrupt these interactions specifically without global alterations of cell-surface sialylation and/or making the sialoside inaccessible to Siglec-8 while not impacting its detection by the MAL-II lectin. These results implicate cis ligands in restraining Siglec-8 function on eosinophils and mast cells and reveal a promising approach to the selective depletion of mast cells in patients with mast cell-mediated diseases. | |||||||||||||||
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| DOI: | 10.21430/M3TOG3LL8H | |||||||||||||||
| Subjects: | 2 | |||||||||||||||
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| Publications: | None | |||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||
| SDY2369: Immune repertoire sequencing of Coeliac patients | ||||||||||
| Status: | New | |||||||||
| Description: | Study subjects with CeD undergoing upper GI endoscopy were identified via the Oxford University Hospitals NHS Foundation Trust (OUHFT) coeliac disease service (Oxford, United Kingdom). Control subjects were identified through the OUHFT endoscopy service, these were all patients with symptoms of gastrointestinal disorders who were not diagnosed with CeD. Intestinal biopsies were taken at endoscopy under the study Oxford Gastrointestinal Illnesses Biobank (REC Ref: 16/YH/0247). Duodenal biopsies were collected at endoscopy and transported in R10 (RPMI-1640 [Lonza] with 10% FCS [Sigma- Aldrich] plus 1% penicillin/streptomycin [Sigma-Aldrich]). Lymphocytes were isolated from intestinal mucosal biopsies as previously described in (20). Briefly, duodenal samples were incubated in R10 with 1 mg/ml Collagenase D (Roche) and 100 mg/ml DNase (Thermo Fisher Scientific) for 1 hour at 37oC while agitated in a shaking incubator. Biopsies were then dissociated using a GentleMACS Dissociator (Miltenyi Biotec), and strained through a 70 ?m filter. Cells were washed twice with R10 media. For surface marker staining, cells were stained in FACS buffer (PBS + 1 mM EDTA + 0.05% BSA) for 20-30 minutes at 4oC. Antibodies were purchased from BioLegend, BD Biosciences, Miltenyi Biotec, or Thermo Fisher Scientific. After staining, cells were stored at 4oC protected from light until data acquisition. For fluorescence-activated cell sorting (FACS), samples were surface stained, with DAPI (Thermo Fisher Scientific) used as viability dye. FACS was performed on an AriaIII (BD Biosciences; 70 ?m nozzle). Intestinal CD4+ T cells (CD3+, ??+, ??-, CD4+, CD8-, live lymphocytes) were sorted. Sort purity was assessed for each sort, and was >98% in all cases. Sorted cells were collected in PBS with 2% BSA before Trizol nucleic acid extraction. A Trizol RNA extraction was used for low numbers of lymphocytes, as previously described (21,22), except that 1.5ml Eppendorf tubes replaced phase-lock gel tubes. Briefly, after sorting, cells were centrifuged (500 g, 5 minutes), resuspended in 1 ml Trizol, then frozen at -80oC. For RNA extraction, samples were brought to room temperature, mixed with 200 ?l chloroform and centrifuged at 12500 rpm for 5 minutes. 500 ?l of the aqueous phase was taken and RNA extracted using the Agencourt RNAdvance Tissue Isolation kit. RNA concentration and purity was assessed using a 2100 Bioanalyzer instrument (Agilent Technologies). Bulk TCR repertoire sequencing was performed using the amplicon-rescued multiplex (ARM)-PCR method (iRepertoire, Inc., USA). This method performs an initial first-round RT-PCR with TCR V and C gene-specific primers for the relevant TCR chain, followed by further amplification steps with universal primers for the exponential phase of amplification. This method is designed to provide quantitative, deep sequencing of the TCR repertoire, with minimal bias. Library generation was performed in-house following manufacturer?s instructions, except for performing the library generation in 96-well plates. The quality, size distribution, concentration, and presence of contaminating primer dimers was assessed using gel electrophoresis, spectral photometry (Nanodrop, Thermofisher Scientific), and a 2100 Bioanalyzer (Agilent Technologies). Libraries were quantified using the KAPA Library Quantification Kit (Roche) before equimolar pooling. A PhiX library 10% spike-in was added, before 300bp paired-end sequencing on an Illumina MiSeq instrument at the Oxford Genomics Centre (WTCHG, University of Oxford). | |||||||||
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| DOI: | 10.21430/M3IXIPWF5G | |||||||||
| Subjects: | 20 | |||||||||
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| Publications: | None | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2398: Mucosal antibody responses to SARS-CoV-2 booster vaccination and breakthrough infection | ||||||||||
| Status: | New | |||||||||
| Description: | Here, the investigators analyzed samples from the PARIS (Protection Associated with Rapid Immunity to SARS-CoV-2) study and measured serum IgG, saliva IgG and saliva secretory IgA responses in individuals who experienced breakthrough infections and who received COVID-19 mRNA booster vaccinations. | |||||||||
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| DOI: | 10.21430/M3JDI4T17W | |||||||||
| Subjects: | 111 | |||||||||
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| Publications: | None | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2399: Preconception Genetic Carrier Screening for Miscarriage Risk Assessment: A Bioinformatic Approach to Identifying Candidate Lethal Genes and Variants | |||||||
| Status: | New | ||||||
| Description: | Purpose: Miscarriage, due to genetically heterogeneous etiology, is a common outcome of pregnancy. Preconception genetic carrier screening (PGCS) currently identifies at-risk partners for newborn genetic disorders; however, miscarriage-related genes are currently not part of the PGCS panels. Here we assessed the theoretical impact of known and candidate genes on prenatal lethality and the PGCS among diverse populations. Methods: We used a bioinformatic approach to define genes essential for human fetal survival (lethal genes), identify variants that are absent in a homozygous state in healthy human population, and to estimate heterozygous carrier rates for known recessive lethal Mendelian conditions and candidate lethal genes. Results: A total of 3080 known and candidate lethal genes were identified. Allele carrier frequencies were evaluated for 20398 pathogenic/likely pathogenic and loss-of-function (LoF) variants in 468 known human lethal genes, and 62815 LoF variants in 2612 candidate genes. In 163 genes, potential lethal variants are present in the general population with high frequency of at least 0.1%. Conclusion: This study identified a set of genes and variants potentially associated with lethality across different ethnic backgrounds. The diversity of these genes amongst the various ethnic groups underscores the importance of designing a pan-ethnic PGCS panel comprising miscarriage-related genes. Keywords: population carrier screening, lethal genes, intolerome, pregnancy loss, miscarriage. | ||||||
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| DOI: | 10.21430/M32PG4UUJV | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2400: Effects of Inhibiting Early Inflammation in Kidney Transplant Patients (CTOT-19) | |||||||
| Status: | New | ||||||
