DR48 DataRelease
Release Date: 05/31/2023
New Studies: 58
Updated Studies: 103
New Studies
| SDY1177: T and B Cell Responses across Autoimmune Diseases | |||||||
| Status: | New | ||||||
| Description: | This is a non-randomized, multi-center study in which 280 participants who are healthy or have a confirmed or suspected diagnosis of type 1diabetes (T1D), multiple sclerosis (MS), psoriasis (Ps), Crohns disease (CD), or rheumatoid arthritis (RA) will be asked to donate a blood sample. Approximately 80 healthy adult controls and at least 40 participants per disease group with confirmed diagnosis will be analyzed. No follow-ups are planned. The study aims to establish whether defects in T and B cell function are shared across multiple immune-mediated diseases and whether these are driven by shared genetic risk variants. We will deeply immunophenotype T and B cells from each donor and correlate differences to variants known to drive immune disease risk. We will also investigate one putative disease pathway the IL23R signaling cascade in more detail to establish whether alterations to this function are present in multiple diseases. | ||||||
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| DOI: | 10.21430/M3FL8HIEF7 | ||||||
| Subjects: | 74 | ||||||
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| Publications: | None | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1726: Genomics of Kidney Transplantation (GEN-03) | |||||||
| Status: | New | ||||||
| Description: | The two major problems in clinical kidney transplantation today are late graft loss (LGL) and the shortage of organs. The Genomics of Kidney Transplantation study will specifically evaluate the role of genetics in clinical outcomes of chronic graft dysfunction, changes in graft function, acute rejection, and graft loss. It will also thoroughly evaluate pharmacogenetics by studying the influence of drug related genetic SNPs on acute rejection, chronic graft dysfunction, immunosuppression related toxicity and exposure (measured through pharmacokinetics) to immune suppressants. | ||||||
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| DOI: | 10.21430/M3TP2S2DBR | ||||||
| Subjects: | 2119 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1828: Romiplostim (Nplate) Efficacy Study with or without Pegfilgrastim (Neulasta) in a Rhesus Macaque H-ARS Model | |||||||
| Status: | New | ||||||
| Description: | Nplate was given subcutaneously (5 mg/kg on Day 1) to Co-60 irradiated (target LD70/60) rhesus macaques. Neulasta was given subcutaneously (0.3 mg/kg on Days 1 and 8) to rhesus macaques. Each group consisted of 20 male and 20 female animals. Survival was compared to a control group that received injections of the appropriate vehicles. 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/M35SO7682U | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1904: Tocilizumab (TCZ) in New-onset Type 1 Diabetes (ITN058AI) | ||||||||||
| Status: | New | |||||||||
| Description: | Staggered enrollment is planned for this trial. Prior to initiating the study in the pediatric age group (6-17 years old), 30-99 eligible adults (ages 18-45 years) will be randomized 2:1 to tocilizumab or placebo, respectively. Once the first thirty adult participants have completed 12 weeks of treatment, the FDA and Data and Safety Monitoring Board (DSMB) will review available data (e.g., interim analysis) to weigh potential risks and benefits before opening the trial to pediatric participants. As of ? May 15, 2017: Study enrollment limited to participants ages 6 to 17 years inclusive. | |||||||||
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| DOI: | 10.21430/M3BJT9805B | |||||||||
| Subjects: | 136 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY1998: Stereotactic Body Radiation Therapy in Treating Patients With Metastatic Kidney Cancer Undergoing Surgery | |||||||
| Status: | New | ||||||
| Description: | Purpose?While stereotactic body radiation therapy (SBRT) can reduce tumor volumes in metastatic renal cell carcinoma (mRCC) patients, little is known regarding the immunomodulatory effects of high-dose radiation in the tumor microenvironment. The main objectives of this pilot study were to assess the safety and feasibility of nephrectomy following SBRT treatment of mRCC patients and analyze the immunological impact of high-dose radiation. Experimental Design?Human RCC cell lines were irradiated and evaluated for immunomodulation. In a single-arm feasibility study, mRCC patients were treated with 15 Gray (Gy) SBRT at the primary lesion in a single fraction followed 4 weeks later by cytoreductive nephrectomy. RCC specimens were analyzed for tumor-associated antigen (TAA) expression and T cell infiltration. The trial has reached accrual (ClinicalTrials.gov identifier: NCT01892930). Results?RCC cells treated in vitro with radiation had increased TAA expression compared to untreated tumor cells. Fourteen patients received SBRT followed by surgery and treatment was well tolerated. SBRT-treated tumors had increased expression of the immunomodulatory molecule calreticulin and TAA (CA9, 5T4, NY-ESO-1, and MUC-1). Ki67+ proliferating CD8+ T cells and FOXP3+ cells were increased in SBRT-treated patient specimens in tumors and at the tumorstromal interface compared with archived patient specimens. Conclusions?It is feasible to perform nephrectomy following SBRT with acceptable toxicity. Following SBRT, patient RCC tumors have increased expression of calreticulin, TAA, as well as a higher percentage of proliferating T cells compared to archived RCC tumors. Collectively, these studies provide evidence of immunomodulation following SBRT in mRCC. | ||||||
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| DOI: | 10.21430/M3VXKEXMQ9 | ||||||
| Subjects: | 11 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2060: Immune memory to COVID-19 vaccines | |||||||||||||
| Status: | New | ||||||||||||
| Description: | The present 6-month longitudinal study was designed to establish the magnitude and duration of vaccine-induced SARS-CoV-2-spike-specific immune memory. Comparisons of cellular and serological immune components were made for three different vaccine platforms, namely two different mRNA vaccines (Moderna mRNA-1273 and Pfizer/BioNTech BNT162b2), a viral vector-based vaccine (Janssen Ad26.COV2.S), the protein-based adjuvanted vaccine Novavax NVX-CoV2373 as well as natural infection for reference. | ||||||||||||
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| DOI: | 10.21430/M3CPPWCLW4 | ||||||||||||
| Subjects: | 124 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2079: Sex and Dose Rate Effects in High Throughput Cytogenetics | |||||||
| Status: | New | ||||||
| Description: | Blood from adult and pediatric donors was collected into sodium heparin vacutainer tubes. Blood from each donor was diluted (1:4) in RPMI and exposed to 0, 3 or8 Gy f radiation at various dose rates with the irradiation taking between 5 usec and 48h. Samples were then assayed for micronucleus formation and for dicentric chromosomes using a high throughput assay in 96-well plates. We have seen essentially no effect of Sex on the dicentric or micronucleus yields. High dose rates resulted in decrease in both micronucleus and dicentric yields, primarily at high doses. Age data has not yet been analyzed. | ||||||
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| DOI: | 10.21430/M33REGWY6X | ||||||
| Subjects: | 295 | ||||||
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| Publications: | None | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2159: Cytotoxic T cells targeting spike glycoprotein are associated with hybrid immunity to SARS-CoV-2 | |||||||
| Status: | New | ||||||
| Description: | Intracellular Cytokine Staining data from SARS-CoV-2-naive and convalescent individuals before and after receiving two-dose mRNA vaccine series. The overall polyfunctionality of CD4 T cell responses to spike glycoprotein were similar between the two groups after mRNA vaccination despite a significant difference in pre-vaccine functional profiles. Convalescent individuals demonstrated greater magnitudes of cytotoxic CD4 T cell responses to both the S1 and S2 domains of spike glycoprotein. | ||||||
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| DOI: | 10.21430/M3I68FWBGK | ||||||
| Subjects: | 30 | ||||||
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| Publications: | None | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2195: Randomized MMF Withdrawal in Systemic Lupus Erythematosus (SLE) (ALE06) | |||||||
| Status: | New | ||||||
| Description: | One hundred twenty eligible subjects will be randomized in a 1:1 ratio to one of the two study treatment arms ? continuing MMF treatment for 60 weeks or tapering off MMF within 12 weeks. All subjects will continue on their anti-malarials and may continue the use of their corticosteroids. Subject visits to assess endpoints will occur every 4 weeks from Day 0 through Week 24 and then at Weeks 32, 40, 48, and 60. As disease flares occur, subjects will be brought in for urgent, flare or endpoint visits to document symptoms, collect biological samples, and determine whether primary endpoint has been met. | ||||||
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| DOI: | 10.21430/M3C5M9STYC | ||||||
| Subjects: | 123 | ||||||
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| Publications: | None | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2196: Secretory activity of human bone marrow mesenchymal stem cells | |||||||
| Status: | New | ||||||
| Description: | This study is part of a manuscript title ?Substrate topographies modulate the secretory activity of human bone marrow mesenchymal stem cells", which was submitted for publication to the Journal of Stem Cell Research and Therapy. Our research studied the effect of topographical cues of the culture substrate on the secretory profile and potency of bone marrow-derived mesenchymal stem cells. We designed a polystyrene topographical array using razor printing, polishing and plasma treatment. Human bone marrow -derived mesenchymal stem cells from four different donors were cultured in these topographical substrates, consisting of defined roughness and geometries. Conditioned media and lysate samples of human bone marrow-derived mesenchymal stem cells cultured on the topographical substrates were sent to Raybiotech Inc. Services for protein detection. They performed a Quantibody? Multiplex ELISA of 200 human proteins. These results were used to further perform a differential statistical analysis on the expression of the quantified proteins using R statistical software. Enriched bioprocesses were identified using the enrichGO tool from the clusterprofiler package in Bioconductor (R studio). Differential protein expression and gene ontology analyses identified enhanced bio processes associated with immune regulation in the topographical substates. Additional potency assays in this study confirmed the immune potency of the cells in the topographical substrates. | ||||||
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| DOI: | 10.21430/M3LNHD4PZM | ||||||
| Subjects: | 0 | ||||||
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| Publications: | None | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2213: Drivers of Heterogeneity in Synovial Fibroblasts in Rheumatoid Arthritis. | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Rheumatoid arthritis (RA), a systemic autoimmune disease with predominantly articular manifestations, is characterized by hyperplasia of both the synovial lining, which interfaces the synovial fluid-filled joint space, as well as the synovial sublining, which exhibits increased vascularization and an influx of leukocytes. Both the lining and sublining fibroblast-like synoviocytes (FLS) undergo proliferation and activation, assuming states in which they stimulate angiogenesis, produce pro-inflammatory cytokines and chemokines, and invade adjacent articular cartilage and bone. Expression of MHC class II molecules by activated FLS is associated with synovial inflammation and correlates with disease activity4. HLA-DR+ FLS expression of soluble mediators, including the proinflammatory cytokines IL-6 and IL-15, and chemokines CCL2, CXCL9, and CXCL12 along with adhesion molecules such as ICAM1 and VCAM1 suggests that these features of FLS might be imparted by their interactions with leukocytes. In support of this possibility, prior in vitro studies have shown that HLA-DR+ FLS are capable of presenting antigens to CD4+ T cells. Furthermore, production of the aforementioned proinflammatory chemokines by FLS likely acts as a feedforward mechanism to further facilitate recruitment of diverse immune cell types expressing the corresponding receptors. Indeed, recent studies of the overall cellular makeup of synovial tissue from RA patients using single cell RNA sequencing (scRNA-seq) analysis identified a diverse mix of migratory and resident cell types of hematopoietic and non-hematopoietic origin including different CD4+ and CD8+ T cell subsets, myeloid cells, and FLS. These observations suggest that states of FLS activation in the RA synovium are likely driven by a diversity of infiltrating innate and adaptive immune cell and that this modulation ultimately impacts disease pathogenesis. Thus, we sought to undertake an in-depth investigation of the spectrum of FLS states in the inflamed RA synovium as well as the drivers underlying the observed heterogeneity through paired scRNA and assay for transposase-accessible chromatin with sequencing (scRNA/ATAC-seq) and in vitro modeling of FLS transcriptional responses to key immune cell-derived proinflammatory cytokines. We then mapped the spatial distribution of FLS heterogeneity and transcriptional responses by employing spatial transcriptomic (ST) analyses and multiplex imaging. Our findings suggest that spatially constrained FLS responses to three leukocyte-derived cytokines, TNF?, IFN?, and IL-1?, or lack thereof, drive the formation of four distinct FLS states found in the inflamed RA synovium. | ||||||||||||
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| DOI: | 10.21430/M3M8AX1TI9 | ||||||||||||
| Subjects: | 6 | ||||||||||||
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| Publications: | None | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2216: Waning and boosting of antibody Fc-effector functions upon SARS-CoV-2 vaccination | |||||||
| Status: | New | ||||||
| Description: | Since the emergence of SARS-CoV-2, vaccines targeting COVID-19 have been developed with unprecedented speed and efficiency. CoronaVac, utilising an inactivated form of the COVID-19 virus and the mRNA26 based Pfizer/BNT162b2 vaccines are widely distributed. Beyond the ability of vaccines to induce production of neutralizing antibodies, they might lead to the generation of antibodies attenuating the disease by recruiting cytotoxic and opsonophagocytic functions. However, the Fc-effector functions of vaccine induced antibodies are much less studied than virus neutralization. Here, using systems serology, we follow the longitudinal Fc-effector profiles induced by CoronaVac and BNT162b2 up until five months following the two-dose vaccine regimen. Compared to BNT162b2, CoronaVac responses wane more slowly, albeit the levels remain lower than that of BNT162b2 recipients throughout the entire observation period. However, mRNA vaccine boosting of CoronaVac responses, including response to the Omicron variant, induce significantly higher peak of antibody functional responses with increased humoral breadth. In summary, we show that vaccine platform-induced humoral responses are not limited to virus neutralization but rather utilise antibody dependent effector functions. We demonstrate that this functionality wanes with different kinetics and can be rescued and expanded via boosting with subsequent homologous and heterologous vaccination. | ||||||
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| DOI: | 10.21430/M365O4LM7J | ||||||
| Subjects: | 0 | ||||||
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| Publications: | None | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2220: A serological assay for seroconversion detection | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description: | A serological enzyme-linked immunosorbent assay for the screening and identification of human SARS-CoV-2 seroconverters which does not require the handling of infectious virus. Additionally, it can be adjusted to detect different antibody types in serum and plasma and is amenable to scaling. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| DOI: | 10.21430/M3ACSP6BVR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Subjects: | 126 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Publications: | None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| SDY2221: Respiratory mucosal immunity against SARS-CoV-2 following mRNA vaccination | |||||||||
| Status: | New | ||||||||
| Description: | SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S-specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19 vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2) and Omicron BA.1.1 in the BAL compared to COVID-19 convalescents, despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses, not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during re-infection, but offer limited protection against breakthrough infection, especially by Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by Omicron sublineage and future VOCs. | ||||||||
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| DOI: | 10.21430/M3N3Q6QZUY | ||||||||
| Subjects: | 8 | ||||||||
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| SDY2222: Durability of Booster mRNA Vaccine against SARS-CoV-2 BA.2.12.1, BA.4, and BA.5 Subvariants | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | ""Mounting concern about the long-term efficacy of messenger RNA (mRNA) booster vaccines against coronavirus disease 2019 (Covid-19) has been exacerbated by the recent emergence of the B.1.1.529 (omicron) subvariants BA.2.12.1 and BA.4 and BA.5 (hereafter, BA.4/5) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which have high degrees of immune escape.To address this concern, we used our previously reported pseudotyped lentivirus neutralization assay (see the Supplementary Appendix, available with the full text of this letter at NEJM.org) to examine neutralizing-antibody titers against major SARS-CoV-2 variants in a longitudinal cohort of health care workers from the Ohio State University Wexner Medical Center in Columbus who had received homologous vaccine and booster doses of an mRNA vaccine. A total of 24 participants received the mRNA-1273 vaccine (Moderna), and 22 received the BNT162b2 vaccine (Pfizer?BioNTech). We classified participant samples into three groups according to the timing of booster-dose administration: 1 to 3 months, 4 to 6 months, and 7 to 9 months before the sample was obtained (Table S1 in the Supplementary Appendix). Over the course of the study, 14 participants had a breakthrough infection; 9 cases occurred during the omicron waves."" | ||||||||||||||||||
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| DOI: | 10.21430/M3XHDQGSWQ | ||||||||||||||||||
| Subjects: | 3 | ||||||||||||||||||
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| SDY2224: Retained spike-binding and neutralizing activity against emerging SARS-CoV-2 variants | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Post-vaccine sera were collected from participants in the PARIS study to determine neutralizing activity against 7 emerging variants using a microneutralization assay designed to allow for multi-cycle replication with sera/antibodies being present in the overlay at all times to better mimic physiological conditions. Binding assays against recombinant RBD and full-length spike proteins of several VoIs and VoCs were also performed. | ||||||||||||
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| DOI: | 10.21430/M30MUQM1BQ | ||||||||||||
| Subjects: | 30 | ||||||||||||
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| Publications: | None | ||||||||||||
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| SDY2226: Neutralization of SARS-CoV-2 Variants of Concern Harboring Q677H | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | The sensitivity of SARS-CoV-2 variants of concern (VOCs) to neutralizing antibodies has largely been studied in the context of key receptor binding domain (RBD) mutations, including E484K and N501Y. Little is known about the epistatic effects of combined SARS-CoV-2 spike mutations. We now investigate the neutralization sensitivity of variants containing the non-RBD mutation Q677H, including B.1.525 (Nigerian isolate) and Bluebird (U.S. isolate) variants. The effect on neutralization of Q677H was determined in the context of the RBD mutations and in the background of major VOCs, including B.1.1.7 (United Kingdom, Alpha), B.1.351 (South Africa, Beta), and P1-501Y-V3 (Brazil, Gamma). We demonstrate that the Q677H mutation increases viral infectivity and syncytium formation, as well as enhancing resistance to neutralization for VOCs, including B.1.1.7 and P1-501Y-V3. Our work highlights the importance of epistatic interactions between SARS-CoV-2 spike mutations and the continued need to monitor Q677H-bearing VOCs. IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, is rapidly evolving to be more transmissible and to evade acquired immunity. To date, most investigations of SARS-CoV-2 variants have focused on RBD mutations. However, the impact of non-RBD mutations and their synergy with studied RBD mutations are poorly understood. Here, we examine the role of the non-RBD Q677H mutation arising in many SARS-CoV-2 lineages, including VOCs. We demonstrate that the Q677H mutation enhances viral infectivity and confers neutralizing antibody resistance, particularly in the background of other SARS-CoV-2 VOCs. | ||||||||||||||||||
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| DOI: | 10.21430/M3X4D5L0FT | ||||||||||||||||||
| Subjects: | 3 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2227: The COVID-19 vaccine concerns scale: Development and validation of a new measure | |||||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||||
| 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: | 1 | ||||||||||||||||||||||||
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| Assays: | None | ||||||||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||||||||
| SDY2228: COVID-19 Vaccinations in EMS Professionals: Prevalence and Predictors | |||||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||||
| 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: | 1 | ||||||||||||||||||||||||