| Description: | The objective of the study is to determine the efficacy of intravenous infliximab administered at the time of transplantation, prior to reperfusion, on 2-year kidney transplant survival and function. This is a phase II, multicenter, randomized, double blind, and placebo-controlled, 2-arm study of 300 deceased donor kidney transplant recipients randomized 1:1 to the experimental and control arms (150 patients per arm). Subjects in the control arm will be treated with rATG plus placebo (sterile normal saline) induction followed by tacrolimus, a mycophenolic acid derivative (either MMF or enteric coated MPA), and corticosteroids. Subjects in the experimental arm will receive infliximab plus rATG induction followed by tacrolimus, a mycophenolic acid derivative (either MMF or enteric coated MPA), and corticosteroids. | ||||||
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| DOI: | 10.21430/M315VHMRPS | ||||||
| Subjects: | 289 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2401: Decay of coronavirus disease 2019 mRNA vaccine-induced immunity in people with HIV | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | Current coronavirus disease 2019 (COVID-19) mRNA vaccines induce robust SARS-CoV-2-specific humoral and cellular responses in people with HIV (PWH). However, the rate of decay of effector immune responses has not been studied in these individuals. Here, we report a significant waning of antibody responses but persistent T-cell responses 6 months post vaccination in virally suppressed PWH with high CD4+ T-cell counts. These responses are comparable with those seen in healthy donors. | |||||||||||||||
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| DOI: | 10.21430/M31X313HWS | |||||||||||||||
| 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: | New | |||||||||
| 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 | |||||||||
| SDY2403: mRNA-1273 and BNT162b2 mRNA vaccines have reduced neutralizing activity against the SARS-CoV-2 omicron variant | ||||||||||
| Status: | New | |||||||||
| Description: | The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant emerged in November 2021 and consists of several mutations within the spike. We use serum from mRNA-vaccinated individuals to measure neutralization activity against omicron in a live-virus assay. At 2-4 weeks after a primary series of vaccinations, we observe a 30-fold reduction in neutralizing activity against omicron. Six months after the initial two-vaccine doses, sera from naive vaccinated subjects show no neutralizing activity against omicron. In contrast, COVID-19-recovered individuals 6 months after receiving the primary series of vaccinations show a 22-fold reduction, with the majority of the subjects retaining neutralizing antibody responses. In naive individuals following a booster shot (third dose), we observe a 14-fold reduction in neutralizing activity against omicron, and over 90% of subjects show neutralizing activity. These findings show that a third dose is required to provide robust neutralizing antibody responses against the omicron variant. | |||||||||
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| DOI: | 10.21430/M3X6EM3TV0 | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2404: Durability of immune responses to the BNT162b2 mRNA vaccine | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | The development of two highly efficacious mRNA vaccines in less than a year since the emergence of SARS-CoV-2 represents a landmark in vaccinology. However, reports of waning vaccine efficacy1 coupled with the emergence of variants of concern that are resistant to antibody neutralization have raised concerns about the potential lack of durability of immunity to vaccination. Studies examining the durability of immune responses to mRNA12732 or BNT162b23 point to a significant decay of serum-neutralizing antibody titers, while a stable pool of memory B cells are established.4 We recently reported findings from a comprehensive analysis of innate and adaptive immune responses in 56 healthy volunteers who received two doses of the BNT162b2 vaccination.5 Here, we analyzed antibody responses to the homologous Wu strain as well as several variants of concern?Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2)? and the Mu (B.1.621) variant of interest in a subset of these volunteers at 6 months (day 210 post-primary vaccination) after the second dose. | |||||||||||||||
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| DOI: | 10.21430/M36XN11O1Y | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
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| SDY2405: Rapid decline in vaccine-boosted neutralizing antibodies against SARS-CoV-2 Omicron variant | ||||||||||
| Status: | New | |||||||||
| Description: | The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibits reduced susceptibility to vaccine-induced neutralizing antibodies, requiring a boost to generate protective immunity. We assess the magnitude and short-term durability of neutralizing antibodies after homologous and heterologous boosting with mRNA and Ad26.COV2.S vaccines. All prime-boost combinations substantially increase the neutralization titers to Omicron, although the boosted titers decline rapidly within 2 months from the peak response compared with boosted titers against the prototypic D614G variant. Boosted Omicron neutralization titers are substantially higher for homologous mRNA vaccine boosting, and for heterologous mRNA and Ad26.COV2.S vaccine boosting, compared with homologous Ad26.COV2.S boosting. Homologous mRNA vaccine boosting generates nearly equivalent neutralizing activity against Omicron sublineages BA.1, BA.2, and BA.3 but modestly reduced neutralizing activity against BA.2.12.1 and BA.4/BA.5 compared with BA.1. These results have implications for boosting requirements to protect against Omicron and future variants of SARS-CoV-2. This trial was conducted under ClincalTrials.gov: NCT04889209. | |||||||||
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| DOI: | 10.21430/M322SV4PV1 | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2406: Maternal SARS-CoV-2 infection elicits sexually dimorphic placental immune responses | |||||||||||||
| Status: | New | ||||||||||||
| 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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| SDY2407: Infant rhesus macaques immunized against SARS-CoV-2 are protected against heterologous virus challenge 1 year later | |||||||||||||||||
| Status: | New | ||||||||||||||||
| 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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| SDY2408: Discovery and intranasal administration of a SARS-CoV-2 broadly acting neutralizing antibody with activity against multiple Omicron subvariants | |||||||||||||||||
| Status: | New | ||||||||||||||||
| Description: | Background: The continual emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern, in particular the newly emerged Omicron (B.1.1.529) variant and its BA.X lineages, has rendered ineffective a number of previously FDA emergency use authorized SARS-CoV-2 neutralizing antibody therapies. Furthermore, those approved antibodies with neutralizing activity against Omicron BA.1 are reportedly ineffective against the subset of Omicron subvariants that contain a R346K substitution, BA.1.1, and the more recently emergent BA.2, demonstrating the continued need for discovery and characterization of candidate therapeutic antibodies with the breadth and potency of neutralizing activity required to treat newly diagnosed COVID-19 linked to recently emerged variants of concern. Methods: Following a campaign of antibody discovery based on the vaccination of Harbor H2L2 mice with defined SARS-CoV-2 spike domains, we have characterized the activity of a large collection of spike-binding antibodies and identified a lead neutralizing human IgG1 LALA antibody, STI-9167. Findings: STI-9167 has potent, broad-spectrum neutralizing activity against the current SARS-COV-2 variants of concern and retained activity against each of the tested Omicron subvariants in both pseudotype and live virus neutralization assays. Furthermore, STI-9167 nAb administered intranasally or intravenously provided protection against weight loss and reduced virus lung titers to levels below the limit of quantitation in Omicron-infected K18-hACE2 transgenic mice. Conclusions: With this established activity profile, a cGMP cell line has been developed and used to produce cGMP drug product intended for intravenous or intranasal use in human clinical trials. Funding: Funded by CRIPT (no. 75N93021R00014), DARPA (HR0011-19-2-0020), and NCI Seronet (U54CA260560). | ||||||||||||||||
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| DOI: | 10.21430/M3MX4R10P8 | ||||||||||||||||
| Subjects: | 0 | ||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||
| SDY2409: Antigen-adjuvant interactions, stability, and immunogenicity profiles of a SARS-CoV-2 receptor-binding domain (RBD) antigen formulated with aluminum salt and CpG adjuvants | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Low-cost, refrigerator-stable COVID-19 vaccines will facilitate global access and improve vaccine coverage in low- and middle-income countries. To this end, subunit-based approaches targeting the receptor-binding domain (RBD) of SARS-CoV-2 Spike protein remain attractive. Antibodies against RBD neutralize SARS-CoV-2 by blocking viral attachment to the host cell receptor, ACE2. Here, a yeast-produced recombinant RBD antigen (RBD-L452K-F490W or RBD-J) was formulated with various combinations of aluminum-salt (Alhydrogel?, AH; AdjuPhos?, AP) and CpG 1018 adjuvants. We assessed the effect of antigen-adjuvant interactions on the stability and mouse immunogenicity of various RBD-J preparations. While RBD-J was 50% adsorbed to AH and <15% to AP, addition of CpG resulted in complete AH binding, yet no improvement in AP adsorption. ACE2 competition ELISA analyses of formulated RBD-J stored at varying temperatures (4, 25, 37?C) revealed that RBD-J was destabilized by AH, an effect exacerbated by CpG. DSC studies demonstrated that aluminum-salt and CpG adjuvants decrease the conformational stability of RBD-J and suggest a direct CpG-RBD-J interaction. Although AH+CpG-adjuvanted RBD-J was the least stable in vitro, the formulation was most potent at eliciting SARS-CoV-2 pseudovirus neutralizing antibodies in mice. In contrast, RBD-J formulated with AP+CpG showed minimal antigen-adjuvant interactions, a better stability profile, but suboptimal immune responses. Interestingly, the loss of in vivo potency associated with heat-stressed RBD-J formulated with AH+CpG after one dose was abrogated by a booster. Our findings highlight the importance of elucidating the key interrelationships between antigen-adjuvant interactions, storage stability, and in vivo performance to enable successful formulation development of stable and efficacious subunit vaccines. | ||||||||||||
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| DOI: | 10.21430/M3YEZOFRTU | ||||||||||||
| 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: | New | |||||||||
| 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 | |||||||||
Updated Studies
| SDY1809: Efficacy of clinical evaluations for COVID-19 on the front line | ||||||||||
| Status: | Updated | |||||||||
| Description: | We conducted a retrospective review of patients assessed for possible COVID-19 illness at our urban medical center in Los Angeles, California. We carefully reviewed all clinical records to ascertain the provider's level of clinical suspicion for COVID-19 illness and compared these assessments with available results of SARS-CoV-2 testing, in addition to longitudinal data on clinical outcomes. We found that the vast majority of patients (96% of N = 25) clinically assessed to have a low probability of COVID-19 illness were subsequently confirmed to have either a negative SARS-CoV-2 test result or, in the absence of testing, clinical stability without any further concern for COVID-19 illness. All clinical assessments were performed by a physician, with some (16%) conducted by a nurse practitioner or physician assistant in conjunction with physician supervision. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M39YVOOYSV | |||||||||
| Subjects: | 0 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY1849: Estimating SARS-CoV-2 seroprevalence and epidemiological parameters with uncertainty from serological surveys | ||||||||||
| Status: | Updated | |||||||||
| Description: | Establishing how many people have been infected by SARS-CoV-2 remains an urgent priority for controlling the COVID-19 pandemic. Serological tests that identify past infection can be used to estimate cumulative incidence, but the relative accuracy and robustness of various sampling strategies have been unclear. We developed a flexible framework that integrates uncertainty from test characteristics, sample size, and heterogeneity in seroprevalence across subpopulations to compare estimates from sampling schemes. Using the same framework and making the assumption that seropositivity indicates immune protection, we propagated estimates and uncertainty through dynamical models to assess uncertainty in the epidemiological parameters needed to evaluate public health interventions and found that sampling schemes informed by demographics and contact networks outperform uniform sampling. The framework can be adapted to optimize serosurvey design given test characteristics and capacity, population demography, sampling strategy, and modeling approach, and can be tailored to support decision-making around introducing or removing interventions. | |||||||||
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| DOI: | 10.21430/M3M73PFN8O | |||||||||
| Subjects: | 0 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY1850: Model-informed COVID-19 vaccine prioritization strategies by age and serostatus | ||||||||||
| Status: | Updated | |||||||||
| Description: | Limited initial supply of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine raises the question of how to prioritize available doses. We used a mathematical model to compare five age-stratified prioritization strategies. A highly effective transmission-blocking vaccine prioritized to adults ages 20 to 49 years minimized cumulative incidence, but mortality and years of life lost were minimized in most scenarios when the vaccine was prioritized to adults greater than 60 years old. Use of individual-level serological tests to redirect doses to seronegative individuals improved the marginal impact of each dose while potentially reducing existing inequities in COVID-19 impact. Although maximum impact prioritization strategies were broadly consistent across countries, transmission rates, vaccination rollout speeds, and estimates of naturally acquired immunity, this framework can be used to compare impacts of prioritization strategies across contexts. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3NEXZIAC5 | |||||||||