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| Assays: | None | ||||||||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||||||||
| SDY2229: An Opportunity to Understand Concerns about COVID-19 Vaccination: Perspectives from EMS Professionals | ||||||||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||||||||
| 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 | |||||||||||||||||||||||||||
| Subjects: | 1 | |||||||||||||||||||||||||||
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| Assays: | None | |||||||||||||||||||||||||||
| Clinical Assessments: | None | |||||||||||||||||||||||||||
| SDY2230: Closing the Gap on COVID-19 Vaccinations in First Responders and Beyond: Increasing Trust | |||||||||||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||||||||||
| 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 | ||||||||||||||||||||||||||||||
| Subjects: | 1 | ||||||||||||||||||||||||||||||
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| Assays: | None | ||||||||||||||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||||||||||||||
| SDY2231: Symptomology following mRNA vaccination against SARS-CoV-2. | ||||||||||||||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||||||||||||||
| Description: | Despite demonstrated efficacy of vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease-2019 (COVID-19), widespread hesitancy to vaccination persists. Improved knowledge regarding frequency, severity, and duration of vaccine-associated symptoms may help reduce hesitancy. In this prospective observational study, we studied 1032 healthcare workers who received both doses of the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine and completed post-vaccine symptom surveys both after dose 1 and after dose 2. We defined appreciable post-vaccine symptoms as those of at least moderate severity and lasting at least 2 days. We found that symptoms were more frequent following the second vaccine dose than the first (74% vs. 60%, P < 0.001), with >80% of all symptoms resolving within 2 days. The most common symptom was injection site pain, followed by fatigue and malaise. Overall, 20% of participants experienced appreciable symptoms after dose 1 and 30% after dose 2. In multivariable analyses, female sex was associated with greater odds of appreciable symptoms after both dose 1 (OR, 95% CI 1.73, 1.19-2.51) and dose 2 (1.76, 1.28-2.42). Prior COVID-19 was also associated with appreciable symptoms following dose 1, while younger age and history of hypertension were associated with appreciable symptoms after dose 2. We conclude that most post-vaccine symptoms are reportedly mild and last <2 days. Appreciable post-vaccine symptoms are associated with female sex, prior COVID-19, younger age, and hypertension. This information can aid clinicians in advising patients on the safety and expected symptomatology associated with vaccination | |||||||||||||||||||||||||||||||||
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| DOI: | 10.21430/M3A8F4A3NU | |||||||||||||||||||||||||||||||||
| Subjects: | 6 | |||||||||||||||||||||||||||||||||
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| Assays: | None | |||||||||||||||||||||||||||||||||
| Clinical Assessments: | None | |||||||||||||||||||||||||||||||||
| SDY2232: Antibody responses to the BNT162b2 mRNA vaccine in individuals previously infected with SARS-CoV-2. | ||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||
| Description: | In a cohort of BNT162b2 (Pfizer-BioNTech) mRNA vaccine recipients (n = 1,090), we observed that spike-specific IgG antibody levels and ACE2 antibody binding inhibition responses elicited by a single vaccine dose in individuals with prior SARS-CoV-2 infection (n = 35) were similar to those seen after two doses of vaccine in individuals without prior infection (n = 228). Post-vaccine symptoms were more prominent for those with prior infection after the first dose, but symptomology was similar between groups after the second dose. | |||||||||||||||||||||
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| DOI: | 10.21430/M3K6396YAI | |||||||||||||||||||||
| Subjects: | 1 | |||||||||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||||||||
| SDY2233: Practice Patterns and Patient Outcomes After Widespread Adoption of Remote Heart Failure Care | ||||||||||
| Status: | New | |||||||||
| Description: | Background : An unprecedented shift to remote heart failure outpatient care occurred during the coronavirus disease 2019 (COVID-19) pandemic. Given challenges inherent to remote care, we studied whether remote visits (video or telephone) were associated with different patient usage, clinician practice patterns, and outcomes. Methods : We included all ambulatory cardiology visits for heart failure at a multisite health system from April 1, 2019, to December 31, 2019 (pre-COVID) or April 1, 2020, to December 31, 2020 (COVID era), resulting in 10?591 pre-COVID in-person, 7775 COVID-era in-person, 1009 COVID-era video, and 2322 COVID-era telephone visits. We used multivariable logistic and Cox proportional hazards regressions with propensity weighting and patient clustering to study ordering practices and outcomes. Results : Compared with in-person visits, video visits were used more often by younger (mean 64.7 years [SD 14.5] versus 74.2 [14.1]), male (68.3% versus 61.4%), and privately insured (45.9% versus 28.9%) individuals (P<0.05 for all). Remote visits were more frequently used by non-White patients (35.8% video, 37.0% telephone versus 33.2% in-person). During remote visits, clinicians were less likely to order diagnostic testing (odds ratio, 0.20 [0.18?0.22] video versus in-person, 0.18 [0.17?0.19] telephone versus in-person) or prescribe ?-blockers (0.82 [0.68?0.99], 0.35 [0.26?0.47]), mineralocorticoid receptor antagonists (0.69 [0.50?0.96], 0.48 [0.35?0.66]), or loop diuretics (0.67 [0.53?0.85], 0.45 [0.37?0.55]). During telephone visits, clinicians were less likely to prescribe ACE (angiotensin-converting enzyme) inhibitor/ARB (angiotensin receptor blockers)/ARNIs (angiotensin receptor-neprilysin inhibitors; 0.54 [0.40?0.72]). Telephone visits but not video visits were associated with higher rates of 90-day mortality (1.82 [1.14?2.90]) and nonsignificant trends towards higher rates of 90-day heart failure emergency department visits (1.34 [0.97?1.86]) and hospitalizations (1.36 [0.98?1.89]). Conclusions : Remote visits for heart failure care were associated with reduced diagnostic testing and guideline-directed medical therapy prescription. Telephone but not video visits were associated with increased 90-day mortality. | |||||||||
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| DOI: | 10.21430/M3C2Q25ENQ | |||||||||
| Subjects: | 4 | |||||||||
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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: | New | ||||||
| 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: | 1 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2236: SARS-CoV-2 Serosurveys: How antigen, isotype and threshold choices affect the outcome | ||||||||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||||||||
| 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: | 5 | |||||||||||||||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||||||||||||||
| SDY2238: D614G Spike Mutation Increases SARS CoV-2 Susceptibility to Neutralization | ||||||||||
| Status: | New | |||||||||
| Description: | The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein acquired a D614G mutation early in the pandemic that confers greater infectivity and is now the globally dominant form. To determine whether D614G might also mediate neutralization escape that could compromise vaccine efficacy, sera from spike-immunized mice, nonhuman primates, and humans were evaluated for neutralization of pseudoviruses bearing either D614 or G614 spike. In all cases, the G614 pseudovirus was moderately more susceptible to neutralization. The G614 pseudovirus also was more susceptible to neutralization by receptor-binding domain (RBD) monoclonal antibodies and convalescent sera from people infected with either form of the virus. Negative stain electron microscopy revealed a higher percentage of the 1-RBD ""up"" conformation in the G614 spike, suggesting increased epitope exposure as a mechanism of enhanced vulnerability to neutralization. Based on these findings, the D614G mutation is not expected to be an obstacle for current vaccine development. | |||||||||
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| DOI: | 10.21430/M32KSB7VCX | |||||||||
| Subjects: | 51 | |||||||||
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| Publications: | None | |||||||||
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| SDY2239: SARS-CoV-2 -specific immune responses in boosted vaccine recipients with breakthrough infections during the Omicron variant surge | |||||||||||||
| Status: | New | ||||||||||||
| Description: | BACKGROUND. Breakthrough SARS-CoV-2 infections in vaccinated individuals have been previously associated with suboptimal humoral immunity. However, less is known about breakthrough infections with the Omicron variant. METHODS. We analyzed SARS-CoV-2 specific antibody and cellular responses in healthy vaccine recipients who experienced breakthrough infections a median of 50 days after receiving a booster mRNA vaccine with an ACE2 binding inhibition assay and an ELISpot assay respectively. Results: We found high levels of antibodies that inhibited vaccine strain spike protein binding to ACE2 but lower levels that inhibited Omicron variant spike protein binding to ACE2 in four boosted vaccine recipients prior to infection. The levels of antibodies that inhibited vaccine strain and Omicron spike protein binding after breakthrough in 18 boosted vaccine recipients were similar to levels seen in COVID-19 negative boosted vaccine recipients. In contrast, boosted vaccine recipients had significantly stronger T cells responses to both vaccine strain and Omicron variant spike proteins at the time of breakthrough. CONCLUSIONS. Our data suggest that breakthrough infections with the Omicron variant can occur despite robust immune responses to the vaccine strain spike protein. | ||||||||||||
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| DOI: | 10.21430/M3Q3C0UDD8 | ||||||||||||
| Subjects: | 5 | ||||||||||||
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| SDY2240: Neutralization of SARS-CoV-2 Omicron sub-lineages BA.1, BA.1.1, and BA.2 | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Recent reports of SARS-CoV-2 Omicron variant sub-lineages, BA.1, BA.1.1, and BA.2, have reignited concern over potential escape from vaccine- and infection-induced immunity. We examine the sensitivity of these sub-lineages and other major variants to neutralizing antibodies from mRNA-vaccinated and boosted individuals, as well as recovered COVID-19 patients, including those infected with Omicron. We find that all Omicron sub-lineages, especially BA.1 and BA.1.1, exhibit substantial immune escape that is largely overcome by mRNA vaccine booster doses. While Omicron BA.1.1 escapes almost completely from neutralization by early-pandemic COVID-19 patient sera and to a lesser extent from sera of Delta-infected patients, BA.1.1 is sensitive to Omicron-infected patient sera. Critically, all Omicron sub-lineages, including BA.2, are comparably neutralized by Omicron patient sera. These results highlight the importance of booster vaccine doses for protection against all Omicron variants and provide insight into the immunity from natural infection against Omicron sub-lineages. | ||||||||||||
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| DOI: | 10.21430/M32EKWILLC | ||||||||||||
| Subjects: | 5 | ||||||||||||
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| SDY2241: Neutralization of the SARS-CoV-2 Deltacron and BA.3 Variants | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | We used a pseudotyped virus neutralization assay to examine neutralizing-antibody titers in serum samples obtained from vaccinated health care workers at the Wexner Medical Center at Ohio State University as well as from patients with confirmed Covid-19 during the delta and omicron waves in the Columbus, Ohio, area. We evaluated neutralizing-antibody titers against the ancestral SARS-CoV-2 strain bearing the D614G mutation, along with the understudied BA.3 and deltacron variants, and compared the responses with previously reported results for the BA.1, BA.2, and delta variants. | ||||||||||||||||||
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| DOI: | 10.21430/M3WD13IVPV | ||||||||||||||||||
| Subjects: | 3 | ||||||||||||||||||
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| SDY2242: Perspectives of Volunteer Firefighters during the COVID-19 Pandemic: Stumbling Blocks and Silver Linings | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | The COVID-19 pandemic has profoundly affected the lives of almost every individual in every nation, with numbers of infections continuing to grow. Across these nations, first responders are essential in their roles addressing emergencies, despite their risk of exposure to COVID-19 in the course of their work. We sought to understand the impacts of the COVID-19 pandemic on the lives of volunteer firefighters in the United States, an understudied group of these first responders. Interviews were conducted with volunteer firefighters between September and November 2021. Interviews were analyzed using deductive dominant thematic analysis. Thirty-three firefighters were interviewed who had an average of 22 years of service and a mean age of 52 years. Interviewees described pandemic-related challenges including the fear of COVID exposure and frustrations with work and personal relationships. They also identified unexpected work-related benefits including a deepened commitment to serve and improvements to training and safety. Further, some volunteers noted personal benefits such as developing stronger connections with others, having a new outlook on life, and observing goodwill. Our findings provide insight into the multifaceted and complex impact of the COVID-19 pandemic on volunteer firefighters. | ||||||||||||||||||
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| DOI: | 10.21430/M3743KKGHE | ||||||||||||||||||
| Subjects: | 1 | ||||||||||||||||||
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| SDY2243: Ultrasensitive detection of salivary SARS-CoV-2 IgG antibodies in individuals with natural and COVID-19 vaccine-induced immunity | |||||||||||||
| Status: | New | ||||||||||||
| Description: | We assessed the feasibility of a highly sensitive immunoassay method based on single molecule array (Simoa) technology to detect IgG and IgA antibodies against SARS-CoV-2 spike protein receptor binding domain (RBD) in saliva from individuals with natural or vaccine-induced COVID-19 immunity. The performance of the method was compared to a laboratory-developed SARS-CoV-2 RBD total antibody enzyme-linked immunosorbent assay (ELISA). Paired serum and saliva specimens were collected from individuals (n = 40) prior to and 2 weeks after receiving an initial prime COVID-19 vaccine dose (Pfizer/BioNTech BNT162b2 or Moderna mRNA-1273). Saliva was collected using a commercially available collection device (OraSure Inc.) and SARS-CoV-2 RBD IgG antibodies were measured by an indirect ELISA using concentrated saliva samples and a Simoa immunoassay using unconcentrated saliva samples. The IgG results were compared with paired serum specimens that were analyzed for total RBD antibodies using the ELISA method. The analytical sensitivity of the saliva-based Simoa immunoassay was five orders of magnitude higher than the ELISA assay: 0.24 pg/mL compared to 15 ng/mL. The diagnostic sensitivity of the saliva ELISA method was 90% (95% CI 76.3-97.2%) compared to 91.7% (95% CI 77.5-98.2%) for the Simoa immunoassay without total IgG-normalization and 100% (95% CI 90.3-100%) for the Simoa immunoassay after total IgG-normalization when compared to the serum ELISA assay. When analyzed using the SARS-CoV-2 RBD IgG antibody ELISA, the average relative increase in antibody index (AI) between the saliva of the post- and pre-vaccinated individuals was 8.7 (AIpost/pre). An average relative increase of 431 pg/mL was observed when the unconcentrated saliva specimens were analyzed using the Simoa immunoassay (SARS-CoV-2 RBD IgGpost/pre). These findings support the suitability of concentrated saliva specimens for the measurement of SARS-CoV-2 RBD IgG antibodies via ELISA, and unconcentrated saliva specimens for the measurement of SARS-CoV-2 RBD IgG and IgA using an ultrasensitive Simoa immunoassay | ||||||||||||
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| DOI: | 10.21430/M3VWJ6W5M3 | ||||||||||||
| Subjects: | 2 | ||||||||||||
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| SDY2244: Outcomes of Convalescent Plasma with Defined High versus Lower Neutralizing Antibody Titers against SARS-CoV-2 among Hospitalized Patients: CoronaVirus Inactivating Plasma (CoVIP) Study | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | COVID-19 convalescent plasma (CCP) was an early and widely adopted putative therapy for severe COVID-19. Results from randomized control trials and observational studies have failed to demonstrate a clear therapeutic role for CCP for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Underlying these inconclusive findings is a broad heterogeneity in the concentrations of neutralizing antibodies (nAbs) between different CCP donors. We conducted this study to evaluate the effectiveness and safety of nAb titer-defined CCP in adults admitted to an academic referral hospital. Patients positive by a SARS-CoV-2 nucleic acid amplification test and with symptoms for <10 days were eligible. Participants received either CCP with nAb titers of >1:640 (high-titer group) or ?1:160 to 1:640 (standard-titer group) in addition to standard of care treatments. The primary clinical outcome was time to hospital discharge, with mortality and respiratory support evaluated as secondary outcomes. Adverse events were contrasted by CCP titer. Between 28 August and 4 December 2020, 316 participants were screened, and 55 received CCP, with 14 and 41 receiving high- versus standard-titer CCP, respectively. Time to hospital discharge was shorter among participants receiving high- versus standard-titer CCP, accounting for death as a competing event (hazard ratio, 1.94; 95% confidence interval [CI], 1.05 to 3.58; Gray's P = 0.02). Severe adverse events (SAEs) (?grade 3) occurred in 4 (29%) and 23 (56%) of participants receiving the high versus standard titer, respectively, by day 28 (risk ratio, 0.51; 95% CI, 0.21 to 1.22; Fisher's P = 0.12). There were no observed treatment-related AEs. (This study has been registered at ClinicalTrials.gov under registration no. NCT04524507). IMPORTANCE In this study, in a high-risk population of patients admitted for COVID-19, we found an earlier time to hospital discharge among participants receiving CCP with nAb titers of >1:640 compared with participants receiving CCP with a lower nAb titer and no CCP-related AEs. The significance of our research is in identifying a dose response of CCP and clinical outcomes based on nAb titer. Although limited by a small study size, these findings support further study of high-nAb-titer CCP defined as >1:640 in the treatment of COVID-19. | ||||||||||||||||||
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| DOI: | 10.21430/M37S4576ZH | ||||||||||||||||||
| Subjects: | 2 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2245: Newcastle disease virus (NDV) expressing the spike protein of SARS-CoV-2 as a live virus vaccine candidate | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Ten-week old female BALB/cJ mice were used to assess and study the potential neutralizing capacity of NDV vector vaccines expressing the spike protein of SARS-CoV-2 | ||||||||||||
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| DOI: | 10.21430/M3NC2L1UYI | ||||||||||||
| Subjects: | 50 | ||||||||||||
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| Publications: | None | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2246: Convalescent plasma anti-SARS-CoV-2 spike protein ectodomain and receptor-binding domain IgG correlate with virus neutralization | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description: | The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the urgent need for assays that detect protective levels of neutralizing antibodies. We studied the relationship among anti-spike ectodomain (anti-ECD), anti-receptor-binding domain (anti-RBD) IgG titers, and SARS-CoV-2 virus neutralization (VN) titers generated by 2 in vitro assays using convalescent plasma samples from 68 patients with COVID-19. We report a strong positive correlation between both plasma anti-RBD and anti-ECD IgG titers and in vitro VN titers. The probability of a VN titer of greater than or equal to 160, the FDA-recommended level for convalescent plasma used for COVID-19 treatment, was greater than or equal to 80 percent when anti-RBD or anti-ECD titers were greater than or equal to 1:1350. Of all donors, 37 percent lacked VN titers of greater than or equal to 160. Dyspnea, hospitalization, and disease severity were significantly associated with higher VN titer. Frequent donation of convalescent plasma did not significantly decrease VN or IgG titers. Analysis of 2814 asymptomatic adults found 73 individuals with anti-ECD IgG titers of greater than or equal to 1:50 and strong positive correlation with anti-RBD and VN titers. Fourteen of these individuals had VN titers of greater than or equal to 1:160, and all of them had anti-RBD titers of greater than or equal to 1:1350. We conclude that anti-RBD or anti-ECD IgG titers can serve as a surrogate for VN titers to identify suitable plasma donors. Plasma anti-RBD or anti-ECD titers of greater than or equal to 1:1350 may provide critical information about protection against COVID-19 disease. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| DOI: | 10.21430/M3D2VNZC41 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Subjects: | 68 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Publications: | None | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| SDY2247: Preserved recognition of Omicron spike following COVID-19 messenger RNA vaccination in pregnancy | |||||||
| Status: | New | ||||||