| Subjects: | 0 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY1851: Interpreting vaccine efficacy trial results for infection and transmission | ||||||||||
| Status: | Updated | |||||||||
| Description: | Randomized controlled trials (RCTs) have shown high efficacy of multiple vaccines against SARS-CoV-2 disease (COVID-19), and recent studies have shown the vaccines are also effective against infection. Evidence for the effect of each of these vaccines on ability to transmit the virus is also beginning to emerge. We describe an approach to estimate these vaccines' effects on viral positivity, a prevalence measure which under the reasonable assumption that vaccinated individuals who become infected are no more infectious than unvaccinated individuals forms a lower bound on efficacy against transmission. Specifically, we recommend separate analysis of positive tests triggered by symptoms (usually the primary RCT outcome) and cross-sectional prevalence of positive tests obtained regardless of symptoms. The odds ratio of carriage for vaccine vs. placebo provides an unbiased estimate of vaccine effectiveness against viral positivity, under certain assumptions, and we show through simulations that likely departures from these assumptions will only modestly bias this estimate. Applying this approach to published data from the RCT of the Moderna vaccine, we estimate that one dose of vaccine reduces the potential for transmission by at least 61%, possibly considerably more. We describe how these approaches can be translated into observational studies of vaccine effectiveness. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3S4GR1BIO | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY1852: Modeling the impact of racial and ethnic disparities on COVID-19 epidemic dynamics | |||||||
| Status: | Updated | ||||||
| Description: | Background: The impact of variable infection risk by race and ethnicity on the dynamics of SARS-CoV-2 spread is largely unknown. Methods: Here, we fit structured compartmental models to seroprevalence data from New York State and analyze how herd immunity thresholds (HITs), final sizes, and epidemic risk change across groups. Results: A simple model where interactions occur proportionally to contact rates reduced the HIT, but more realistic models of preferential mixing within groups increased the threshold toward the value observed in homogeneous populations. Across all models, the burden of infection fell disproportionately on minority populations: in a model fit to Long Island serosurvey and census data, 81% of Hispanics or Latinos were infected when the HIT was reached compared to 34% of non-Hispanic whites. Conclusions: Our findings, which are meant to be illustrative and not best estimates, demonstrate how racial and ethnic disparities can impact epidemic trajectories and result in unequal distributions of SARS-CoV-2 infection. Funding: K.C.M. was supported by National Science Foundation GRFP grant DGE1745303. Y.H.G. and M.L. were funded by the Morris-Singer Foundation. M.L. was supported by SeroNet cooperative agreement U01 CA261277 | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M33DAWUEID | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1944: Flow cytometer data for investigation into an integrated microfluidic system for basophil isolation from whole blood | ||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||
| Description: | Purity and recovery of basophils isolated from 100 uL of whole blood are measured for the integrated system and subcomponents of the system; artificial activation of basophils by the integrated system is quantified, and basophils are shown to be functional in downstream activation experiments. | |||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3K94PIVEY | |||||||||||||||||||||
| Subjects: | 8 | |||||||||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||||||||
| SDY1969: Mathematical Modeling to Inform Vaccination Strategies and Testing Approaches for Coronavirus Disease 2019 (COVID-19) in Nursing Homes | ||||||||||
| Status: | Updated | |||||||||
| Description: | Background: Nursing home residents and staff were included in the first phase of coronavirus disease 2019 vaccination in the United States. Because the primary trial endpoint was vaccine efficacy (VE) against symptomatic disease, there are limited data on the extent to which vaccines protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the ability to infect others (infectiousness). Assumptions about VE against infection and infectiousness have implications for changes to infection prevention guidance for vaccinated populations, including testing strategies.Methods: We use a stochastic agent-based Susceptible-Exposed-Infectious (Asymptomatic/Symptomatic)-Recovered model of a nursing home to simulate SARS-CoV-2 transmission. We model 3 scenarios, varying VE against infection, infectiousness, and symptoms, to understand the expected impact of vaccination in nursing homes, increasing staff vaccination coverage, and different screening testing strategies under each scenario.Results: Increasing vaccination coverage in staff decreases total symptomatic cases in the nursing home (among staff and residents combined) in each VE scenario. In scenarios with 50% and 90% VE against infection and infectiousness, increasing staff coverage reduces symptomatic cases among residents. If vaccination only protects against symptoms, and asymptomatic cases remain infectious, increased staff coverage increases symptomatic cases among residents. However, this is outweighed by the reduction in symptomatic cases among staff. Higher frequency testing-more than once weekly-is needed to reduce total symptomatic cases if the vaccine has lower efficacy against infection and infectiousness, or only protects against symptoms.Conclusions: Encouraging staff vaccination is not only important for protecting staff, but might also reduce symptomatic cases in residents if a vaccine confers at least some protection against infection or infectiousness. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M31WZ81NLC | |||||||||
| Subjects: | 0 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY1972: Population impact of SARS-CoV-2 variants with enhanced transmissibility and/or partial immune escape | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | SARS-CoV-2 variants of concern exhibit varying degrees of transmissibility and, in some cases, escape from acquired immunity. Much effort has been devoted to measuring these phenotypes, but understanding their impact on the course of the pandemic-especially that of immune escape-has remained a challenge. Here, we use a mathematical model to simulate the dynamics of wild-type and variant strains of SARS-CoV-2 in the context of vaccine rollout and nonpharmaceutical interventions. We show that variants with enhanced transmissibility frequently increase epidemic severity, whereas those with partial immune escape either fail to spread widely or primarily cause reinfections and breakthrough infections. However, when these phenotypes are combined, a variant can continue spreading even as immunity builds up in the population, limiting the impact of vaccination and exacerbating the epidemic. These findings help explain the trajectories of past and present SARS-CoV-2 variants and may inform variant assessment and response in the future. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3EWP60HPZ | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Assays: | None | ||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY2026: SARS-CoV-2 transmission and impacts of unvaccinated-only screening in populations of mixed vaccination status | ||||||||||
| Status: | Updated | |||||||||
| Description: | Screening programs that test only the unvaccinated population have been proposed and implemented to mitigate SARS-CoV-2 spread, implicitly assuming that the unvaccinated population drives transmission. To evaluate this premise and quantify the impact of unvaccinated-only screening programs, we introduce a model for SARS-CoV-2 transmission through which we explore a range of transmission rates, vaccine effectiveness scenarios, rates of prior infection, and screening programs. We find that, as vaccination rates increase, the proportion of transmission driven by the unvaccinated population decreases, such that most community spread is driven by vaccine-breakthrough infections once vaccine coverage exceeds 55% (omicron) or 80% (delta), points which shift lower as vaccine effectiveness wanes. Thus, we show that as vaccination rates increase, the transmission reductions associated with unvaccinated-only screening decline, identifying three distinct categories of impact on infections and hospitalizations. More broadly, these results demonstrate that effective unvaccinated-only screening depends on population immunity, vaccination rates, and variant. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3T90LW0CA | |||||||||
| Subjects: | 0 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2033: Vaccine protection against the SARS-CoV-2 Omicron variant in macaques | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | The rapid spread of the SARS-CoV-2 Omicron (B.1.1.529) variant, including in highly vaccinated populations, has raised important questions about the efficacy of current vaccines. In this study, we show that the mRNA-based BNT162b2 vaccine and the adenovirus-vector-based Ad26.COV2.S vaccine provide robust protection against high-dose challenge with the SARS-CoV-2 Omicron variant in cynomolgus macaques. We vaccinated 30 macaques with homologous and heterologous prime-boost regimens with BNT162b2 and Ad26.COV2.S. Following Omicron challenge, vaccinated macaques demonstrated rapid control of virus in bronchoalveolar lavage, and most vaccinated animals also controlled virus in nasal swabs. However, 4 vaccinated animals that had moderate Omicron-neutralizing antibody titers and undetectable Omicron CD8+ T cell responses failed to control virus in the upper respiratory tract. Moreover, virologic control correlated with both antibody and T cell responses. These data suggest that both humoral and cellular immune responses contribute to vaccine protection against a highly mutated SARS-CoV-2 variant. | ||||||||||||||
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| DOI: | 10.21430/M36QZ9VXR6 | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
| SDY2125: Production of the Receptor-binding Domain of the Viral Spike Proteins from 2003 and 2019 SARS CoVs and the Four Common Human Coronaviruses for Serologic Assays and Inhibitor Screening | ||||||||||
| Status: | Updated | |||||||||
| Description: | The recombinant receptor-binding domain (RBD) of the viral spike protein from SARS-CoV-1 and 2 are reliable antigens for detecting viral-specific antibodies in humans. We and others have shown that the levels of RBD-binding antibodies and SARS-CoV-2 neutralizing antibodies in patients are correlated. Here, we report the expression and purification of properly folded RBD proteins from SARS and common-cold HCoVs in mammalian cells. RBD proteins were produced with cleavable tags for affinity purification from the cell culture medium and to support multiple immunoassay platforms and drug discovery efforts. Graphic abstract: High-Yield Production of Viral Spike RBDs for Diagnostics and Drug Discovery | |||||||||
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| DOI: | 10.21430/M3310R6FVA | |||||||||
| Subjects: | 0 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2166: mRNA vaccines induce rapid antibody responses in mice | |||||||||
| Status: | Updated | ||||||||
| Description: | mRNA vaccines can be developed and produced quickly, making them prime candidates for immediate outbreak responses. Furthermore, clinical trials have demonstrated rapid protection following mRNA vaccination. Thus, we sought to investigate how quickly mRNA vaccines elicit antibody responses compared to other vaccine modalities. We first compared the immune kinetics of mRNA and DNA vaccines expressing SARS-CoV-2 spike in mice. We observed rapid induction of antigen-specific binding and neutralizing antibodies by day 5 following mRNA (4??g/mouse), but not DNA (50??g/mouse), immunization. Comparing innate responses hours post immunization, the mRNA vaccine induced increased levels of IL-5, IL-6, and MCP-1 cytokines which maybe promoting humoral responses downstream. We then evaluated the immune kinetics of an HIV-1 mRNA vaccine in comparison to DNA, protein, and rhesus adenovirus 52 (RhAd52) vaccines of the same HIV-1 envelope antigen in mice. Again, induction of envelope-specific antibodies was observed by day 5 following mRNA vaccination, whereas antibodies were detected by day 7?14 following DNA, protein, and RhAd52 vaccination. Thus, eliciting rapid humoral immunity may be a unique and advantageous property of mRNA vaccines for controlling infectious disease outbreaks. | ||||||||
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| DOI: | 10.21430/M3BG3TEVVT | ||||||||
| Subjects: | 0 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY2175: Modeling in higher dimensions to improve diagnostic testing accuracy: theory and examples for multiplex saliva-based SARS-CoV-2 antibody assays | |||||||
| Status: | Updated | ||||||
| Description: | The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has emphasized the importance and challenges of correctly interpreting antibody test results. Identification of positive and negative samples requires a classification strategy with low error rates, which is hard to achieve when the corresponding measurement values overlap. Additional uncertainty arises when classification schemes fail to account for complicated structure in data. We address these problems through a mathematical framework that combines high dimensional data modeling and optimal decision theory. Specifically, we show that appropriately increasing the dimension of data better separates positive and negative populations and reveals nuanced structure that can be described in terms of mathematical models. We combine these models with optimal decision theory to yield a classification scheme that better separates positive and negative samples relative to traditional methods such as confidence intervals (CIs) and receiver operating characteristics. We validate the usefulness of this approach in the context of a multiplex salivary SARS-CoV-2 immunoglobulin G assay dataset. This example illustrates how our analysis: (i) improves the assay accuracy (e.g. lowers classification errors by up to 42 % compared to CI methods); (ii) reduces the number of indeterminate samples when an inconclusive class is permissible (e.g. by 40 % compared to the original analysis of the example multiplex dataset); and (iii) decreases the number of antigens needed to classify samples. Our work showcases the power of mathematical modeling in diagnostic classification and highlights a method that can be adopted broadly in public health and clinical settings. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M39EFSK7EI | ||||||