| Description: | This study aims to test whether vaccine-induced antibodies raised during pregnancy continue to bind to and leverage Fc receptors to protect against variants of concern including the Omicron variant. The receptor binding domain or whole spike-specific antibody isotype binding titers and Fc gamma receptor binding directed toward variants of concern, including the Omicron variant, were analyzed in pregnant women after receiving the full dose regimen of either the Pfizer/BioNTech BNT62b2 (n=10) or Moderna mRNA-1273 (n=10) vaccination using a multiplexing Luminex assay. Reduced isotype recognition of the Omicron receptor binding domain was observed following administration of either vaccine with relatively preserved, albeit reduced, recognition of the whole Omicron spike by immunoglobulin M and G antibodies. Despite the near complete loss of Fc receptor binding to the Omicron receptor binding domain, Fc receptor binding to the Omicron spike was more variable but largely preserved. Reduced binding titers to the Omicron receptor binding domain aligns with the observed loss of neutralizing activity. Despite the loss of neutralization, preserved, albeit reduced, Omicron spike recognition and Fc receptor binding potentially continue to attenuate disease severity in pregnant women. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3SQTEAH4V | ||||||
| Subjects: | 2 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2248: Humoral Responses Against SARS-CoV-2 and Variants of Concern After mRNA Vaccines in Patients With Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | PURPOSE Patients with non-Hodgkin lymphoma including chronic lymphocytic leukemia (NHL/CLL) are at higher risk of severe SARS-CoV-2 infection. We investigated vaccine-induced antibody responses in patients with NHL/CLL against the original SARS-CoV-2 strain and variants of concern including B.1.167.2 (Delta) and B.1.1.529 (Omicron). MATERIALS AND METHODS Blood from 121 patients with NHL/CLL receiving two doses of vaccine were collected longitudinally. Antibody binding against the full-length spike protein, the receptor-binding, and N-terminal domains of the original strain and of variants was measured using a multiplex assay. Live-virus neutralization against Delta, Omicron, and the early WA1/2020 strains was measured using a focus reduction neutralization test. B cells were measured by flow cytometry. Correlation between vaccine response and clinical factors was determined. RESULTS Mean anti-SARS-CoV-2 spike immunoglobulin G?binding titers were 85-fold lower in patients with NHL/CLL compared with healthy controls, with seroconversion occurring in only 67% of patients. Neutralization titers were also lower and correlated with binding titers (P < .0001). Treatment with anti-CD20-directed therapies within 1 year resulted in 136-fold lower binding titers. Peripheral blood B-cell count also correlated with vaccine response. At 3 months from last anti-CD20-directed therapy, B-cell count ? 4.31/?L blood around the time of vaccination predicted response (OR 7.46, P = .04). Antibody responses also correlated with age. Importantly, neutralization titers against Delta and Omicron were reduced six- and 42-fold, respectively, with 67% of patients seropositive for WA1/2020 exhibiting seronegativity for Omicron. CONCLUSION Antibody binding and live-virus neutralization against SARS-CoV-2 and its variants of concern including Delta and Omicron were substantially lower in patients with NHL/CLL compared with healthy vaccinees. Anti-CD20-directed therapy < 1 year before vaccination and number of circulating B cells strongly predict vaccine response. | |||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3DBDOJHGH | |||||||||||||||
| Subjects: | 3 | |||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||
| SDY2249: Functional Effects of Cardiomyocyte Injury in COVID-19 | |||||||||
| Status: | New | ||||||||
| Description: | COVID-19 affects multiple organs. Clinical data from the Mount Sinai Health System show that substantial numbers of COVID-19 patients without prior heart disease develop cardiac dysfunction. How COVID-19 patients develop cardiac disease is not known. We integrated cell biological and physiological analyses of human cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the presence of interleukins (ILs) with clinical findings related to laboratory values in COVID-19 patients to identify plausible mechanisms of cardiac disease in COVID-19 patients. We infected hiPSC-derived cardiomyocytes from healthy human subjects with SARS-CoV-2 in the absence and presence of IL-6 and IL-1?. Infection resulted in increased numbers of multinucleated cells. Interleukin treatment and infection resulted in disorganization of myofibrils, extracellular release of troponin I, and reduced and erratic beating. Infection resulted in decreased expression of mRNA encoding key proteins of the cardiomyocyte contractile apparatus. Although interleukins did not increase the extent of infection, they increased the contractile dysfunction associated with viral infection of cardiomyocytes, resulting in cessation of beating. Clinical data from hospitalized patients from the Mount Sinai Health System show that a significant portion of COVID-19 patients without history of heart disease have elevated troponin and interleukin levels. A substantial subset of these patients showed reduced left ventricular function by echocardiography. Our laboratory observations, combined with the clinical data, indicate that direct effects on cardiomyocytes by interleukins and SARS-CoV-2 infection might underlie heart disease in COVID-19 patients. IMPORTANCE SARS-CoV-2 infects multiple organs, including the heart. Analyses of hospitalized patients show that a substantial number without prior indication of heart disease or comorbidities show significant injury to heart tissue, assessed by increased levels of troponin in blood. We studied the cell biological and physiological effects of virus infection of healthy human iPSC-derived cardiomyocytes in culture. Virus infection with interleukins disorganizes myofibrils, increases cell size and the numbers of multinucleated cells, and suppresses the expression of proteins of the contractile apparatus. Viral infection of cardiomyocytes in culture triggers release of troponin similar to elevation in levels of COVID-19 patients with heart disease. Viral infection in the presence of interleukins slows down and desynchronizes the beating of cardiomyocytes in culture. The cell-level physiological changes are similar to decreases in left ventricular ejection seen in imaging of patients' hearts. These observations suggest that direct injury to heart tissue by virus can be one underlying cause of heart disease in COVID-19. | ||||||||
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| DOI: | 10.21430/M3FOBFTUPV | ||||||||
| Subjects: | 4 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY2250: Cas13d knockdown of lung protease Ctsl prevents and treats SARS-CoV-2 infection | |||||||||||
| Status: | New | ||||||||||
| 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. | ||||||||||
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| DOI: | 10.21430/M3SYJZ2G47 | ||||||||||
| Subjects: | 0 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2251: Immunogenicity of NDV-HRP-S in Sprague Dawley Rats | ||||||||||
| Status: | New | |||||||||
| Description: | Nine- to ten-week old Sprague Dawley rats were used to assess the immunogenicity of live Newcastle disease virus vector expressing a pre-fusion stabilized version of the spike protein | |||||||||
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| DOI: | 10.21430/M3GAL2KQYS | |||||||||
| Subjects: | 200 | |||||||||
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| Publications: | None | |||||||||
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| SDY2252: Reduced pathogenicity of the SARS-CoV-2 omicron variant in hamsters | ||||||||||
| Status: | New | |||||||||
| 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 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2253: Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody | |||||||||||||||
| Status: | New | ||||||||||||||
| Description: | The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. We employed a directed evolution approach to engineer three severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains and neutralizes representative epidemic sarbecoviruses with high potency. Structural and biochemical studies demonstrate that ADG-2 employs a distinct angle of approach to recognize a highly conserved epitope that overlaps the receptor binding site. In immunocompetent mouse models of SARS and COVID-19, prophylactic administration of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate against clade 1 sarbecoviruses. | ||||||||||||||
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| DOI: | 10.21430/M3WRG2RJ32 | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
| SDY2254: Cross-reactive coronavirus antibodies with diverse epitope specificities and Fc effector functions | |||||||||||||||
| Status: | New | ||||||||||||||
| Description: | The continual emergence of novel coronaviruses (CoV), such as severe acute respiratory syndrome-(SARS)-CoV-2, highlights the critical need for broadly reactive therapeutics and vaccines against this family of viruses. From a recovered SARS-CoV donor sample, we identify and characterize a panel of six monoclonal antibodies that cross-react with CoV spike (S) proteins from the highly pathogenic SARS-CoV and SARS-CoV-2, and demonstrate a spectrum of reactivity against other CoVs. Epitope mapping reveals that these antibodies recognize multiple epitopes on SARS-CoV-2 S, including the receptor-binding domain, the N-terminal domain, and the S2 subunit. Functional characterization demonstrates that the antibodies mediate phagocytosis-and in some cases trogocytosis-but not neutralization in vitro. When tested in vivo in murine models, two of the antibodies demonstrate a reduction in hemorrhagic pathology in the lungs. The identification of cross-reactive epitopes recognized by functional antibodies expands the repertoire of targets for pan-coronavirus vaccine design strategies. | ||||||||||||||
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| DOI: | 10.21430/M3FVTBWJG1 | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
| SDY2255: Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses | |||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||
| 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: | 9 | ||||||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||||||
| SDY2256: SARS-CoV-2 vaccines elicit durable immune responses in infant rhesus macaques | |||||||||||||||||
| Status: | New | ||||||||||||||||
| Description: | The inclusion of infants in the SARS-CoV-2 vaccine roll-out is important to prevent severe complications of pediatric SARS-CoV-2 infections and to limit transmission and could possibly be implemented via the global pediatric vaccine schedule. However, age-dependent differences in immune function require careful evaluation of novel vaccines in the pediatric population. Toward this goal, we assessed the safety and immunogenicity of two SARS-CoV-2 vaccines. Two groups of 8 infant rhesus macaques (RMs) were immunized intramuscularly at weeks 0 and 4 with stabilized prefusion SARS-CoV-2 S-2P spike (S) protein encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or the purified S protein mixed with 3M-052, a synthetic TLR7/8 agonist in a squalene emulsion (Protein+3M-052-SE). Neither vaccine induced adverse effects. Both vaccines elicited high magnitude IgG binding to RBD, N terminus domain, S1, and S2, ACE2 blocking activity, and high neutralizing antibody titers, all peaking at week 6. S-specific memory B cells were detected by week 4 and S-specific T cell responses were dominated by the production of IL-17, IFN-?, or TNF-?. Antibody and cellular responses were stable through week 22. The immune responses for the mRNA-LNP vaccine were of a similar magnitude to those elicited by the Moderna mRNA-1273 vaccine in adults. The S-2P mRNA-LNP and Protein-3M-052-SE vaccines were well-tolerated and highly immunogenic in infant RMs, providing proof-of concept for a pediatric SARS-CoV-2 vaccine with the potential for durable immunity that might decrease the transmission of SARS-CoV-2 and mitigate the ongoing health and socioeconomic impacts of COVID-19. | ||||||||||||||||
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| DOI: | 10.21430/M30RR7BFU2 | ||||||||||||||||
| Subjects: | 0 | ||||||||||||||||
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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: | New | ||||||||||||
| 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. | ||||||||||||
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| DOI: | 10.21430/M3QM7OZTAC | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2258: Role of miR-2392 in driving SARS-CoV-2 infection | |||||||||||||
| Status: | New | ||||||||||||
| Description: | MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provide an exciting avenue toward antiviral therapeutics. From patient transcriptomic data, we determined that a circulating miRNA, miR-2392, is directly involved with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia, as well as promoting many symptoms associated with coronavirus disease 2019 (COVID-19) infection. We demonstrate that miR-2392 is present in the blood and urine of patients positive for COVID-19 but is not present in patients negative for COVID-19. These findings indicate the potential for developing a minimally invasive COVID-19 detection method. Lastly, using in vitro human and in vivo hamster models, we design a miRNA-based antiviral therapeutic that targets miR-2392, significantly reduces SARS-CoV-2 viability in hamsters, and may potentially inhibit a COVID-19 disease state in humans. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3RUAVH163 | ||||||||||||
| Subjects: | 13 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY2259: Antibody binding and neutralization of live SARS-CoV-2 variants including BA.4/5 following booster vaccination of patients with B-cell malignancies | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | Non-Hodgkin lymphoma and chronic lymphocytic leukemia (NHL/CLL) patients elicit inadequate antibody responses after initial SARS-CoV-2 vaccination and remain at high risk of severe COVID-19 disease. We investigated IgG, IgA, and IgM responses after booster vaccination against recent SARS-CoV-2 variants including Omicron BA.5 in 67 patients. Patients had lower fold increase and total anti-spike binding titers after booster than healthy individuals. Antibody responses negatively correlated with recent anti-CD20 therapy and low B cell numbers. Antibodies generated after booster demonstrated similar binding properties against SARS-CoV-2 variants compared to those generated by healthy controls with lower binding against Omicron variants. Importantly, 43% of patients showed anti-Omicron BA.1 neutralizing antibodies after booster and all these patients also had anti-Omicron BA.5 neutralizing antibodies. NHL/CLL patients demonstrated inferior antibody responses after booster vaccination, particularly against Omicron variants. Prioritization of prophylactic and treatment agents and vaccination of patients and close contacts with updated vaccine formulations are essential. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M306PUGY2I | ||||||||||||||||||
| Subjects: | 2 | ||||||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2260: A bivalent SARS-CoV-2 monoclonal antibody combination does not impact the immunogenicity of a vector-based COVID-19 vaccine in macaques | |||||||||||
| Status: | New | ||||||||||
| Description: | Human monoclonal antibodies (mAbs) that target the spike glycoprotein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) offer a promising approach for the prevention and treatment of coronavirus disease 2019 (COVID-19). Given suboptimal global vaccination rates, waning immunity in vaccinated individuals, and the emergence of SARS-CoV-2 variants of concern, the use of mAbs for COVID-19 prevention may increase and may need to be administered together with vaccines in certain settings. However, it is unknown whether administration of mAbs will impact the immunogenicity of SARS-CoV-2 vaccines. Using an adenovirus vector-based SARS-CoV-2 vaccine, we show that simultaneous administration of the vaccine with SARS-CoV-2 mAbs does not diminish vaccine-induced humoral or cellular immunity in cynomolgus macaques. These results suggest that SARS-CoV-2 mAbs and viral vector-based SARS-CoV-2 vaccines can be administered together without loss of potency of either product. Additional studies will be required to evaluate co-administration of mAbs with other vaccine platforms. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3YQRTHK52 | ||||||||||
| Subjects: | 4 | ||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||
| SDY2261: Enhanced neutralization resistance of SARS-CoV-2 Omicron subvariants BQ.1, BQ.1.1, BA.4.6, BF.7, and BA.2.75.2 | ||||||||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||||||||
| Description: | The continued evolution of SARS-CoV-2 has led to the emergence of several new Omicron subvariants, including BQ.1, BQ.1.1, BA.4.6, BF.7, and BA.2.75.2. Here, we examine the neutralization resistance of these subvariants against sera from 3-dose vaccinated healthcare workers, hospitalized BA.1-wave patients, and BA.4/5-wave patients. We found enhanced neutralization resistance in all new subvariants, especially in the BQ.1 and BQ.1.1 subvariants driven by N460K and K444T mutations, as well as the BA.2.75.2 subvariant driven largely by its F486S mutation. All Omicron subvariants maintained their weakened infectivity in Calu-3 cells, with the F486S mutation driving further diminished titer for the BA.2.75.2 subvariant. Molecular modeling revealed the mechanisms of antibody-mediated immune evasion by R346T, K444T, F486S, and D1199N mutations. Altogether, these findings shed light on the evolution of newly emerging SARS-CoV-2 Omicron subvariants. | |||||||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3KAR6H0RO | |||||||||||||||||||||||||||
| Subjects: | 5 | |||||||||||||||||||||||||||
| Study PI, contact: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | |||||||||||||||||||||||||||
| SDY2262: Evasion of neutralizing antibody responses by the SARS-CoV-2 BA.2.75 variant | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | The newly emerged BA.2.75 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant contains 9 additional mutations in its spike (S) protein compared to the ancestral BA.2 variant. Here, we examine the neutralizing antibody escape of BA.2.75 in mRNA-vaccinated and BA.1-infected individuals, as well as the molecular basis underlying functional changes in S. Notably, BA.2.75 exhibits enhanced neutralization resistance over BA.2 but less than the BA.4/5 variant. The G446S and N460K mutations of BA.2.75 are primarily responsible for its enhanced resistance to neutralizing antibodies. The R493Q mutation, a reversion to the prototype sequence, reduces BA.2.75 neutralization resistance. The impact of these mutations is consistent with their locations in common neutralizing antibody epitopes. Further, BA.2.75 shows enhanced cell-cell fusion over BA.2, driven largely by the N460K mutation, which enhances S processing. Structural modeling reveals enhanced receptor contacts introduced by N460K, suggesting a mechanism of potentiated receptor utilization and syncytia formation. | |||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M31CXJD6IK | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Clinical Assessments: | None | |||||||||||||||
| SDY2263: In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies | |||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||
| 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-? (Fc?R)-mediated enhancement of virus infection in vitro, while five non-neutralizing NTD antibodies mediated Fc?R-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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| Publications: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||||||||||||
| SDY2266: Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals | |||||||||||||
| Status: | New | ||||||||||||
| Description: | The emergence of SARS-CoV-2 variants with evidence of antibody escape highlight the importance of addressing whether the total CD4+ and CD8+ T cell recognition is also affected. Here, we compare SARS-CoV-2-specific CD4+ and CD8+ T cells against the B.1.1.7, B.1.351, P.1, and CAL.20C lineages in COVID-19 convalescents and in recipients of the Moderna (mRNA-1273) or Pfizer/BioNTech (BNT162b2) COVID-19 vaccines. The total reactivity against SARS-CoV-2 variants is similar in terms of magnitude and frequency of response, with decreases in the 10%?22% range observed in some assay/VOC combinations. A total of 7% and 3% of previously identified CD4+ and CD8+ T cell epitopes, respectively, are affected by mutations in the various VOCs. Thus, the SARS-CoV-2 variants analyzed here do not significantly disrupt the total SARS-CoV-2 T cell reactivity; however, the decreases observed highlight the importance for active monitoring of T cell reactivity in the context of SARS-CoV-2 evolution. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3NH5EQL6V | ||||||||||||
| Subjects: | 0 | ||||||||||||
| 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 | ||||||||||||
| SDY2267: Correlates of Neutralization against SARS-CoV-2 Variants of Concern by Early Pandemic Sera | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Emerging SARS-CoV-2 variants of concern that overcome natural and vaccine-induced immunity threaten to exacerbate the COVID-19 pandemic. Increasing evidence suggests that neutralizing antibody (NAb) responses are a primary mechanism of protection against infection. However, little is known about the extent and mechanisms by which natural immunity acquired during the early COVID-19 pandemic confers cross-neutralization of emerging variants. In this study, we investigated cross-neutralization of the B.1.1.7 and B.1.351 SARS-CoV-2 variants in a well-characterized cohort of early pandemic convalescent subjects. We observed modestly decreased cross-neutralization of B.1.1.7 but a substantial 4.8-fold reduction in cross-neutralization of B.1.351. Correlates of cross-neutralization included receptor binding domain (RBD) and N-terminal domain (NTD) binding antibodies, homologous NAb titers, and membrane-directed T cell responses. These data shed light on the cross-neutralization of emerging variants by early pandemic convalescent immune responses. IMPORTANCE Widespread immunity to SARS-CoV-2 will be necessary to end the COVID-19 pandemic. NAb responses are a critical component of immunity that can be stimulated by natural infection as well as vaccines. However, SARS-CoV-2 variants are emerging that contain mutations in the spike gene that promote evasion from NAb responses. These variants may therefore delay control of the COVID-19 pandemic. We studied whether NAb responses from early COVID-19 convalescent patients are effective against the two SARS-CoV-2 variants, B.1.1.7 and B.1.351. We observed that the B.1.351 variant demonstrates significantly reduced susceptibility to early pandemic NAb responses. We additionally characterized virological, immunological, and clinical features that correlate with cross-neutralization. These studies increase our understanding of emerging SARS-CoV-2 variants. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3GEIOFI1N | ||||||||||||