| Subjects: | 0 | ||||||
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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. | ||||||||||||||
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| DOI: | 10.21430/M3XZN09QFF | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
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| Publications: | None | ||||||||||||||
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| Assays: | None | ||||||||||||||
| Clinical Assessments: | None | ||||||||||||||
| SDY2227: The COVID-19 vaccine concerns scale: Development and validation of a new measure | |||||||||||||||||||||||||
| Status: | Updated | ||||||||||||||||||||||||
| Description: | Reasons for COVID-19 hesitancy are multi-faceted and tend to differ from those for general vaccine hesitancy. We developed the COVID-19 Vaccine Concerns Scale (CVCS), a self-report measure intended to better understand individuals' concerns about COVID-19 vaccines. We validated the scale using data from a convenience sample of 2,281 emergency medical services providers, a group of professionals with high occupational COVID-19 risk. Measures included the CVCS items, an adapted Oxford COVID-19 vaccine hesitancy scale, a general vaccine hesitancy scale, demographics, and self-reported COVID-19 vaccination status. The CVCS had high internal consistency reliability (? = .89). A one-factor structure was determined by exploratory and confirmatory factor analyses (EFA and CFA), resulting in a seven-item scale. The model had good fit (X2[14] = 189.26, p < .001; CFI = .95, RMSEA = .11 [.09, .12], NNFI = .93, SRMR = .03). Moderate Pearson correlations with validated scales of general vaccine hesitancy (r = .71 , p < .001; n = 2144) and COVID-19 vaccine hesitancy (r = .82; p < .001; n = 2279) indicated construct validity. The CVCS predicted COVID-19 vaccination status (B = -2.21, Exp(B) = .11 [95% CI = .09, .13], Nagelkerke R2 = .55), indicating criterion-related validity. In sum, the 7-item CVCS is a reliable and valid self-report measure to examine fears and concerns about COVID-19 vaccines. The scale predicts COVID-19 vaccination status and can be used to inform efforts to reduce COVID-19 vaccine hesitancy | ||||||||||||||||||||||||
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| DOI: | 10.21430/M3XUZ51AF8 | ||||||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||||||
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| Assays: | None | ||||||||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||||||||
| SDY2228: COVID-19 Vaccinations in EMS Professionals: Prevalence and Predictors | |||||||||||||||||||||||||
| Status: | Updated | ||||||||||||||||||||||||
| Description: | Background: Immunizations for emergency medical services (EMS) professionals during pandemics are an important tool to increase the safety of the workforce as well as their patients. The purpose of this study was to better understand EMS professionals' decisions to receive or decline a COVID-19 vaccine.Methods: We conducted a cross-sectional analysis of nationally certified EMS professionals (18-85 years) in April 2021. Participants received an electronic survey asking whether they received a vaccine, why or why not, and their associated beliefs using three validated scales: perceived risk of COVID-19, medical mistrust, and confidence in the COVID-19 vaccine. Data were merged with National Registry dataset demographics. Analyses included descriptive analysis and multivariable logistic regression (OR, 95% CI). Multivariate imputation by chained equations was used for missingness.Results: A total of 2,584 respondents satisfied inclusion criteria (response rate = 14%). Overall, 70% of EMS professionals were vaccinated. Common reasons for vaccination among vaccinated respondents were to protect oneself (76%) and others (73%). Common reasons for non-vaccination among non-vaccinated respondents included concerns about vaccine safety (53%) and beliefs that vaccination was not necessary (39%). Most who had not received the vaccine did not plan to get it in the future (84%). Hesitation was most frequently related to wanting to see how the vaccine was working for others (55%). Odds of COVID-19 vaccination were associated with demographics including age (referent <28 years; 39-50 years: 1.56, 1.17-2.08; >51 years: 2.22, 1.64-3.01), male sex (1.26, 1.01-1.58), residing in an urban/suburban area (referent rural; 1.36, 1.08-1.70), advanced education (referent GED/high school and below; bachelor's and above: 1.72, 1.19-2.47), and working at a hospital (referent fire-based agency; 1.53, 1.04-2.24). Additionally, vaccination odds were significantly higher with greater perceived risk of COVID-19 (2.05, 1.68-2.50), and higher vaccine confidence (2.84, 2.40-3.36). Odds of vaccination were significantly lower with higher medical mistrust (0.54, 0.46-0.63).Conclusion: Despite vaccine availability, not all EMS professionals had been vaccinated. The decision to receive a COVID-19 vaccine was associated with demographics, beliefs regarding COVID-19 and the vaccine, and medical mistrust. Efforts to increase COVID-19 vaccination rates should emphasize the safety and efficacy of vaccines. | ||||||||||||||||||||||||
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| DOI: | 10.21430/M397IY0TSF | ||||||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||||||
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| SDY2229: An Opportunity to Understand Concerns about COVID-19 Vaccination: Perspectives from EMS Professionals | ||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||
| Description: | Some healthcare professionals, including emergency medical service (EMS) professionals, remain hesitant about receiving COVID-19 vaccines. This study sought to understand EMS professionals' perspectives regarding COVID-19 vaccination. Using open-ended comments from a national survey deployed electronically to over 19,000 EMS professionals in April of 2021, we examined perspectives about acceptance of and hesitancy toward COVID-19 vaccines. Survey comments revealed differences in perspectives between vaccinated and unvaccinated EMS professionals regarding their personal role in improving public health through COVID-19 vaccination as well as vaccine benefits and the protection conferred by vaccination. Unvaccinated individuals also expressed concerns over the research and development of the COVID-19 vaccines that led to their decision not to get vaccinated. Individuals who were vaccinated suggested ways to increase uptake of the vaccine including having healthcare professionals serve as leaders for vaccination and educating individuals about COVID-19 vaccination through credible resources. Vaccine hesitancy remains a challenge to achieving herd immunity to COVID-19 through vaccination, even among healthcare professionals. Understanding the perspectives of those who have chosen not to be vaccinated can help direct strategies to reduce confusion and concerns. The perspectives of vaccinated individuals may also be valuable in identifying opportunities to promote vaccination in the professional setting. | |||||||||||||||||||||||||||
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| DOI: | 10.21430/M3154E9F43 | |||||||||||||||||||||||||||
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| SDY2230: Closing the Gap on COVID-19 Vaccinations in First Responders and Beyond: Increasing Trust | |||||||||||||||||||||||||||||||
| Status: | Updated | ||||||||||||||||||||||||||||||
| Description: | Although COVID-19 vaccines are widely available in the U.S. and much of the world, many have chosen to forgo this vaccination. Emergency medical services (EMS) professionals, despite their role on the frontlines and interactions with COVID-positive patients, are not immune to vaccine hesitancy. Via a survey conducted in April 2021, we investigated the extent to which first responders in the U.S. trusted various information sources to provide reliable information about COVID-19 vaccines. Those vaccinated generally trusted healthcare providers as a source of information, but unvaccinated first responders had fairly low trust in this information source-a group to which they, themselves, belong. Additionally, regardless of vaccination status, trust in all levels of government, employers, and their community as sources of information was low. Free-response explanations provided some context to these findings, such as preference for other COVID-19 management options, including drugs proven ineffective. A trusted source of COVID-19 vaccination information is not readily apparent. Individuals expressed a strong desire for the autonomy to make vaccination decisions for themselves, as opposed to mandates. Potential reasons for low trust, possible solutions to address them, generalizability to the broader public, and implications of low trust in official institutions are discussed. | ||||||||||||||||||||||||||||||
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| DOI: | 10.21430/M3AGU15EQU | ||||||||||||||||||||||||||||||
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| Assays: | None | ||||||||||||||||||||||||||||||
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| SDY2234: Optimizing prevalence estimates for a novel pathogen by reducing uncertainty in test characteristics | |||||||
| Status: | Updated | ||||||
| Description: | Emergence of a novel pathogen drives the urgent need for diagnostic tests that can aid in defining disease prevalence. The limitations associated with rapid development and deployment of these tests result in a dilemma: In efforts to optimize prevalence estimates, would tests be better used in the lab to reduce uncertainty in test characteristics or to increase sample size in field studies? Here, we provide a framework to address this question through a joint Bayesian model that simultaneously analyzes lab validation and field survey data, and we define the impact of test allocation on inferences of sensitivity, specificity, and prevalence. In many scenarios, prevalence estimates can be most improved by apportioning additional effort towards validation rather than to the field. The joint model provides superior estimation of prevalence, sensitivity, and specificity, compared with typical analyses that model lab and field data separately, and it can be used to inform sample allocation when testing is limited. | ||||||
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| DOI: | 10.21430/M3O5E1Q8JY | ||||||
| Subjects: | 0 | ||||||
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| SDY2236: SARS-CoV-2 Serosurveys: How antigen, isotype and threshold choices affect the outcome | ||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||
| Description: | Background: Evaluating the performance of SARS-CoV-2 serological assays and clearly articulating the utility of selected antigen, isotypes and thresholds is crucial to understanding the prevalence of infection within selected communities. Methods: This cross-sectional study, implemented in 2020, screened PCR-confirmed COVID-19 patients (n = 86), banked pre-pandemic and negative donors (n = 96), health care workers and family members (n = 552), and university employees (n = 327) for anti-SARS-CoV-2 receptor-binding domain (RBD), trimeric spike protein (S), and nucleocapsid protein (N) IgG and IgA antibodies with a laboratory developed Enzyme-Linked Immunosorbent Assay (ELISA) and tested how antigen, isotype and threshold choices affected the seroprevalence. The following threshold methods were evaluated: (i) mean + 3 standard deviations of the negative controls; (ii) 100% specificity for each antigen/isotype combination; and (iii) the maximal Youden index. Results: We found vastly different seroprevalence estimates depending on selected antigens, isotypes and the applied threshold method, ranging from 0.0% to 85.4% . Subsequently, we maximized specificity and reported a seroprevalence, based on more than one antigen, ranging from 9.3% to 25.9%. Conclusions: This study revealed the importance of evaluating serosurvey tools for antigen, isotype, and threshold-specific sensitivity and specificity, in order to interpret qualitative serosurvey outcomes reliably and consistently across studies. | |||||||||||||||||||||||||||
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| DOI: | 10.21430/M38M5AU5PJ | |||||||||||||||||||||||||||
| Subjects: | 0 | |||||||||||||||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||||||||||||||
| SDY2315: Seasonal COVID-19 surge related hospital volumes and case fatality rates | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Background: Seasonal and regional surges in COVID-19 have imposed substantial strain on healthcare systems. Whereas sharp inclines in hospital volume were accompanied by overt increases in case fatality rates during the very early phases of the pandemic, the relative impact during later phases of the pandemic are less clear. We sought to characterize how the 2020 winter surge in COVID-19 volumes impacted case fatality in an adequately-resourced health system. Methods: We performed a retrospective cohort study of all adult diagnosed with COVID-19 in a large academic healthcare system between August 25, 2020 to May 8, 2021, using multivariable logistic regression to examine case fatality rates across 3 sequential time periods around the 2020 winter surge: pre-surge, surge, and post-surge. Subgroup analyses of patients admitted to the hospital and those receiving ICU-level care were also performed. Additionally, we used multivariable logistic regression to examine risk factors for mortality during the surge period. Results: We studied 7388 patients (aged 52.8 ? 19.6 years, 48% male) who received outpatient or inpatient care for COVID-19 during the study period. Patients treated during surge (N = 6372) compared to the pre-surge (N = 536) period had 2.64 greater odds (95% CI 1.46-5.27) of mortality after adjusting for sociodemographic and clinical factors. Adjusted mortality risk returned to pre-surge levels during the post-surge period. Notably, first-encounter patient-level measures of illness severity appeared higher during surge compared to non-surge periods. Conclusions: We observed excess mortality risk during a recent winter COVID-19 surge that was not explained by conventional risk factors or easily measurable variables, although recovered rapidly in the setting of targeted facility resources. These findings point to how complex interrelations of population- and patient-level pandemic factors can profoundly augment health system strain and drive dynamic, if short-lived, changes in outcomes. | ||||||||||||