| Subjects: | 0 | ||||||||||||
| 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 | ||||||||||||
| SDY2268: Immune cells in bronchoalveolar lavage fluid of Ugandan adults who resist versus those who develop latent Mycobacterium tuberculosis infection | ||||||||||
| Status: | New | |||||||||
| Description: | An observational study using flow cytometry to measure and compare immune cell percentages in peripheral blood and bronchoalveolar lavage fluid in Mtb infected participants and those who are resistant to Mtb infection. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3THLZ4OPE | |||||||||
| Subjects: | 0 | |||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2270: COVID19 SARS Vaccinations: Systemic Allergic Reactions to SARS-CoV-2 Vaccinations | |||||||||||||
| Status: | New | ||||||||||||
| Description: | This is a multicenter, randomized, initially blinded (masked), phase 2 trial to assess SARS-CoV-2 vaccination reactions in two populations: One population including individuals with a history of allergic reactions or Mast Cell Disorder (HA/MCD), and One comparison population without severe allergies or mast cell disorders. Approximately 2040 HA/MCD and 1360 comparison participants will be enrolled across participating sites in the United States. Approximately two-thirds of participants enrolled in each of the 2 groups will be female. This is because the vast majority of cases of anaphylaxis to the COVID-19 vaccines have occurred in women. Enrollment of participants who qualify only on the basis of reactions to multiple unrelated drugs will be limited to approximately 300. Enrollment of the MCD group is anticipated to be at least 200 participants, and not more than 300 participants. Participants in each population will be randomized 2:2:1:1 to receive the Pfizer-BioNTech COVID-19 Vaccine, Moderna COVID-19 Vaccine, placebo + Pfizer-BioNTech COVID-19 Vaccine, or placebo + Moderna COVID-19 Vaccine, if enrolled in the initial study period under protocol versions 1.0 -4.0. Participants enrolled under protocol version 5.0 will be randomized 2:1 to receive the Pfizer-BioNTech COVID-19 Vaccine or placebo + Pfizer-BioNTech COVID-19 Vaccine. If enrollment under protocol version 5.0 is robust and sustained, the active vaccine randomization may be changed to the Moderna COVID-19 Vaccine. Participants randomized to one of the placebo groups will receive placebo as a first dose and will receive two doses of their assigned active vaccine at subsequent visits. During the first visit, all participants will be initially-blinded to whether they are receiving placebo or vaccine, and to which vaccine they are receiving (if enrolling under protocol versions 1.0 -4.0). Due to the different dosing schedules for the Pfizer-BioNTech COVID-19 Vaccine and Moderna COVID-19 Vaccine, it will become apparent to both the site staff and the study participant which vaccine has been assigned, once the second injection visit is scheduled. However, the blind over placebo versus vaccine will remain in effect until after the second visit. During a follow-up call, scheduled 3 days after the second injection, participants will be unblinded as to whether they received placebo or active vaccine. However under protocol version 5.0, participants will be told if they received placebo as the first injection during the following up conducted 3 days after. Participants in this phase of the study will also know which company's vaccine they are receiving, as the vaccines are anticipated to be used sequentially and will also be noted in the consent form. Study Duration: Randomized and vaccinated participants will complete study participation in approximately 29 days if vaccinated with the Pfizer-BioNTech COVID-19 Vaccine, 36 days if vaccinated with the Moderna COVID-19 Vaccine. Participants enrolled under protocol versions 1.0 -4.0 will complete study participation in 50 or 64 days if administered placebo before receiving two doses of either the Pfizer-BioNTech COVID-19 Vaccine or the Moderna COVID-19 Vaccine, respectively and participants enrolled under protocol version 5.0 will complete participation in approximately 36 of 43 days, respectively, if they receive placebo first. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3BSI1OE6T | ||||||||||||
| Subjects: | 730 | ||||||||||||
| Study PI, contact: |
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| Publications: | None | ||||||||||||
| Resources: |
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| Assays: | None | ||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY2274: Efficacy of Ustekinumab Followed by Abatacept for the Treatment of Psoriasis Vulgaris (PAUSE) | |||||||
| Status: | New | ||||||
| Description: | Psoriasis Treatment with Abatacept and Ustekinumab: a Study of Efficacy (PAUSE), a parallel-design, double-blind, placebo-controlled randomized clinical trial, was conducted at 10 sites in the US and Canada. Participant enrollment opened on March 19, 2014, and concluded on April 11, 2016. Participants were adults with moderate to severe plaque psoriasis and received ustekinumab in a lead-in phase. Those who responded to ustekinumab at week 12 were randomized 1:1 to either the continued with ustekinumab group (ustekinumab group) or the switched to abatacept group (abatacept group). Treatment was discontinued at week 39, and participants were followed up for psoriasis relapse until week 88. Statistical analyses were performed in the intention-to-treat (ITT) and safety samples from May 3, 2018, to July 6, 2021. Interventions: Participants received subcutaneous ustekinumab at weeks 0 and 4 (45 mg per dose for those ?100 kg; 90 mg per dose for those >100 kg). Participants randomized to the abatacept group at week 12 received subcutaneous abatacept, 125 mg weekly, from weeks 12 to 39 and ustekinumab placebo at weeks 16 and 28. Participants randomized to the ustekinumab group received ustekinumab at weeks 16 and 28 and abatacept placebo weekly from weeks 12 to 39. Main outcomes and measures: The primary end point was the proportion of participants with psoriasis relapse (loss of ?50% of the initial Psoriasis Area and Severity Index improvement) between weeks 12 and 88. Secondary end points included time to psoriasis relapse, proportion of participants with psoriasis relapse between weeks 12 and 40, and adverse events. The psoriasis transcriptome and serum cytokines were evaluated. Results: A total of 108 participants (mean [SD] age, 46.1 [12.1] years; 73 [67.6%] men) were treated with open-label ustekinumab; 91 were randomized to blinded treatment. Similar proportions of participants in the abatacept group and the ustekinumab group relapsed between weeks 12 and 88 (41 of 45 [91.1%] vs 40 of 46 [87.0%]; P = .41). Median time to relapse from the last dose of ustekinumab was similar between groups as well: 36 weeks (95% CI, 36-48 weeks) in the abatacept group vs 32 weeks (95% CI, 28-40 weeks) in the ustekinumab group. Similar numbers and rates of adverse events occurred. Abatacept did not maintain suppression of the pathogenic IL-23-mediated psoriasis molecular signature in lesions after ustekinumab withdrawal, and serum IL-19 levels increased. Conclusions and relevance: This parallel-design, double-blind randomized clinical trial found that abatacept did not prevent psoriasis relapse that occurred after ustekinumab withdrawal because it did not completely block the pathogenic psoriasis molecular pathways that led to relapse. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M35RXA4O4R | ||||||
| Subjects: | 108 | ||||||
| Study PI, contact: |
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2275: CALIBRATE ITN055AI: Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | Lupus nephritis is a severe form of systemic lupus erythematosus (SLE) with active disease in the kidneys. SLE is a complex disease in which the body's own immune system attacks some of the body parts: the skin, the joints, the kidneys, the nervous system, the heart, the lungs and the blood. The cause of SLE is not known. Treatment for SLE usually involves drugs that are designed to block the immune system attacks. When SLE affects the kidneys (nephritis), stronger immune suppressing treatment is usually needed. The drugs used in treatment of lupus nephritis often do not cure the disease and can cause serious side effects, including lowering the immune system too much. When the immune system is too low, a person is at a higher risk of getting infections. Therefore, research into new treatments with fewer serious side effects is needed for lupus nephritis | |||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3U7UE12VC | |||||||||||||||
| Subjects: | 43 | |||||||||||||||
| Study PI, contact: |
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| Assays: | None | |||||||||||||||
| Clinical Assessments: | None | |||||||||||||||
Updated Studies
| SDY1025: Asthma Phenotypes in the Inner City (APIC/ICAC-19) | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | This study looks to define the phenotypic characteristics of Difficult-to-Treat asthma, among 650 children between the ages of 6 to 17 years, receiving one year of guidelines-based therapy for asthma and rhinitis/rhinosinusitis. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M39SEUM79K | ||||||||||||||||||
| Subjects: | 717 | ||||||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Assays: | None | ||||||||||||||||||
| Clinical Assessments: |
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| SDY1538: Systems Biology to Identify Biomarkers of Neonatal Vaccine Immunogenicity | ||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||
| Description: | Infection is the most common cause of death in early life, especially for newborns and can be reduced by immunization but insufficient knowledge of how vaccines protect the very young limits their optimal use. To gain insight into how vaccines induce protection of the most vulnerable, our project employs two novel approaches studying newborn responses to hepatitis B vaccine (HBV): (a) systems biology that uses technologies which comprehensively measure global changes in molecules such as transcriptomics (RNA) and proteomics (proteins), as well as cell composition of the blood and (b) use of human newborn blood components, collected prior to immunization, to model vaccine responses in vitro (outside the body). Characterizing vaccine-induced molecular patterns (signatures) that correspond to vaccine-mediated protection will accelerate development and optimization of vaccines against early life infections of major global health importance. | |||||||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M35PWV2M56 | |||||||||||||||||||||||||||
| Subjects: | 720 | |||||||||||||||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | |||||||||||||||||||||||||||
| SDY1644: Urban Environmental Factors and Childhood Asthma (URECA) (ICAC-07) | ||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||
| Description: | The purpose of this study is to determine the way environmental factors (like the components of inner-city household dust) affect immune system development and symptoms of asthma in inner city children. The study is divided into three periods, as the subjects age from birth to 10 years old. Each age bracket will explore different objectives and endpoints. Study Objectives/Hypotheses: Subjects age 0 to 3 years old: Environmental factors in the inner city adversely influence the development of the immune system to promote cytokine dysregulation, allergy, and recurrent wheezing by age 3. Children who have had a viral lower respiratory infection and have developed cytokine dysregulation by age 3 are at increased risk for the development of asthma by age 6. Subjects age 4 to 7 years old: There is a unique pattern of immune development that is driven by specific urban exposures in early life, and this pattern of immune development is characterized by: 1) impairment of antiviral responses and 2) accentuation of Th2-like responses (e.g. cockroach-specific Interleukin-13(IL-13)). The clinical effects of these changes in immune development are frequent virus-induced wheezing and allergic sensitization by 3-4 years of age, and these characteristics synergistically increase the risk of asthma at age 7 years. Subjects age 7 to 10 years old: There are unique combinations of environmental exposures (cockroach allergens, indoor pollutants [Environmental Tobacco Smoke (ETS) and Nitrogen Dioxide (NO2)], lack of microbial exposure), and family characteristics (stress, genetic factors related to innate immunity) that synergistically promote asthma onset, persistence, and morbidity in urban neighborhoods. These exposures and characteristics influence immune expression and lung development during critical periods of growth, resulting in specific asthma phenotypes. Subjects age 10 to 16 years old: To determine the wheezing, asthma and atopy phenotypes in minority children growing up in poor urban neighborhoods as they develop from birth through adolescence. | |||||||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3H1YHLR5Z | |||||||||||||||||||||||||||
| Subjects: | 1218 | |||||||||||||||||||||||||||
| Study PI, contact: |
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| SDY1781: Proinflammatory IgG Fc structures in patients with severe COVID-19 | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 infections can cause coronavirus disease 2019 (COVID-19), which manifests with a range of severities from mild illness to life-threatening pneumonia and multi-organ failure. Severe COVID-19 is characterized by an inflammatory signature, including high levels of inflammatory cytokines, alveolar inflammatory infiltrates and vascular microthrombi. Here we show that patients with severe COVID-19 produced a unique serologic signature, including an increased likelihood of IgG1 with afucosylated Fc glycans. This Fc modification on severe acute respiratory syndrome coronavirus 2 IgGs enhanced interactions with the activating Fc-Gamma receptor Fc-Gamma RIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including interleukin-6 and tumor necrosis factor. These results show that disease severity in COVID-19 correlates with the presence of proinflammatory IgG Fc structures, including afucosylated IgG1. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
| Study PI, contact: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY1798: Discovery and functional interrogation of SARS-CoV-2 RNA-host protein interactions | |||||||||||
| Status: | Updated | ||||||||||
| Description: | SARS-CoV-2 is the cause of a pandemic with growing global mortality. Using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS), we identified 309 host proteins that bind the SARS-CoV-2 RNA during active infection. Integration of this data with ChIRP-MS data from three other RNA viruses defined viral specificity of RNA-host protein interactions. Targeted CRISPR screens revealed that the majority of functional RNA-binding proteins protect the host from virus-induced cell death, and comparative CRISPR screens across seven RNA viruses revealed shared and SARS-specific antiviral factors. Finally, by combining the RNA-centric approach and functional CRISPR screens, we demonstrated a physical and functional connection between SARS-CoV-2 and mitochondria, highlighting this organelle as a general platform for antiviral activity. Altogether, these data provide a comprehensive catalog of functional SARS-CoV-2 RNA-host protein interactions, which may inform studies to understand the host-virus interface and nominate host pathways that could be targeted for therapeutic benefit. | ||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||
| Subjects: | 2 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Clinical Assessments: | None | ||||||||||
| SDY1800: Durable SARS-CoV-2 B cell immunity after mild or severe disease | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Multiple studies have shown loss of severe acute respiratory syndrome coronavirus 2-specific (SARS-CoV-2-specific) antibodies over time after infection, raising concern that humoral immunity against the virus is not durable. If immunity wanes quickly, millions of people may be at risk for reinfection after recovery from coronavirus disease 2019 (COVID-19). However, memory B cells (MBCs) could provide durable humoral immunity even if serum neutralizing antibody titers decline. We performed multidimensional flow cytometric analysis of S protein receptor binding domain-specific (S-RBD-specific) MBCs in cohorts of ambulatory patients with COVID-19 with mild disease (n = 7), and hospitalized patients with moderate to severe disease (n = 7), at a median of 54 days (range, 39-104 days) after symptom onset. We detected S-RBD-specific class-switched MBCs in 13 of 14 participants, failing only in the individual with the lowest plasma levels of anti-S-RBD IgG and neutralizing antibodies. Resting MBCs (rMBCs) made up the largest proportion of S-RBD-specific MBCs in both cohorts. FCRL5, a marker of functional memory on rMBCs, was more dramatically upregulated on S-RBD-specific rMBCs after mild infection than after severe infection. These data indicate that most SARS-CoV-2-infected individuals develop S-RBD-specific, class-switched rMBCs that resemble germinal center-derived B cells induced by effective vaccination against other pathogens, providing evidence for durable B cell-mediated immunity against SARS-CoV-2 after mild or severe disease. | ||||||||||||
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| DOI: | None | ||||||||||||
| Subjects: | 3 | ||||||||||||
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| SDY1803: Neutralizing antibody against SARS-CoV-2 spike in COVID-19 patients, health care workers, and convalescent plasma donors | |||||||||||||||||||||||||
| Status: | Updated | ||||||||||||||||||||||||
| Description: | Rapid and specific antibody testing is crucial for improved understanding, control, and treatment of COVID-19 pathogenesis. Herein, we describe and apply a rapid, sensitive, and accurate virus neutralization assay for SARS-CoV-2 antibodies. The assay is based on an HIV-1 lentiviral vector that contains a secreted intron Gaussia luciferase (Gluc) or secreted nano-luciferase reporter cassette, pseudotyped with the SARS-CoV-2 spike (S) glycoprotein, and is validated with a plaque-reduction assay using an authentic, infectious SARS-CoV-2 strain. The assay was used to evaluate SARS-CoV-2 antibodies in serum from individuals with a broad range of COVID-19 symptoms; patients included those in the intensive care unit (ICU), health care workers (HCWs), and convalescent plasma donors. The highest neutralizing antibody titers were observed among ICU patients, followed by general hospitalized patients, HCWs, and convalescent plasma donors. Our study highlights a wide phenotypic variation in human antibody responses against SARS-CoV-2 and demonstrates the efficacy of a potentially novel lentivirus pseudotype assay for high-throughput serological surveys of neutralizing antibody titers in large cohorts. | ||||||||||||||||||||||||
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| DOI: | None | ||||||||||||||||||||||||
| Subjects: | 5 | ||||||||||||||||||||||||
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| 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. | |||||||||
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| DOI: | None | |||||||||
| Subjects: | 1 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY1810: Pseudo-safety in a cohort of patients with COVID-19 discharged home from the emergency department | ||||||||||
| Status: | Updated | |||||||||
| Description: | Introduction: Emergency Departments (ED) are often the first line of contact with individuals infected with COVID-19 and play a key role in triage. However, there is currently little specific guidance for deciding when patients with COVID-19 require hospitalisation and when they may be safely observed as an outpatient. Methods: In this retrospective study, we characterised all patients with COVID-19 discharged home from EDs in our US multisite healthcare system from March 2020 to August 2020, focusing on individuals who returned within 2 weeks and required hospital admission. We restricted analyses to first-encounter data that do not depend on laboratory or imaging diagnostics in order to inform point-of-care assessments in resource-limited environments. Vitals and comorbidities were extracted from the electronic health record. We performed ordinal logistic regression analyses to identify predictors of inpatient admission, intensive care and intubation. Results: Of n=923 patients who were COVID-19 positive discharged from the ED, n=107 (11.6%) returned within 2 weeks and were admitted. In a multivariable-adjusted model including n=788 patients with complete risk factor information, history of hypertension increased odds of hospitalisation and severe illness by 1.92-fold (95% CI 1.07 to 3.41), diabetes by 2.20-fold (1.18 to 4.02), chronic lung disease by 2.21-fold (1.22 to 3.92) and fever by 2.89-fold (1.71 to 4.82). Having at least two of these risk factors increased the odds of future hospitalisation by 6.68-fold (3.54 to 12.70). Patients with hypertension, diabetes, chronic lung disease or fever had significantly longer hospital stays (median 5.92 days, 3.08-10.95 vs 3.21, 1.10-5.75, p<0.01) with numerically higher but not significantly different rates of intensive care unit admission (27.02% vs 14.30%, p=0.27) and intubation (12.16% vs 7.14%, p=0.71). Discussion: Patients infected with COVID-19 may appear clinically safe for home convalescence. However, those with hypertension, diabetes, chronic lung disease and fever may in fact be only 'pseudo-safe' and are most at risk for subsequent hospitalisation with more severe illness and longer hospital stays. | |||||||||
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| DOI: | None | |||||||||
| Subjects: | 1 | |||||||||
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| SDY1812: Repeated cross-sectional sero-monitoring of SARS-CoV-2 in New York City | ||||||||||
| Status: | Updated | |||||||||
| Description: | In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first detected in China and has since caused a pandemic of coronavirus disease 2019 (COVID-19). The first case of COVID-19 in New York City was officially confirmed on 1 March 2020 followed by a severe local epidemic1. Here, to understand seroprevalence dynamics, we conduct a retrospective, repeated cross-sectional analysis of anti-SARS-CoV-2 spike antibodies in weekly intervals from the beginning of February to July 2020 using more than 10,000 plasma samples from patients at Mount Sinai Hospital in New York City. We describe the dynamics of seroprevalence in an 'urgent care' group, which is enriched in cases of COVID-19 during the epidemic, and a 'routine care' group, which more closely represents the general population. Seroprevalence increased at different rates in both groups; seropositive samples were found as early as mid-February, and levelled out at slightly above 20% in both groups after the epidemic wave subsided by the end of May. From May to July, seroprevalence remained stable, suggesting lasting antibody levels in the population. Our data suggest that SARS-CoV-2 was introduced in New York City earlier than previously documented and describe the dynamics of seroconversion over the full course of the first wave of the pandemic in a major metropolitan area. | |||||||||
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| DOI: | None | |||||||||
| Subjects: | 6 | |||||||||
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| SDY1813: Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | T cells are involved in control of SARS-CoV-2 infection. To establish the patterns of immunodominance of different SARS-CoV-2 antigens and precisely measure virus-specific CD4+ and CD8+ T cells, we study epitope-specific T cell responses of 99 convalescent coronavirus disease 2019 (COVID-19) cases. The SARS-CoV-2 proteome is probed using 1,925 peptides spanning the entire genome, ensuring an unbiased coverage of human leukocyte antigen (HLA) alleles for class II responses. For HLA class I, we study an additional 5,600 predicted binding epitopes for 28 prominent HLA class I alleles, accounting for wide global coverage. We identify several hundred HLA-restricted SARS-CoV-2-derived epitopes. Distinct patterns of immunodominance are observed, which differ for CD4+ T cells, CD8+ T cells, and antibodies. The class I and class II epitopes are combined into epitope megapools to facilitate identification and quantification of SARS-CoV-2-specific CD4+ and CD8+ T cells. | ||||||||||||
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| DOI: | None | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY1815: Functional characterization of CD4+ T cell receptors crossreactive for SARS-CoV-2 and endemic coronaviruses | |||||||
| Status: | Updated | ||||||
| Description: | Recent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unexposed donors, possibly due to crossrecognition by T cells specific for common cold coronaviruses (CCCs). True T cell crossreactivity, defined as the recognition by a single TCR of more than one distinct peptide-MHC ligand, has never been shown in the context of SARS-CoV-2.METHODS: We used the viral functional expansion of specific T cells (ViraFEST) platform to identify T cell responses crossreactive for the spike (S) glycoproteins of SARS-CoV-2 and CCCs at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2-unexposed donors. Confirmation of SARS-CoV-2/CCC crossreactivity and assessments of functional avidity were performed using a TCR cloning and transfection system.RESULTS: Memory CD4+ T cell clonotypes that crossrecognized the S proteins of SARS-CoV-2 and at least one other CCC were detected in 65% of CCPs and unexposed donors. Several of these TCRs were shared among multiple donors. Crossreactive T cells demonstrated significantly impaired SARS-CoV-2-specific proliferation in vitro relative to monospecific CD4+ T cells, which was consistent with lower functional avidity of their TCRs for SARS-CoV-2 relative to CCC.CONCLUSIONSOur data confirm, for what we believe is the first time, the existence of unique memory CD4+ T cell clonotypes crossrecognizing SARS-CoV-2 and CCCs. The lower avidity of crossreactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that preexisting CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these crossreactive T cell responses affect clinical outcomes in COVID-19 patients. | ||||||
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| DOI: | 10.21430/M3C1CZ1MF2 | ||||||
| Subjects: | 2 | ||||||
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| SDY1816: Vascular Disease and Thrombosis in SARS-CoV-2-Infected Rhesus Macaques | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | The COVID-19 pandemic has led to extensive morbidity and mortality throughout the world. Clinical features that drive SARS-CoV-2 pathogenesis in humans include inflammation and thrombosis, but the mechanistic details underlying these processes remain to be determined. In this study, we demonstrate endothelial disruption and vascular thrombosis in histopathologic sections of lungs from both humans and rhesus macaques infected with SARS-CoV-2. To define key molecular pathways associated with SARS-CoV-2 pathogenesis in macaques, we performed transcriptomic analyses of bronchoalveolar lavage and peripheral blood and proteomic analyses of serum. We observed macrophage infiltrates in lung and upregulation of macrophage, complement, platelet activation, thrombosis, and proinflammatory markers, including C-reactive protein, MX1, IL-6, IL-1, IL-8, TNF-Alpha, and NF-KappaB. These results suggest a model in which critical interactions between inflammatory and thrombosis pathways lead to SARS-CoV-2-induced vascular disease. Our findings suggest potential therapeutic targets for COVID-19. | ||||||||||||
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| DOI: | None | ||||||||||||
| Subjects: | 2 | ||||||||||||
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| SDY1818: Correlates of Protection Against SARS-CoV-2 in Rhesus Macaques | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | Recent studies have reported protective efficacy of both natural immunity and vaccine-induced immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge in rhesus macaques. However, the importance of humoral and cellular immunity for protection against SARS-CoV-2 infection remains to be determined. Here we show that adoptive transfer of purified IgG from convalescent macaques protects naive recipient rhesus macaques against SARS-CoV-2 challenge in a dose dependent fashion. Depletion of CD8+ T cells in convalescent animals partially abrogated the protective efficacy of natural immunity against SARS-CoV-2 re-challenge, suggesting the importance of cellular immunity in the context of waning or subprotective antibody titers. These data demonstrate that relatively low antibody titers are sufficient for protection against SARS-CoV-2 in rhesus macaques, and that cellular immune responses may also contribute to protection if antibody responses are suboptimal. We also show that higher antibody titers are required for therapy of SARS-CoV-2 infection in macaques. These findings have important implications for the development of SARS-CoV-2 vaccines and immune-based therapeutics. | |||||||||||||||
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| DOI: | None | |||||||||||||||
| Subjects: | 7 | |||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||
| SDY1819: Comparison of Subgenomic and Total RNA in SARS-CoV-2 Challenged Rhesus Macaques | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Respiratory virus challenge studies involve administration of the challenge virus and sampling to assess for protection in the same anatomical locations. It can therefore be difficult to differentiate actively replicating virus from input challenge virus. For SARS-CoV-2, specific monitoring of actively replicating virus is critical for investigating the protective and therapeutic efficacy of vaccines, monoclonal antibodies, and antiviral drugs. We adapted a SARS-CoV-2 subgenomic RNA (sgRNA) RT-PCR assay to differentiate productive infection from inactivated or neutralized virus. Subgenomic RNAs are generated after cell entry and are poorly incorporated into mature virions, and thus may provide a marker for actively replicating virus. We show envelope (E) sgRNA was degraded by RNase in infected cell lysates, while genomic RNA (gRNA) was protected, presumably due to packaging into virions. To investigate the capacity of the sgRNA assay to distinguish input challenge virus from actively replicating virus in vivo, we compared the E sgRNA assay to a standard nucleoprotein (N) or E total (both gRNA and sgRNA) RNA in convalescent rhesus macaques and in antibody-treated rhesus macaques after experimental SARS-CoV-2 challenge. In both studies, the E sgRNA assay was negative, suggesting protective efficacy, whereas the N and E total RNA assays remained positive. These data suggest the potential utility of sgRNA to monitor actively replicating virus in prophylactic and therapeutic SARS-CoV-2 studies. Importance: Developing therapeutic and prophylactic countermeasures for the SARS-CoV-2 virus is a public health priority. During challenge studies, respiratory viruses are delivered and sampled from the same anatomical location. It is therefore important to distinguish actively replicating virus from input challenge virus. The most common assay for detecting SARS-CoV-2 virus, reverse transcription polymerase chain reaction (RT-PCR) targeting nucleocapsid total RNA, cannot distinguish neutralized input virus from replicating virus. In this study, we assess SARS-CoV-2 subgenomic RNA as a potential measure of replicating virus in rhesus macaques. | ||||||||||||
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| DOI: | None | ||||||||||||
| Subjects: | 4 | ||||||||||||
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| SDY1821: MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Recent studies have profiled the innate immune signatures in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and suggest that cellular responses to viral challenge may affect disease severity. Yet the molecular events that underlie cellular recognition and response to SARS-CoV-2 infection remain to be elucidated. Here, we find that SARS-CoV-2 replication induces a delayed interferon (IFN) response in lung epithelial cells. By screening 16 putative sensors involved in sensing of RNA virus infection, we found that MDA5 and LGP2 primarily regulate IFN induction in response to SARS-CoV-2 infection. Further analyses revealed that viral intermediates specifically activate the IFN response through MDA5-mediated sensing. Additionally, we find that IRF3, IRF5, and NF-B/p65 are the key transcription factors regulating the IFN response during SARS-CoV-2 infection. In summary, these findings provide critical insights into the molecular basis of the innate immune recognition and signaling response to SARS-CoV-2. | ||||||||||||
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| DOI: | None | ||||||||||||
| Subjects: | 3 | ||||||||||||
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| SDY1829: Severely ill COVID-19 patients display impaired exhaustion features in SARS-CoV-2-reactive CD8+ T cells | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | The molecular properties of CD8+ T cells that respond to SARS-CoV-2 infection are not fully known. Here, we report on the single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells, obtained using a modified Antigen-Reactive T cell Enrichment (ARTE) assay, from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patients segregated into two groups based on whether the dominant CD8+ T cell response to SARS-CoV-2 was 'exhausted' or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed lesser cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the dominant non-exhausted subset from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival NF-KappaB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8+ T cell memory responses in patients with severe COVID-19 illness. CD8+ T cells reactive to influenza and respiratory syncytial virus from healthy subjects displayed polyfunctional features and enhanced glycolysis. Cells with such features were largely absent in SARS-CoV-2-reactive cells from both COVID-19 patients and healthy controls non-exposed to SARS-CoV-2. Overall, our single-cell analysis revealed substantial diversity in the nature of CD8+ T cells responding to SARS-CoV-2. | ||||||||||||
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| DOI: | None | ||||||||||||
| Subjects: | 4 | ||||||||||||
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| SDY1831: Serological analysis reveals an imbalanced IgG subclass composition associated with COVID-19 disease severity | |||||||||||||||||||||||||
| Status: | Updated | ||||||||||||||||||||||||
| Description: | Coronavirus disease 2019 (COVID-19) is associated with a wide spectrum of disease presentation, ranging from asymptomatic infection to acute respiratory distress syndrome (ARDS). Paradoxically, a direct relationship has been suggested between COVID-19 disease severity and the levels of circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies, including virus-neutralizing titers. A serological analysis of 536 convalescent healthcare workers reveals that SARS-CoV-2-specific and virus-neutralizing antibody levels are elevated in individuals that experience severe disease. The severity-associated increase in SARS-CoV-2-specific antibody is dominated by immunoglobulin G (IgG), with an IgG subclass ratio skewed toward elevated receptor binding domain (RBD)- and S1-specific IgG3. In addition, individuals that experience severe disease show elevated SARS-CoV-2-specific antibody binding to the inflammatory receptor Fc?RIIIa. Based on these correlational studies, we propose that spike-specific IgG subclass utilization may contribute to COVID-19 disease severity through potent Fc-mediated effector functions. These results may have significant implications for SARS-CoV-2 vaccine design and convalescent plasma therapy. | ||||||||||||||||||||||||
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| DOI: | None | ||||||||||||||||||||||||
| Subjects: | 5 | ||||||||||||||||||||||||
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| SDY1832: Immunological imprinting of the antibody response in COVID-19 patients | ||||||||||
| Status: | Updated | |||||||||
| Description: | In addition to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), humans are also susceptible to six other coronaviruses, for which consecutive exposures to antigenically related and divergent seasonal coronaviruses are frequent. Despite the prevalence of COVID-19 pandemic and ongoing research, the nature of the antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here we longitudinally profile the early humoral immune response against SARS-CoV-2 in hospitalized coronavirus disease 2019 (COVID-19) patients and quantify levels of pre-existing immunity to OC43, HKU1 and 229E seasonal coronaviruses, and find a strong back-boosting effect to conserved but not variable regions of OC43 and HKU1 betacoronaviruses spike protein. However, such antibody memory boost to human coronaviruses negatively correlates with the induction of IgG and IgM against SARS-CoV-2 spike and nucleocapsid protein. Our findings thus provide evidence of immunological imprinting by previous seasonal coronavirus infections that can potentially modulate the antibody profile to SARS-CoV-2 infection. | |||||||||
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| DOI: | None | |||||||||
| Subjects: | 3 | |||||||||
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| SDY1835: Delayed Rise of Oral Fluid Antibodies, Elevated BMI, and Absence of Early Fever Correlate With Longer Time to SARS-CoV-2 RNA Clearance in a Longitudinally Sampled Cohort of COVID-19 Outpatients | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Sustained molecular detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in the upper respiratory tract (URT) in mild to moderate coronavirus disease 2019 (COVID-19) is common. We sought to identify host and immune determinants of prolonged SARS-CoV-2 RNA detection. Methods : Ninety-five symptomatic outpatients self-collected midturbinate nasal, oropharyngeal (OP), and gingival crevicular fluid (oral fluid) samples at home and in a research clinic a median of 6 times over 1-3 months. Samples were tested for viral RNA, virus culture, and SARS-CoV-2 and other human coronavirus antibodies, and associations were estimated using Cox proportional hazards models. Results : Viral RNA clearance, as measured by SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR), in 507 URT samples occurred a median (interquartile range) 33.5 (17-63.5) days post-symptom onset. Sixteen nasal-OP samples collected 2-11 days post-symptom onset were virus culture positive out of 183 RT-PCR-positive samples tested. All participants but 1 with positive virus culture were negative for concomitant oral fluid anti-SARS-CoV-2 antibodies. The mean time to first antibody detection in oral fluid was 8-13 days post-symptom onset. A longer time to first detection of oral fluid anti-SARS-CoV-2 S antibodies (adjusted hazard ratio [aHR], 0.96; 95% CI, 0.92-0.99; P = .020) and body mass index (BMI) >=25 kg/m2 (aHR, 0.37; 95% CI, 0.18-0.78; P = .009) were independently associated with a longer time to SARS-CoV-2 viral RNA clearance. Fever as 1 of first 3 COVID-19 symptoms correlated with shorter time to viral RNA clearance (aHR, 2.06; 95% CI, 1.02-4.18; P = .044). Conclusions : We demonstrate that delayed rise of oral fluid SARS-CoV-2-specific antibodies, elevated BMI, and absence of early fever are independently associated with delayed URT viral RNA clearance. | ||||||||||||
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| DOI: | None | ||||||||||||
| Subjects: | 3 | ||||||||||||
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| SDY1840: Tissue-based SARS-CoV-2 detection in fatal COVID-19 infections: Sustained direct viral-induced damage is not necessary to drive disease progression | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Coronavirus disease 2019 (COVID-19) is an ongoing pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although viral infection is known to trigger inflammatory processes contributing to tissue injury and organ failure, it is unclear whether direct viral damage is needed to sustain cellular injury. An understanding of pathogenic mechanisms has been handicapped by the absence of optimized methods to visualize the presence and distribution of SARS-CoV-2 in damaged tissues. We first developed a positive control cell line (Vero E6) to validate SARS-CoV-2 detection assays. We then evaluated multiple organs (lungs, kidneys, heart, liver, brain, intestines, lymph nodes, and spleen) from fourteen COVID-19 autopsy cases using immunohistochemistry (IHC) for the spike and the nucleoprotein proteins, and RNA in situ hybridization (RNA ISH) for the spike protein mRNA. Tissue detection assays were compared with quantitative polymerase chain reaction (qPCR)-based detection. SARS-CoV-2 was histologically detected in the Vero E6 positive cell line control, 1 of 14 (7%) lungs, and none (0%) of the other 59 organs. There was perfect concordance between the IHC and RNA ISH results. qPCR confirmed high viral load in the SARS-CoV-2 ISH-positive lung tissue, and absent or low viral load in all ISH-negative tissues. In patients who die of COVID-19-related organ failure, SARS-CoV-2 is largely not detectable using tissue-based assays. Even in lungs showing widespread injury, SARS-CoV-2 viral RNA or proteins were detected in only a small minority of cases. This observation supports the concept that viral infection is primarily a trigger for multiple-organ pathogenic proinflammatory responses. Direct viral tissue damage is a transient phenomenon that is generally not sustained throughout disease progression. | ||||||||||
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| DOI: | None | ||||||||||
| Subjects: | 2 | ||||||||||
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| 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. | |||||||||
| Program/Contract: |
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| DOI: | None | |||||||||
| Subjects: | 1 | |||||||||
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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: | None | |||||||||
| Subjects: | 1 | |||||||||
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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: | None | |||||||||
| Subjects: | 2 | |||||||||
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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: | None | ||||||
| Subjects: | 2 | ||||||
| Study PI, contact: |
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1868: Critical ACE2 Determinants of SARS-CoV-2 and Group 2B Coronavirus Infection and Replication | |||||||||
| Status: | Updated | ||||||||
| Description: | The angiotensin-converting enzyme 2 (ACE2) receptor is a major severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) host range determinant, and understanding SARS-CoV-2-ACE2 interactions will provide important insights into COVID-19 pathogenesis and animal model development. SARS-CoV-2 cannot infect mice due to incompatibility between its receptor binding domain and the murine ACE2 receptor. Through molecular modeling and empirical in vitro validation, we identified 5 key amino acid differences between murine and human ACE2 that mediate SARS-CoV-2 infection, generating a chimeric humanized murine ACE2. Additionally, we examined the ability of the humanized murine ACE2 receptor to permit infection by an additional preemergent group 2B coronavirus, WIV-1, providing evidence for the potential pan-virus capabilities of this chimeric receptor. Finally, we predicted the ability of these determinants to inform host range identification of preemergent coronaviruses by evaluating hot spot contacts between SARS-CoV-2 and additional potential host receptors. Our results identify residue determinants that mediate coronavirus receptor usage and host range for application in SARS-CoV-2 and emerging coronavirus animal model development. | ||||||||
| Program/Contract: |
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| DOI: | None | ||||||||
| Subjects: | 7 | ||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||