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| DOI: | 10.21430/M3JSHP7C23 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2334: Case-Control Study of Individuals with Discrepant Nucleocapsid and Spike Protein SARS-CoV-2 IgG Results | ||||||||||
| Status: | Updated | |||||||||
| Description: | Laboratory-based methods for SARS- CoV-2 antibody detection vary widely in performance. However, there are limited prospectively-collected data on assay performance, and minimal clinical information to guide interpretation of discrepant results. Over a 2-week period, 1080 consecutive plasma samples submitted for clinical SARS-CoV-2 IgG testing were tested in parallel for anti-nucleocap- sid IgG (anti-N, Abbott) and anti-spike IgG (anti-S1, EUROIMMUN). Chart review was conducted for samples testing positive or borderline on either assay, and for an age/sex-matched cohort of samples negative by both assays. CDC surveillance case definitions were used to determine clinical sensitivity/specificity and conduct receiver operating characteristics curve analysis. There were 52 samples positive by both meth- ods, 2 positive for anti-N only, 34 positive for anti-S1 only, and 27 borderline for anti-S1. Of the 34 individu- als positive for anti-S1 alone, 8 (24%) had confirmed COVID-19. No anti-S1 borderline cases were positive for anti-N or had confirmed/probable COVID-19. The anti-N assay was less sensitive (84.2% [95% CI 72.1- 92.5%] vs 94.7% [95% CI 85.4-98.9%]) but more spe- cific (99.2% [95% CI 95.5-100%] vs 86.9% [95% CI 79.6-92.3%]) than anti-S1. Abbott anti-N sensitivity could be improved to 96.5% with minimal effect on specificity if the index threshold was lowered from 1.4 to 0.6. Real-world concordance between differ- ent serologic assays may be lower than previously described in retrospective studies. These findings have implications for the interpretation of SARS-CoV-2 IgG results, especially with the advent of spike antigen- targeted vaccination, as a subset of patients with true infection are anti-N negative and anti-S1 positive. | |||||||||
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| DOI: | 10.21430/M3DS84ZIC4 | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2378: Characterization of immune responses in fully vaccinated individuals after breakthrough infection with the SARS-CoV-2 delta variant | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have been reported frequently in vaccinated individuals with waning immunity. In particular, a cluster of over 1000 infections with the SARS-CoV-2 delta variant was identified in a predominantly fully vaccinated population in Provincetown, Massachusetts in July 2021. In this study, vaccinated individuals who tested positive for SARS-CoV-2 (n = 16) demonstrated substantially higher serum antibody responses than vaccinated individuals who tested negative for SARS-CoV-2 (n = 23), including 32-fold higher binding antibody titers and 31-fold higher neutralizing antibody titers against the SARS-CoV-2 delta variant. Vaccinated individuals who tested positive also showed higher mucosal antibody responses in nasal secretions and higher spike protein-specific CD8+ T cell responses in peripheral blood than did vaccinated individuals who tested negative. These data demonstrate that fully vaccinated individuals developed robust anamnestic antibody and T cell responses after infection with the SARS-CoV-2 delta variant. Moreover, these findings suggest that population immunity will likely increase over time by a combination of widespread vaccination and breakthrough infections. | ||||||||||||
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| DOI: | 10.21430/M3EK86TJV6 | ||||||||||||
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| SDY2381: Right Ventricular Abnormality in Patients Hospitalized With COVID-19 Infection During Omicron Variant Surge. | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | We aimed at studying the association of in-hospital mortality with echocardiographic measures of RV performance during the COVID-19 infection surge in New York City attributed to the spread of the Omicron variant. | ||||||||||||
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| DOI: | 10.21430/M3YP5OULP0 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| 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 (?g/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 ?g/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: ? = 0.76, RBD: ? = 0.83, S: ? = 0.82; all p < 0.001). Correlations of plasma SARS-CoV-2 nAb assay area under the curve (AUC) with salivary MIA IgG (N: ? = 0.68, RBD: ? = 0.78, S: ? = 0.79; all p < 0.001) and with plasma ELISA IgG (N: ? = 0.76, RBD: ? = 0.79, S: ? = 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. | ||||||||||||
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| DOI: | 10.21430/M369ETTADW | ||||||||||||
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| SDY2390: Conflict in the EMS Workforce: An Analysis of an Open-Ended Survey Question Reveals a Complex Assemblage of Stress, Burnout, and Pandemic-Related Factors Influencing Well-Being | ||||||||||
| Status: | Updated | |||||||||
| Description: | Emergency Medical Services (EMS) clinicians provide patient care within a high-stakes, unpredictable, and complex work environment in which conflict is inevitable. Our objective was to explore the extent to which added stressors of the pandemic exacerbated EMS workplace conflict. We administered our survey to a sample of U.S. nationally certified EMS clinicians during the COVID-19 pandemic in April 2022. Out of 1881 respondents, 46% (n = 857) experienced conflict and 79% (n = 674) provided free-text descriptions of their experience. The responses were analyzed for themes using qualitative content analysis, and they were then sorted into codes using word unit sets. Code counts, frequencies, and rankings were tabulated, enabling quantitative comparisons of the codes. Of the fifteen codes to emerge, stress (a precursor of burnout) and burnout-related fatigue were the key factors contributing to EMS workplace conflict. We mapped our codes to a conceptual model guided by the National Academies of Sciences, Engineering, and Medicine (NASEM) report on using a systems approach to address clinician burnout and professional well-being to explore implications for addressing conflict within that framework. Factors attributed to conflict mapped to all levels of the NASEM model, lending empirical legitimacy to a broad systems approach to fostering worker well-being. Our findings lead us to propose that active surveillance (enhanced management information and feedback systems) of frontline clinicians' experiences during public health emergencies could increase the effectiveness of regulations and policies across the healthcare system. Ideally, the contributions of the occupational health discipline would become a mainstay of a sustained response to promote ongoing worker well-being. The maintenance of a robust EMS workforce, and by extension the health professionals in its operational sphere, is unquestionably essential to our preparedness for the likelihood that pandemic threats may become more commonplace. | |||||||||
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| DOI: | 10.21430/M3E361589T | |||||||||
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