| SDY1890: SARS-CoV-2 Spreads through Cell-to-Cell Transmission | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible coronavirus responsible for the global COVID-19 pandemic. Herein we provide evidence that SARS-CoV-2 spreads through cell-cell contact in cultures, mediated by the spike glycoprotein. SARS-CoV-2 spike is more efficient in facilitating cell-to-cell transmission than SARS-CoV spike, which reflects, in part, their differential cell-cell fusion activity. Interestingly, treatment of cocultured cells with endosomal entry inhibitors impairs cell-to-cell transmission, implicating endosomal membrane fusion as an underlying mechanism. Compared with cell-free infection, cell-to-cell transmission of SARS-CoV-2 is refractory to inhibition by neutralizing antibody or convalescent sera of COVID-19 patients. While ACE2 enhances cell-to-cell transmission, we find that it is not absolutely required. Notably, despite differences in cell-free infectivity, the variants of concern (VOC) B.1.1.7 and B.1.351 have similar cell-to-cell transmission capability. Moreover, B.1.351 is more resistant to neutralization by vaccinee sera in cell-free infection, whereas B.1.1.7 is more resistant to inhibition by vaccine sera in cell-to-cell transmission. Overall, our study reveals critical features of SARS-CoV-2 spike-mediated cell-to-cell transmission, with important implications for a better understanding of SARS-CoV-2 spread and pathogenesis. | ||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||
| Subjects: | 8 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY1916: Inhibition of elastase enhances the adjuvanticity of alum and promotes anti-SARS-CoV-2 systemic and mucosal immunity | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | Alum, used as an adjuvant in injected vaccines, promotes T helper 2 (Th2) and serum antibody (Ab) responses. However, it fails to induce secretory immunoglobulin (Ig) A (SIgA) in mucosal tissues and is poor in inducing Th1 and cell-mediated immunity. Alum stimulates interleukin 1 (IL-1) and the recruitment of myeloid cells, including neutrophils. We investigated whether neutrophil elastase regulates the adjuvanticity of alum, and whether a strategy targeting neutrophil elastase could improve responses to injected vaccines. Mice coadministered a pharmacological inhibitor of elastase, or lacking elastase, developed high-affinity serum IgG and IgA antibodies after immunization with alum-adsorbed protein vaccines, including the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). These mice also developed broader antigen-specific CD4+ T cell responses, including high Th1 and T follicular helper (Tfh) responses. Interestingly, in the absence of elastase activity, mucosal SIgA responses were induced after systemic immunization with alum as adjuvant. Importantly, lack or suppression of elastase activity enhanced the magnitude of anti-SARS-CoV-2 spike subunit 1 (S1) antibodies, and these antibodies reacted with the same epitopes of spike 1 protein as sera from COVID-19 patients. Therefore, suppression of neutrophil elastase could represent an attractive strategy for improving the efficacy of alum-based injected vaccines for the induction of broad immunity, including mucosal immunity. | ||||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||||
| Subjects: | 6 | ||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||||
| SDY1917: Impaired neutralizing antibody response to COVID-19 mRNA vaccines in cancer patients | ||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||
| Description: | There is currently a critical need to determine the efficacy of SARS-CoV-2 vaccination for immunocompromised patients. In this study, we determined the neutralizing antibody response in 160 cancer patients diagnosed with chronic lymphocytic leukemia (CLL), lung cancer, breast cancer, and various non-Hodgkin's lymphomas (NHL), after they received two doses of mRNA vaccines. Serum from 46 mRNA vaccinated health care workers (HCWs) served as healthy controls. We discovered that (1) cancer patients exhibited reduced neutralizing antibody titer (NT50) compared to HCWs; (2) CLL and NHL patients exhibited the lowest NT50 levels, with 50-60% of them below the detection limit; (3) mean NT50 levels in patients with CLL and NHL was ~2.6 fold lower than those with solid tumors; and (4) cancer patients who received anti-B cell therapy exhibited significantly reduced NT50 levels. Our results demonstrate an urgent need for novel immunization strategies for cancer patients against SARS-CoV-2, particularly those with hematological cancers and those on anti-B cell therapies. | |||||||||||||||||||||
| Program/Contract: |
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| DOI: | None | |||||||||||||||||||||
| Subjects: | 2 | |||||||||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | |||||||||||||||||||||
| SDY1927: Corticosteroid treatment in COVID-19 modulates host inflammatory responses and transcriptional signatures of immune dysregulation | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease-2019 (COVID-19), a respiratory disease that varies in severity from mild to severe/fatal. Several risk factors for severe disease have been identified, notably age, male sex, and pre-existing conditions such as diabetes, obesity, and hypertension. Several advancements in clinical care have been achieved over the past year, including the use of corticosteroids (e.g., corticosteroids) and other immune-modulatory treatments that have now become standard of care for patients with acute severe COVID-19. While the understanding of the mechanisms that underlie increased disease severity with age has improved over the past few months, it remains incomplete. Furthermore, the molecular impact of corticosteroid treatment on host response to acute SARS-CoV-2 infection has not been investigated. In this study, a cross-sectional and longitudinal analysis of Ab, soluble immune mediators, and transcriptional responses in young (< or = 65 years) and aged (> 65 years) diabetic males with obesity hospitalized with acute severe COVID-19 was conducted. Additionally, the transcriptional profiles in samples obtained before and after corticosteroids became standard of care were compared. The analysis indicates that severe COVID-19 is characterized by robust Ab responses, heightened systemic inflammation, increased expression of genes related to inflammatory and pro-apoptotic processes, and reduced expression of those important for adaptive immunity regardless of age. In contrast, COVID-19 patients receiving steroids did not show high levels of systemic immune mediators and lacked transcriptional indicators of heightened inflammatory and apoptotic responses. Overall, these data suggest that inflammation and cell death are key drivers of severe COVID-19 pathogenesis in the absence of corticosteroid therapy. | ||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||
| Subjects: | 8 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY1932: Cross-Reactive Antibodies to SARS-CoV-2 and MERS-CoV in Pre-COVID-19 Blood Samples from Sierra Leoneans | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | Many countries in sub-Saharan Africa have experienced lower COVID-19 caseloads and fewer deaths than countries in other regions worldwide. Under-reporting of cases and a younger population could partly account for these differences, but pre-existing immunity to coronaviruses is another potential factor. Blood samples from Sierra Leonean Lassa fever and Ebola survivors and their contacts collected before the first reported COVID-19 cases were assessed using enzyme-linked immunosorbent assays for the presence of antibodies binding to proteins of coronaviruses that infect humans. Results were compared to COVID-19 subjects and healthy blood donors from the United States. Prior to the pandemic, Sierra Leoneans had more frequent exposures than Americans to coronaviruses with epitopes that cross-react with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), SARS-CoV, and Middle Eastern respiratory syndrome coronavirus (MERS-CoV). The percentage of Sierra Leoneans with antibodies reacting to seasonal coronaviruses was also higher than for American blood donors. Serological responses to coronaviruses by Sierra Leoneans did not differ by age or sex. Approximately a quarter of Sierra Leonian pre-pandemic blood samples had neutralizing antibodies against SARS-CoV-2 pseudovirus, while about a third neutralized MERS-CoV pseudovirus. Prior exposures to coronaviruses that induce cross-protective immunity may contribute to reduced COVID-19 cases and deaths in Sierra Leone. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||||||||
| Subjects: | 3 | ||||||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY1945: A humanized mouse model of chronic COVID-19 | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Coronavirus disease 2019 (COVID-19) is an infectious disease that can present as an uncontrolled, hyperactive immune response, causing severe immunological injury. Existing rodent models do not recapitulate the sustained immunopathology of patients with severe disease. Here we describe a humanized mouse model of COVID-19 that uses adeno-associated virus to deliver human ACE2 to the lungs of humanized MISTRG6 mice. This model recapitulates innate and adaptive human immune responses to severe acute respiratory syndrome coronavirus 2 infection up to 28 days after infection, with key features of chronic COVID-19, including weight loss, persistent viral RNA, lung pathology with fibrosis, a human inflammatory macrophage response, a persistent interferon-stimulated gene signature and T cell lymphopenia. We used this model to study two therapeutics on immunopathology, patient-derived antibodies and steroids and found that the same inflammatory macrophages crucial to containing early infection later drove immunopathology. This model will enable evaluation of COVID-19 disease mechanisms and treatments. | ||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||
| Subjects: | 2 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY1947: Function Is More Reliable Than Quantity to Follow Up the Humoral Response to the Receptor-Binding Domain of SARS-CoV-2-Spike Protein after Natural Infection or COVID-19 Vaccination | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | Both the SARS-CoV-2 pandemic and emergence of variants of concern have highlighted the need for functional antibody assays to monitor the humoral response over time. Antibodies directed against the spike (S) protein of SARS-CoV-2 are an important component of the neutralizing antibody response. In this work, we report that in a subset of patients -despite a decline in total S-specific antibodies- neutralizing antibody titers remain at a similar level for an average of 98 days in longitudinal sampling of a cohort of 59 Hispanic/Latino patients exposed to SARS-CoV-2. Our data suggest that 100% of seroconverting patients make detectable neutralizing antibody responses which can be quantified by a surrogate viral neutralization test. Examination of sera from ten out of the 59 subjects which received mRNA-based vaccination revealed that both IgG titers and neutralizing activity of sera were higher after vaccination compared to a cohort of 21 SARS-CoV-2 naive subjects. One dose was sufficient for the induction of a neutralizing antibody, but two doses were necessary to reach 100% surrogate virus neutralization in subjects irrespective of previous SARS-CoV-2 natural infection status. Like the pattern observed after natural infection, the total anti-S antibodies titers declined after the second vaccine dose; however, neutralizing activity remained relatively constant for more than 80 days after the first vaccine dose. Furthermore, our data indicates that -compared with mRNA vaccination- natural infection induces a more robust humoral immune response in unexposed subjects. This work is an important contribution to understanding the natural immune response to the novel coronavirus in a population severely impacted by SARS-CoV-2. Furthermore, by comparing the dynamics of the immune response after the natural infection vs. the vaccination, these findings suggest that functional neutralizing antibody tests are more relevant indicators than the presence or absence of binding antibodies. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||||||||
| Subjects: | 3 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY1962: Does a lack of vaccine side effects correlate with reduced BNT162b2 mRNA vaccine response among healthcare workers and nursing home residents? | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Background: The BNT162b2 SARS-CoV-2 mRNA vaccination has mitigated the burden of COVID-19 among residents of long-term care facilities considerably, despite being excluded from the vaccine trials. Data on reactogenicity (vaccine side effects) in this population are limited.Aims: To assess reactogenicity among nursing home (NH) residents. To provide a plausible proxy for predicting vaccine response among this population.Methods: We enrolled and sampled NH residents and community-dwelling healthcare workers who received the BNT162b2 mRNA vaccine, to assess local or systemic reactogenicity and antibody levels (immunogenicity).Results: NH residents reported reactions at a much lower frequency and lesser severity than the community-dwelling healthcare workers. These reactions were mild and transient with all subjects experiencing more local than systemic reactions. Based on our reactogenicity and immunogenicity data, we developed a linear regression model predicting log-transformed anti-spike, anti-receptor-binding domain (RBD), and neutralizing titers, with a dichotomous variable indicating the presence or absence of reported reactions which revealed a statistically significant effect, with estimated shifts in log-transformed titers ranging from 0.32 to 0.37 (all p < 0.01) indicating greater immunogenicity in subjects with one or more reported reactions of varying severity.Discussion: With a significantly lower incidence of post-vaccination reactions among NH residents as reported in this study, the BNT162b2 mRNA vaccine appears to be well-tolerated among this vulnerable population. If validated in larger populations, absence of reactogenicity could help guide clinicians in prioritizing vaccine boosters.Conclusions: Reactogenicity is significantly mild among nursing home residents and overall, subjects who reported post-vaccination reactions developed higher antibody titers. | ||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||
| Subjects: | 4 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY1963: Protective efficacy of Ad26.COV2.S against SARS-CoV-2 B.1.351 in macaques | ||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||
| Description: | The emergence of SARS-CoV-2 variants that partially evade neutralizing antibodies poses a threat to the efficacy of current COVID-19 vaccines1,2. The Ad26.COV2.S vaccine expresses a stabilized spike protein from the WA1/2020 strain of SARS-CoV-2, and has recently demonstrated protective efficacy against symptomatic COVID-19 in humans in several geographical regions?including in South Africa, where 95% of sequenced viruses in cases of COVID-19 were the B.1.351 variant3. Here we show that Ad26.COV2.S elicits humoral and cellular immune responses that cross-react with the B.1.351 variant and protects against B.1.351 challenge in rhesus macaques. Ad26.COV2.S induced lower binding and neutralizing antibodies against B.1.351 as compared to WA1/2020, but elicited comparable CD8 and CD4 T cell responses against the WA1/2020, B.1.351, B.1.1.7, P.1 and CAL.20C variants. B.1.351 infection of control rhesus macaques resulted in higher levels of virus replication in bronchoalveolar lavage and nasal swabs than did WA1/2020 infection. Ad26.COV2.S provided robust protection against both WA1/2020 and B.1.351, although we observed higher levels of virus in vaccinated macaques after B.1.351 challenge. These data demonstrate that Ad26.COV2.S provided robust protection against B.1.351 challenge in rhesus macaques. Our findings have important implications for vaccine control of SARS-CoV-2 variants of concern. | |||||||||||||||||||||
| Program/Contract: |
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| DOI: | None | |||||||||||||||||||||
| Subjects: | 6 | |||||||||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||||||||
| SDY1964: Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine | ||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||
| Description: | The CVnCoV (CureVac) mRNA vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was recently evaluated in a phase 2b/3 efficacy trial in humans1. CV2CoV is a second-generation mRNA vaccine containing non-modified nucleosides but with optimized non-coding regions and enhanced antigen expression. Here we report the results of a head-to-head comparison of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in non-human primates. We immunized 18 cynomolgus macaques with two doses of 12??g lipid nanoparticle-formulated CVnCoV or CV2CoV or with sham (n?=?6 per group). Compared with CVnCoV, CV2CoV induced substantially higher titres of binding and neutralizing antibodies, memory B cell responses and T cell responses as well as more potent neutralizing antibody responses against SARS-CoV-2 variants, including the Delta variant. Moreover, CV2CoV was found to be comparably immunogenic to the BNT162b2 (Pfizer) vaccine in macaques. Although CVnCoV provided partial protection against SARS-CoV-2 challenge, CV2CoV afforded more robust protection with markedly lower viral loads in the upper and lower respiratory tracts. Binding and neutralizing antibody titres were correlated with protective efficacy. These data demonstrate that optimization of non-coding regions can greatly improve the immunogenicity and protective efficacy of a non-modified mRNA SARS-CoV-2 vaccine in non-human primates. | |||||||||||||||||||||
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| DOI: | None | |||||||||||||||||||||
| Subjects: | 3 | |||||||||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||||||||
| SDY1965: Virological Characteristics ofHospitalized Children WithSARS-CoV-2 Infection | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | In children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, virological characteristics and correlation with disease severity have not been extensively studied. The primary objective in this study is to determine the correlation between SARS-CoV-2 viral load (VL) in infected children with age, disease severity, and underlying comorbidities.Children ,21 years, screened for SARS-CoV-2 at the time of hospitalization, who tested positive by polymerase chain reaction were included in this study. VL at different sites was determined and compared between groups. Of the 102 children included in this study, 44% of the cohort had asymptomatic infection, and children with .1 comorbidity were the most at risk for severe disease. VL in children with symptomatic infection was significantly higher than in children with asymptomatic infection (3.0 3 105 vs 7.2 3 103 copies per mL; P = .001). VL in the respiratory tract was significantly higher in children ,1 year, compared with older children (3.3 3 107 vs 1.3 3 104 copies per mL respectively; P , .0001), despite most infants presenting with milder illness. Besides the respiratory tract, SARS-CoV-2 RNA was also detectable in samples from the gastrointestinal tract (saliva and rectum) and blood. In 13 children for whom data on duration of polymerase chain reaction positivity was available, 12 of 13 tested positive 2 weeks after initial diagnosis, and 6 of 13 continued to test positive 4 weeks after initial diagnosis. In hospitalized children with SARS-CoV-2, those with .1 comorbid condition experienced severe disease. SARS-CoV-2 VL in the respiratory tract is significantly higher in children with symptomatic disease and children ,1 year of age. | ||||||||||||
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| DOI: | None | ||||||||||||
| Subjects: | 3 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY1966: A combination of two human neutralizing antibodies prevents SARS-CoV-2 infection in cynomolgus macaques | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Background: Human monoclonal antibody (mAb) treatments are promising for COVID-19 prevention or therapy. The pre-exposure prophylactic efficacy of neutralizing antibodies that are engineered with mutations to extend their persistence in human serum and the neutralizing antibody titer in serum required for protection against SARS-CoV-2 infection remain poorly characterized.Methods: The Fc region of two neutralizing mAbs (COV2-2130 and COV2-2381) targeting non-overlapping epitopes on the receptor binding domain of SARS-CoV-2 spike protein was engineered to extend their persistence in humans and reduce interactions with Fc gamma receptors. We assessed protection by individual antibodies or a combination of the two antibodies (designated ADM03820) given prophylactically by an intravenous or intramuscular route in a non-human primate (NHP) model of SARS-CoV-2 infection.Findings: Passive transfer of individual mAbs or ADM03820 conferred virological protection in the NHP respiratory tract in a dose-dependent manner, and ADM03820 potently neutralized SARS-CoV-2 variants of concern in vitro. We defined a protective serum-neutralizing antibody titer and concentration in NHPs for passively transferred human antibodies that acted by direct viral neutralization.Conclusions: In summary, we demonstrate that neutralizing antibodies with extended half-life and lacking Fc-mediated effector functions are efficient for pre-exposure prophylaxis of SARS-CoV-2 infection in NHPs. These results support clinical development of ADM03820 for COVID-19 prevention. | ||||||||||
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| DOI: | None | ||||||||||
| Subjects: | 6 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY1967: Longitudinal SARS-CoV-2 mRNA Vaccine-Induced Humoral Immune Responses in Patients with Cancer | ||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||
| Description: | Longitudinal studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced immune responses in patients with cancer are needed to optimize clinical care. In a prospective cohort study of 366 (291 vaccinated) patients, we measured antibody levels [anti-spike (IgG-(S-RBD) and anti-nucleocapsid immunoglobulin] at three time points. Antibody level trajectories and frequency of breakthrough infections were evaluated by tumor type and timing of treatment relative to vaccination. IgG-(S-RBD) at peak response (median = 42 days after dose 2) was higher (P = 0.002) and remained higher after 4 to 6 months (P = 0.003) in patients receiving mRNA-1273 compared with BNT162b2. Patients with solid tumors attained higher peak levels (P = 0.001) and sustained levels after 4 to 6 months (P < 0.001) compared with those with hematologic malignancies. B-cell targeted treatment reduced peak (P = 0.001) and sustained antibody responses (P = 0.003). Solid tumor patients receiving immune checkpoint inhibitors before vaccination had lower sustained antibody levels than those who received treatment after vaccination (P = 0.043). Two (0.69%) vaccinated and one (1.9%) unvaccinated patient had severe COVID-19 illness during follow-up. Our study shows variation in sustained antibody responses across cancer populations receiving various therapeutic modalities, with important implications for vaccine booster timing and patient selection. SIGNIFICANCE: Long-term studies of immunogenicity of SARS-CoV-2 vaccines in patients with cancer are needed to inform evidence-based guidelines for booster vaccinations and to tailor sequence and timing of vaccinations to elicit improved humoral responses. | |||||||||||||||||||||
| Program/Contract: |
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| DOI: | None | |||||||||||||||||||||
| Subjects: | 3 | |||||||||||||||||||||
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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: | None | |||||||||
| 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: | None | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Assays: | None | ||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY1973: Reduced BNT162b2 Messenger RNA Vaccine Response in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-Naive Nursing Home Residents | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | After BNT162b2 messenger RNA vaccination, antibody levels to spike, receptor-binding domain, and virus neutralization were examined in 149 nursing home residents and 110 healthcare worker controls. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-naive nursing home residents' median post-second vaccine dose antibody neutralization titers are one-quarter that of SARS-CoV-2-naive healthcare workers. | ||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||
| Subjects: | 5 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY1974: Generation of human long-lived plasma cells by developmentally regulated epigenetic imprinting | ||||||||||
| Status: | Updated | |||||||||
| Description: | Antibody secreting cells (ASCs) circulate after vaccination and infection and migrate to the BM where a subset known as long-lived plasma cells (LLPCs) persists and secrete antibodies for a lifetime. The mechanisms by which circulating ASCs become LLPCs are not well elucidated. Here, we show that human blood ASCs have distinct morphology, transcriptomes, and epigenetics compared with BM LLPCs. Compared with blood ASCs, BM LLPCs have decreased nucleus/cytoplasm ratio but increased endoplasmic reticulum and numbers of mitochondria. LLPCs up-regulate pro-survival genes MCL1, BCL2, and BCL-XL while simultaneously down-regulating pro-apoptotic genes HRK1, CASP3, and CASP8 Consistent with reduced gene expression, the pro-apoptotic gene loci are less accessible in LLPCs. Of the pro-survival genes, only BCL2 is concordant in gene up-regulation and loci accessibility. Using a novel in vitro human BM mimetic, we show that blood ASCs undergo similar morphological and molecular changes that resemble ex vivo BM LLPCs. Overall, our study demonstrates that early-minted blood ASCs in the BM microniche must undergo morphological, transcriptional, and epigenetic changes to mature into apoptotic-resistant LLPCs. | |||||||||
| Program/Contract: |
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| DOI: | None | |||||||||
| Subjects: | 6 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY1975: Single-Dose Intranasal Administration of AdCOVID Elicits Systemic and Mucosal Immunity against SARS-CoV-2 and Fully Protects Mice from Lethal Challenge | ||||||||||
| Status: | Updated | |||||||||
| Description: | The coronavirus disease 2019 (COVID-19) pandemic has highlighted the urgent need for effective prophylactic vaccination to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Intranasal vaccination is an attractive strategy to prevent COVID-19 as the nasal mucosa represents the first-line barrier to SARS-CoV-2 entry. The current intramuscular vaccines elicit systemic immunity but not necessarily high-level mucosal immunity. Here, we tested a single intranasal dose of our candidate adenovirus type 5-vectored vaccine encoding the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (AdCOVID) in inbred, outbred, and transgenic mice. A single intranasal vaccination with AdCOVID elicited a strong and focused immune response against RBD through the induction of mucosal IgA in the respiratory tract, serum neutralizing antibodies, and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile. A single AdCOVID dose resulted in immunity that was sustained for over six months. Moreover, a single intranasal dose completely protected K18-hACE2 mice from lethal SARS-CoV-2 challenge, preventing weight loss and mortality. These data show that AdCOVID promotes concomitant systemic and mucosal immunity and represents a promising vaccine candidate. | |||||||||
| Program/Contract: |
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| DOI: | None | |||||||||
| Subjects: | 5 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY1976: Shared B cell memory to coronaviruses and other pathogens varies in human age groups and tissues | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Vaccination and infection promote the formation, tissue distribution, and clonal evolution of B cells, which encode humoral immune memory. We evaluated pediatric and adult blood and deceased adult organ donor tissues to determine convergent antigen-specific antibody genes of similar sequences shared between individuals. B cell memory varied for different pathogens. Polysaccharide antigenspecific clones were not exclusive to the spleen. Adults had higher clone frequencies and greater class switching in lymphoid tissues than blood, while pediatric blood had abundant class-switched convergent clones. Consistent with reported serology, prepandemic children had class-switched convergent clones to severe acute respiratory syndrome coronavirus 2 with weak cross-reactivity to other coronaviruses, while adult blood or tissues showed few such clones. These results highlight the prominence of early childhood B cell clonal expansions and cross-reactivity for future responses to novel pathogens. | ||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||
| Subjects: | 4 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY1977: SARS-CoV-2 vaccine uptake, perspectives, and adverse reactions following vaccination in patients with cancer undergoing treatment | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines were developed, tested, and approved in record time. As patients with cancer were excluded from vaccine trials, some patients may be hesitant,1 given unanswered questions around safety and adverse reactions, especially those undergoing treatment. One study conducted among 134 patients receiving immune checkpoint inhibitors (ICIs) reported an 81% BNT162b2 vaccine uptake rate with similar rates of acute adverse reactions as reported among healthy individuals, except for higher frequency of myalgias among patients with cancer.2 Further research is needed by tumor type and treatment to better inform clinicians and patients during the vaccine decision-making process.We report data on uptake and perspectives on SARS-CoV-2 vaccination and postvaccination adverse reactions in 208 recently diagnosed patients with cancer (median age 63 years, 52.4% women, 33.2% non-White minorities, Table 1 ) at a large healthcare system in Los Angeles spanning the timeline from limited vaccine availability to broader dissemination (November 2020 to July 2021). Vaccine hesitancy and perspectives were measured using a modified version of the World Health Organization Vaccine Hesitancy Scale (Supplementary Material, available at https://doi.org/10.1016/j.annonc.2021.10.005).3 A self-administered symptoms questionnaire was given to vaccinated recipients after dose 1 (D1) and D2 for messenger RNA (mRNA) SARS-CoV-2 vaccines. Electronic medical records provided correlative clinical information. Chi-square tests were used to assess differences for categorical variables and a Wilcoxon rank-sum test for continuous variables (Stata v. 15.1). All tests were two-sided and considered statistically significant at P < 0.05. | |||||||||||||||
| Program/Contract: |
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| DOI: | None | |||||||||||||||
| Subjects: | 2 | |||||||||||||||
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| Assays: | None | |||||||||||||||
| Clinical Assessments: | None | |||||||||||||||
| SDY1978: Roles of antiviral sensing and type I interferon signaling in the restriction of SARS-CoV-2 replication | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | We investigated the role of tissue type and antiviral genes during SARS-CoV-2 infection in nonhuman primate (kidney) and human (liver, respiratory epithelial, gastric) cell lines. We report different viral growth kinetics and release among the cell lines despite comparable ACE2 expression. Transcriptomics revealed that absence of STAT1 in nonhuman primate cells appeared to enhance inflammatory responses without effecting infectious viral titer. Deletion of RL-6 in respiratory epithelial cells increased viral replication. Impaired infectious virus release was detected in Huh7 but not Huh7.5 cells, suggesting a role for RIG1. Gastric cells MKN45 exhibited robust antiviral gene expression and supported viral replication. Data here provide insight into molecular pathogenesis of and alternative cell lines for studying SARS-CoV-2 infection. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M381LM05UM | ||||||||||||
| Subjects: | 7 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY1990: Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | SARS-CoV-2-specific antibodies, CD4+ T cells, and CD8+ T cells are made in response to SARS-CoV-2 infection. Understanding the kinetics and durability of immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines and assessing the likely future course of the COVID-19 pandemic. We assessed the immune memory of all three branches of adaptive immunity (CD4+ T cell, CD8+ T cell, and humoral immunity) in a predominantly cross-sectional study, including a longitudinal subset, extending for up to eight months post-infection. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||||||||
| Subjects: | 1 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2012: Longitudinal COVID-19-vaccination-induced antibody responses and Omicron neutralization in patients with lung cancer | ||||||||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||||||||
| Description: | During the global pandemic with COVID19, early reports indicated that cancer patients in general, and lung cancer patients in particular, who were infected with SARS-CoV-2 had high mortality rates, with a reported 25%?40% case fatality rate (CFR) (Rolfo et al., 2022). The underlying clinical, demographic, and tumor-biologic factors contributing to the aggressive course of infection in this vulnerable cancer population have not been fully elucidated and could arise through multiple mechanisms, including the immunosuppressive activity of lung cancer therapeutics, lung cancer itself, or other co-morbidities particularly related to the respiratory system (Kuderer et al., 2020; Zhang et al., 2021; Lievre et al., 2020). In December 2020, phase III randomized clinical trials demonstrated strong clinical efficacy of SARS-CoV-2 mRNA vaccines, which subsequently became available to the public in the United States, but did not specifically evaluate lung cancer patients (Baden et al., 2021; Chavez-Macgregor et al., 2022). Additionally, the recently emergent Omicron variants largely evade vaccination-induced immunity. It has been shown that third mRNA vaccine doses increase Omicron antibody neutralization in the general population; however, the efficacy of this third dose remains unknown in patients with lung cancer (Planas et al., 2022; Wu et al., 2022; Nemet et al., 2022). Thus, there are major knowledge gaps for managing patients with lung cancer in the COVID-19 era which need to be filled | |||||||||||||||||||||||||||||||||
| Program/Contract: |
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| DOI: | None | |||||||||||||||||||||||||||||||||
| Subjects: | 5 | |||||||||||||||||||||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||||||||||||||||||||
| SDY2024: Durability and Cross-Reactivity of SARS-CoV-2 mRNA Vaccine in Adolescent Children | |||||||||
| Status: | Updated | ||||||||
| Description: | Emergent SARS-CoV-2 variants and waning humoral immunity in vaccinated individuals have resulted in increased infections and hospitalizations. Children are not spared from infection nor complications of COVID-19, and the recent recommendation for boosters in individuals ages 12 years or older calls for broader understanding of the adolescent immune profile after mRNA vaccination. We tested the durability and cross-reactivity of anti-SARS-CoV-2 serologic responses over a six-month time course in vaccinated adolescents against the SARS-CoV-2 D614G (""wild type"") and Omicron antigens. Serum from 77 adolescents showed that anti-Spike antibodies wane significantly over six months. After completion of a two-vaccine series, cross-reactivity against Omicron-specific receptor-binding domain (RBD) was seen. Functional humoral activation against wild type and Omicron SARS-CoV-2 also declines over time in vaccinated adolescent children. Evidence of waning mRNA-induced vaccine immunity underscores vulnerabilities in long-term pediatric protection against SARS-CoV-2 infection, while cross-reactivity highlights the additional benefits of vaccination. Characterization of adolescent immune signatures post-vaccination will inform guidance on vaccine platforms and timelines, and ultimately optimize immunoprotection of children. | ||||||||
| Program/Contract: |
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| DOI: | None | ||||||||
| Subjects: | 1 | ||||||||
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| 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. | |||||||||
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| DOI: | None | |||||||||
| Subjects: | 2 | |||||||||
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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: | 5 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
| SDY2034: mRNA-1273 and BNT162b2 COVID-19 vaccines elicit antibodies with differences in Fc-mediated effector functions | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | The successful development of several coronavirus disease 2019 (COVID-19) vaccines has substantially reduced morbidity and mortality in regions of the world where the vaccines have been deployed. However, in the wake of the emergence of viral variants that are able to evade vaccine-induced neutralizing antibodies, real-world vaccine efficacy has begun to show differences across the two approved mRNA platforms, BNT162b2 and mRNA-1273; these findings suggest that subtle variation in immune responses induced by the BNT162b2 and mRNA-1273 vaccines may confer differential protection. Given our emerging appreciation for the importance of additional antibody functions beyond neutralization, we profiled the postboost binding and functional capacity of humoral immune responses induced by the BNT162b2 and mRNA-1273 vaccines in a cohort of hospital staff. Both vaccines induced robust humoral immune responses to wild-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to variants of concern. However, differences emerged across epitope-specific responses, with higher concentrations of receptor binding domain (RBD)- and N-terminal domain-specific IgA observed in recipients of mRNA-1273. Antibodies eliciting neutrophil phagocytosis and natural killer cell activation were also increased in mRNA-1273 vaccine recipients as compared to BNT162b2 recipients. RBD-specific antibody depletion highlighted the different roles of non-RBD-specific antibody effector functions induced across the mRNA vaccines. These data provide insights into potential differences in protective immunity conferred by these vaccines. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||||||||
| Subjects: | 3 | ||||||||||||||||||
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| SDY2035: SARS-CoV-2 antibodies protect against reinfection for at least 6 months in a multicentre seroepidemiological workplace cohort | ||||||||||
| Status: | Updated | |||||||||
| Description: | Identifying the potential for SARS-CoV-2 reinfection is crucial for understanding possible long-term epidemic dynamics. We analysed longitudinal PCR and serological testing data from a prospective cohort of 4,411 United States employees in 4 states between April 2020 and February 2021. We conducted a multivariable logistic regression investigating the association between baseline serological status and subsequent PCR test result in order to calculate an odds ratio for reinfection. We estimated an odds ratio for reinfection ranging from 0.14 (95% CI: 0.019 to 0.63) to 0.28 (95% CI: 0.05 to 1.1), implying that the presence of SARS-CoV-2 antibodies at baseline is associated with around 72% to 86% reduced odds of a subsequent PCR positive test based on our point estimates. This suggests that primary infection with SARS-CoV-2 provides protection against reinfection in the majority of individuals, at least over a 6-month time period. We also highlight 2 major sources of bias and uncertainty to be considered when estimating the relative risk of reinfection, confounders and the choice of baseline time point, and show how to account for both in reinfection analysis. | |||||||||
| Program/Contract: |
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| DOI: | None | |||||||||
| Subjects: | 1 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2036: Durability of Anti-Spike Antibodies in Infants After Maternal COVID-19 Vaccination or Natural Infection | ||||||||||
| Status: | Updated | |||||||||
| Description: | Understanding the persistence of maternal antibody levels in infants is important because COVID-19 infections in this age group account for a disproportionate burden of pediatric SARS-CoV-2?associated morbidity6 and because COVID-19 vaccines are not currently planned for administration to infants younger than 6 months. Study limitations include the small number of infants, the longer mean time to follow-up in the infected group (due to pragmatic constraints related to timing of COVID-19 surges in Boston and the availability of participants for timely follow-up), and the reporting of antibody titers rather than clinical outcomes. Although the antibody titer known to be protective against COVID-19 in infants isunknown, these findings provide further incentive for pregnant individuals to pursue COVID-19 vaccination. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3CK1F3HPK | |||||||||
| Subjects: | 2 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2037: Passive transfer of Ad26.COV2.S-elicited IgG from humans attenuates SARS-CoV-2 disease in hamsters | |||||||
| Status: | Updated | ||||||
| Description: | SARS-CoV-2 Spike-specific binding and neutralizing antibodies, elicited either by natural infection or vaccination, have emerged as potential correlates of protection. An important question, however, is whether vaccine-elicited antibodies in humans provide direct, functional protection from SARS-CoV-2 infection and disease. In this study, we explored directly the protective efficacy of human antibodies elicited by Ad26.COV2.S vaccination by adoptive transfer studies. IgG from plasma of Ad26.COV2.S vaccinated individuals was purified and transferred into naive golden Syrian hamster recipients, followed by intra-nasal challenge of the hamsters with SARS-CoV-2. IgG purified from Ad26.COV2.S-vaccinated individuals provided dose-dependent protection in the recipient hamsters from weight loss following challenge. In contrast, IgG purified from placebo recipients provided no protection in this adoptive transfer model. Attenuation of weight loss correlated with binding and neutralizing antibody titers of the passively transferred IgG. This study suggests that Ad26.COV2.S-elicited antibodies in humans are mechanistically involved in protection against SARS-CoV-2. | ||||||
| Program/Contract: |
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| DOI: | None | ||||||
| Subjects: | 12 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY2038: Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | A damaging inflammatory response is implicated in the pathogenesis of severe coronavirus disease 2019 (COVID-19), but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated immunoglobulin G (IgG) antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. To study the biology of afucosylated IgG immune complexes, we developed an in vivo model that revealed that human IgG-Fc-gamma receptor (Fc?R) interactions could regulate inflammation in the lung. Afucosylated IgG immune complexes isolated from patients with COVID-19 induced inflammatory cytokine production and robust infiltration of the lung by immune cells. In contrast to the antibody structures that were associated with disease progression, antibodies that were elicited by messenger RNA SARS-CoV-2 vaccines were highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. Vaccine-elicited IgG did not promote an inflammatory lung response. These results show that human IgG-Fc?R interactions regulate inflammation in the lung and define distinct lung activities mediated by the IgG that are associated with protection against, or progression to, severe COVID-19. | |||||||||||||||
| Program/Contract: |
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| DOI: | None | |||||||||||||||
| Subjects: | 9 | |||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | |||||||||||||||
| SDY2039: Antibodies elicited by SARS-CoV-2 infection or mRNA vaccines have reduced neutralizing activity against Beta and Omicron pseudoviruses | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that have mutations associated with increased transmission and antibody escape have arisen over the course of the current pandemic. Although the current vaccines have largely been effective against past variants, the number of mutations found on the Omicron (B.1.1.529) spike protein appear to diminish the protection conferred by preexisting immunity. Using vesicular stomatitis virus (VSV) pseudoparticles expressing the spike protein of several SARS-CoV-2 variants, we evaluated the magnitude and breadth of the neutralizing antibody response over time in individuals after infection and in mRNA-vaccinated individuals. We observed that boosting increases the magnitude of the antibody response to wild-type (D614), Beta, Delta, and Omicron variants; however, the Omicron variant was the most resistant to neutralization. We further observed that vaccinated healthy adults had robust and broad antibody responses, whereas responses may have been reduced in vaccinated pregnant women, underscoring the importance of learning how to maximize mRNA vaccine responses in pregnant populations. Findings from this study show substantial heterogeneity in the magnitude and breadth of responses after infection and mRNA vaccination and may support the addition of more conserved viral antigens to existing SARS-CoV-2 vaccines. | |||||||||||||||
| Program/Contract: |
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| DOI: | None | |||||||||||||||
| Subjects: | 3 | |||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | |||||||||||||||
| SDY2040: Durable Humoral and Cellular Immune Responses 8 Months after Ad26.COV2.S Vaccination | |||||||||
| Status: | Updated | ||||||||
| Description: | These data show that the Ad26.COV2.S vaccine elicited durable humoral and cellular immune responses with minimal decreases for at least 8 months after immunization. In addition, we observed an expansion of neutralizing antibody breadth against SARS-CoV-2 variants over this time period, including against the more transmissible B.1.617.2 variant and the partially neutralization-resistant B.1.351 and P.1 variants, which suggests maturation of B-cell responses even without further boosting. The durability of immune responses elicited by the Ad26.COV2.S vaccine was consistent with the durability recently reported for an Ad26-based Zika vaccine.4 Longitudinal antibody responses to mRNA Covid-19 vaccines have also been reported for 6 months but with different kinetics of decreasing titers.5 The durability of humoral and cellular immune responses 8 months after Ad26.COV2.S vaccination with increased neutralizing antibody responses to SARS-CoV-2 variants over time, including after single-shot vaccination, further supports the use of the Ad26.COV2.S vaccine to combat the global Covid-19 pandemic. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M385J155ZW | ||||||||
| Subjects: | 3 | ||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||
| SDY2041: Immunogenicity of Ad26.COV2.S vaccine against SARS-CoV-2 variants in humans | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | The Ad26.COV2.S vaccine1-3 has demonstrated clinical efficacy against symptomatic COVID-19, including against the B.1.351 variant that is partially resistant to neutralizing antibodies1. However, the immunogenicity of this vaccine in humans against SARS-CoV-2 variants of concern remains unclear. Here we report humoral and cellular immune responses from 20 Ad26.COV2.S vaccinated individuals from the COV1001 phase I-IIa clinical trial2 against the original SARS-CoV-2 strain WA1/2020 as well as against the B.1.1.7, CAL.20C, P.1 and B.1.351 variants of concern. Ad26.COV2.S induced median pseudovirus neutralizing antibody titres that were 5.0-fold and 3.3-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020 on day 71 after vaccination. Median binding antibody titres were 2.9-fold and 2.7-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020. Antibody-dependent cellular phagocytosis, complement deposition and natural killer cell activation responses were largely preserved against the B.1.351 variant. CD8 and CD4 T cell responses, including central and effector memory responses, were comparable among the WA1/2020, B.1.1.7, B.1.351, P.1 and CAL.20C variants. These data show that neutralizing antibody responses induced by Ad26.COV2.S were reduced against the B.1.351 and P.1 variants, but functional non-neutralizing antibody responses and T cell responses were largely preserved against SARS-CoV-2 variants. These findings have implications for vaccine protection against SARS-CoV-2 variants of concern. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3RLFPEUYM | ||||||||||||||||||
| Subjects: | 5 | ||||||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2042: Omicron variant Spike-specific antibody binding and Fc activity are preserved in recipients of mRNA or inactivated COVID-19 vaccines | |||||||
| Status: | Updated | ||||||
| Description: | The Omicron variant of SARS-CoV-2 has been shown to evade neutralizing antibodies elicited by vaccination or infection. Despite the global spread of the Omicron variant, even among highly vaccinated populations, death rates have not increased concomitantly. These data suggest that immune mechanisms beyond antibody-mediated virus neutralization may protect against severe disease. In addition to neutralizing pathogens, antibodies contribute to control and clearance of infections through Fc effector mechanisms. Here, we probed the ability of vaccine-induced antibodies to drive Fc effector activity against the Omicron variant using samples from individuals receiving one of three SARS-CoV-2 vaccines. Despite a substantial loss of IgM, IgA, and IgG binding to the Omicron variant receptor binding domain (RBD) in samples from individuals receiving BNT162b2, mRNA-1273, and CoronaVac vaccines, stable binding was maintained against the full-length Omicron Spike protein. Compromised RBD binding IgG was accompanied by a loss of RBD-specific antibody Fc? receptor (Fc?R) binding in samples from individuals who received the CoronaVac vaccine, but RBD-specific Fc?R2a and Fc?R3a binding was preserved in recipients of mRNA vaccines. Conversely, Spike protein-specific antibodies exhibited persistent but reduced binding to Fc?Rs across all three vaccines, although higher binding was observed in samples from recipients of mRNA vaccines. This was associated with preservation of Fc?R2a and Fc?R3a binding antibodies and maintenance of Spike protein-specific antibody-dependent natural killer cell activation. Thus, despite the loss of Omicron neutralization, vaccine-induced Spike protein-specific antibodies continue to drive Fc effector functions, suggesting a capacity for extraneutralizing antibodies to contribute to disease control. | ||||||
| Program/Contract: |
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| DOI: | None | ||||||
| Subjects: | 4 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY2043: One-Stop Serum Assay Identifies COVID-19 Disease Severity and Vaccination Responses | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | We developed a multiplex immunoassay from serum/plasma of acutely infected and convalescent COVID-19 patients and prepandemic and postpandemic healthy adults. We measured IgA, IgG, and/or IgM against SARS-CoV-2 nucleocapsid (N), spike domain 1 (S1), S1-receptor binding domain (RBD) and S1-N-terminal domain. For diagnosis, the combined [IgA + IgG + IgM] or IgG levels measured for N, S1, and S1-RBD yielded area under the curve values ?0.90. Virus-specific Ig levels were higher in patients with severe/critical compared with mild/moderate infections. A strong prozone effect was observed in sera from severe/critical patients-a possible source of underestimated Ab concentrations in previous studies. Mild/moderate patients displayed a slower rise and lower peak in anti-N and anti-S1 IgG levels compared with severe/critical patients, but anti-RBD IgG and neutralization responses reached similar levels at 2-4 mo after symptom onset. Measurement of the Ab responses in sera from 18 COVID-19-vaccinated patients revealed specific responses for the S1-RBD Ag and none against the N protein. This highly sensitive, SARS-CoV-2-specific, multiplex immunoassay measures the magnitude, complexity, and kinetics of the Ab response and can distinguish serum Ab responses from natural SARS-CoV-2 infections (mild or severe) and mRNA COVID-19 vaccines. | ||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||
| Subjects: | 5 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY2044: Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection with persisting antibody responses and memory B and T cells | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Ending the COVID-19 pandemic will require long-lived immunity to SARS-CoV-2. Here, we evaluate 254 COVID-19 patients longitudinally up to 8 months and find durable broad-based immune responses. SARS-CoV-2 spike binding and neutralizing antibodies exhibit a bi-phasic decay with an extended half-life of >200 days suggesting the generation of longer-lived plasma cells. SARS-CoV-2 infection also boosts antibody titers to SARS-CoV-1 and common betacoronaviruses. In addition, spike-specific IgG+ memory B cells persist, which bodes well for a rapid antibody response upon virus re-exposure or vaccination. Virus-specific CD4+ and CD8+ T cells are polyfunctional and maintained with an estimated half-life of 200 days. Interestingly, CD4+ T cell responses equally target several SARS-CoV-2 proteins, whereas the CD8+ T cell responses preferentially target the nucleoprotein, highlighting the potential importance of including the nucleoprotein in future vaccines. Taken together, these results suggest that broad and effective immunity may persist long-term in recovered COVID-19 patients. | ||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||
| Subjects: | 3 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY2045: Maternal immune response and placental antibody transfer after COVID-19 vaccination across trimester and platforms | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Here, we characterize the antibody profile after Ad26.COV2.S, mRNA-1273 or BNT162b2 vaccination in 158 pregnant individuals and evaluate transplacental antibody transfer by profiling maternal and umbilical cord blood in 175 maternal-neonatal dyads. These analyses reveal lower vaccine-induced functions and Fc receptor-binding after Ad26.COV2.S compared to mRNA vaccination and subtle advantages in titer and function with mRNA-1273 versus BN162b2. mRNA vaccines have higher titers and functions against SARS-CoV-2 variants of concern. First and third trimester vaccination results in enhanced maternal antibody-dependent NK-cell activation, cellular and neutrophil phagocytosis, and complement deposition relative to second trimester. Higher transplacental transfer ratios following first and second trimester vaccination may reflect placental compensation for waning maternal titers. | ||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||
| Subjects: | 5 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY2047: Protective efficacy of rhesus adenovirus COVID-19 vaccines against mouse-adapted SARS-CoV-2 | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | The global COVID-19 pandemic has sparked intense interest in the rapid development of vaccines as well as animal models to evaluate vaccine candidates and to define immune correlates of protection. We recently reported a mouse-adapted SARS-CoV-2 virus strain (MA10) with the potential to infect wild-type laboratory mice, driving high levels of viral replication in respiratory tract tissues as well as severe clinical and respiratory symptoms, aspects of COVID-19 disease in humans that are important to capture in model systems. We evaluated the immunogenicity and protective efficacy of novel rhesus adenovirus serotype 52 (RhAd52) vaccines against MA10 challenge in mice. Baseline seroprevalence is lower for rhesus adenovirus vectors than for human or chimpanzee adenovirus vectors, making these vectors attractive candidates for vaccine development. We observed that RhAd52 vaccines elicited robust binding and neutralizing antibody titers, which inversely correlated with viral replication after challenge. These data support the development of RhAd52 vaccines and the use of the MA10 challenge virus to screen novel vaccine candidates and to study the immunologic mechanisms that underscore protection from SARS-CoV-2 challenge in wild-type mice. | ||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||
| Subjects: | 3 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY2052: Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19 | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | Randomized, double-blind, placebo-controlled clinical trial of Ad26.COV2.S on 25 participants. Participants were randomized to receive single-shot and 2-shot vaccine regimens with either 5 X 1010 or 1 X 1011 viral particles of Ad26.COV2.S or placebo in healthy adults 18 to 55 years of age. | ||||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||||
| Subjects: | 5 | ||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Clinical Assessments: | None | ||||||||||||||
| SDY2053: Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including third-dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is lower after infection compared with all vaccines evaluated but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks postvaccination in some cases. SARS-CoV-2 antibody specificity, breadth, and maturation are affected by imprinting from exposure history and distinct histological and antigenic contexts in infection compared with vaccination. | ||||||||||||
| Program/Contract: |
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| DOI: | None | ||||||||||||
| Subjects: | 8 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY2108: Prior infection with SARS-CoV-2 WA1/2020 partially protects rhesus macaques against reinfection with B.1.1.7 and B.1.351 variants | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that result in increased transmissibility and partial evasion of neutralizing antibodies have recently emerged. Whether natural immunity induced by the original SARS-CoV-2 WA1/2020 strain protects against rechallenge with these SARS-CoV-2 variants remains a critical unresolved question. In this study, we show that natural immunity induced by the WA1/2020 strain leads to partial but incomplete protection against the SARS-CoV-2 variants B.1.1.7 (alpha) and B.1.351 (beta) in rhesus macaques. We challenged rhesus macaques with B.1.1.7 and B.1.351 and showed that infection with these variants resulted in high viral replication in the upper and lower respiratory tract. We then infected rhesus macaques with the WA1/2020 strain and rechallenged them on day 35 with the WA1/2020, B.1.1.7, or B.1.351 variants. Natural immunity to WA1/2020 led to robust protection against rechallenge with WA1/2020 but only partial protection against rechallenge with B.1.351. An intermediate degree of protection was observed in rhesus macaques against rechallenge with B.1.1.7. These data demonstrate partial but incomplete protective efficacy of natural immunity induced by WA1/2020 against SARS-CoV-2 variants of concern. Our findings have important implications for both vaccination and public health strategies in the context of emerging SARS-CoV-2 variants of concern. | ||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3FS3Q3TG6 | ||||||||||||||
| Subjects: | 4 | ||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||||
| SDY2111: Reduced COVID-19 Vaccine Response in Patients Treated with Biologic Therapies for Asthma | ||||||||||
| Status: | Updated | |||||||||
| Description: | It is unclear if patients with severe asthma and atopic dermatit is on biologic therapies have an adequate and durable humoral immune response after vaccination to SARS-CoV-2. To address these questions, we conducted a prospective observational trial from February 2021 to September 2021 with adults who had severe asthma or atopic dermatitis treated with benralizumab (IL-5 receptor antagonist), mepolizumab(IL-5 antagonist), or dupilumab (IL-4 receptor a antagonist). | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3A944EBOX | |||||||||
| Subjects: | 2 | |||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | |||||||||
| SDY2113: Augmentation of humoral and cellular immune responses after third-dose SARS-CoV-2 vaccination and viral neutralization in myeloma patients | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | Despite the efficacy of COVID-19 vaccines in healthy individuals, multiple myeloma (MM) patients are immunocompromised and mount suboptimal humoral and cellular responses after two doses of mRNA vaccine (Addeo et al., 2021; Aleman et al., 2021; Van Oekelen et al., 2021). A broader observation of limited vaccine responses in cancer patients, particularly those with hematologic malignancies (Thakkar et al., 2021), has led to the implementation of additional (i.e., third dose) vaccine administration as a way to increase protection for patients with immune suppression. A third dose of BNT162b2 (Pfizer-BioNTech) COVID19 vaccine has shown to be effective in preventing severe COVID-19 caused by the SARS-CoV-2 B.1.617.2 (Delta) variant in the general population (Bar-On et al., 2021; Barda et al., 2021). Furthermore, third-dose administration of either the BNT162b2 (Pfizer-BioNTech) or mRNA1273 (Moderna) COVID-19 vaccine was associated with augmented immune responses in a diverse cohort of cancer patients (Shapiro et al., 2022). However, the real-world effectiveness of additional dosing in myeloma patients and viral neutralization have not been reported. Additionally, the impact of the currently dominant SARS-CoV-2 B.1.1.529 (Omicron) variant on efficacy of the third dose is largely unknown in patients with hematologic malignancies (Zeng et al., 2022). | |||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3EEDBBP9C | |||||||||||||||
| Subjects: | 2 | |||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | |||||||||||||||
| SDY2114: Longitudinal analysis of severe acute respiratory syndrome coronavirus 2 seroprevalence using multiple serology platforms | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological tests are based on the full-length spike (S), the receptor-binding domain (RBD), or the nucleoprotein (NP) as substrates. Here, we used samples from healthcare workers (HCWs) to perform a longitudinal analysis of the antibody responses using a research-grade RBD and spike-based enzyme-linked immunosorbent assay (ELISA), a commercial RBD and spike-based ELISA, and a commercial NP-based chemiluminescent microparticle immunoassay. Seroprevalence ranged around 28% early during the pandemic and a good correlation was observed between RBD and spike-based ELISAs. Modest correlations were observed between NP and both RBD and spike-based assays. The antibody levels in HCWs declined over time; however, the overall seroprevalence measured by RBD and spike-based assays remained unchanged, while the seroprevalence of NP-reactive antibodies significantly declined. Moreover, RBD and spike-based assays effectively detected seroconversion in vaccinees. Overall, our results consolidate the strength of different serological assays to assess the magnitude and duration of antibodies to SARS-CoV-2. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3S0T656KV | ||||||||||||
| Subjects: | 1 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY2115: Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomised, placebo-controlled, phase 1 trial | |||||||||
| Status: | Updated | ||||||||
| Description: | Background: Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It's being developed by public sector manufacturers in Thailand, Vietnam, and Brazil; herein are initial results from Thailand. Methods: This phase 1 stage of a randomised, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial was conducted at the Vaccine Trial Centre, Mahidol University (Bangkok). Healthy males and non-pregnant females, aged 18-59 years and negative for SARS-CoV-2 antibodies, were eligible. Participants were randomised to receive one of six treatments by intramuscular injection twice, 28 days apart: 1 ?g, 1 ?g+CpG1018 (a toll-like receptor 9 agonist), 3 ?g, 3 ?g+CpG1018, 10 ?g, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited and spontaneously reported adverse events (AEs) during 7 and 28 days after each vaccination, respectively. Secondary outcomes were immunogenicity measures (anti-S IgG and pseudotyped virus neutralisation). An interim analysis assessed safety at day 57 in treatment-exposed individuals and immunogenicity through day 43 per protocol. ClinicalTrials.gov (NCT04764422). Findings: Between March 20 and April 23, 2021, 377 individuals were screened and 210 were enroled (35 per group); all received dose one; five missed dose two. The most common solicited AEs among vaccinees, all predominantly mild, were injection site pain (<63%), fatigue (<35%), headache (<32%), and myalgia (<32%). The proportion reporting a vaccine-related AE ranged from 5?7% to 17?1% among vaccine groups and was 2?9% in controls; there was no vaccine-related serious adverse event. The 10 ?g formulation's immunogenicity ranked best, followed by 3 ?g+CpG1018, 3 ?g, 1 ?g+CpG1018, and 1 ?g formulations. On day 43, the geometric mean concentrations of 50% neutralising antibody ranged from 122?23 international units per mL (IU/mL; 1 ?g, 95% confidence interval (CI) 86?40-172?91) to 474?35 IU/mL (10 ?g, 95% CI 320?90-701?19), with 93?9% to 100% of vaccine groups attaining a ? 4-fold increase over baseline. Interpretation: NDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 ?g and 3 ?g+CpG1018 formulations advanced to phase 2 | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M301KI6WVE | ||||||||
| Subjects: | 6 | ||||||||
| Study PI, contact: |
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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: | 5 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2117: Decreased infectivity following BNT162b2 vaccination: A prospective cohort study in Israel | ||||||||||
| Status: | Updated | |||||||||
| Description: | Background: BNT162b2 was shown to be 92% effective in preventing COVID-19. Prioritizing vaccine rollout, and achievement of herd immunity depend on SARS-CoV-2 transmission reduction. The vaccine's effect on infectivity is thus a critical priority. Methods: Among all 9650 HCW of a large tertiary medical center in Israel, we calculated the prevalence of positive SARS-CoV-2 qRT-PCR cases with asymptomatic presentation, tested following known or presumed exposure and the infectious subset (N-gene-Ct-value<30) of these. Additionally, infection incidence rates were calculated for symptomatic cases and infectious (Ct<30) cases. Vaccine effectiveness within three months of vaccine rollout was measured as one minus the relative risk or rate ratio, respectively. To further assess infectiousness, we compared the mean Ct-value and the proportion of infections with a positive SARS-CoV-2 antigen test of vaccinated vs. unvaccinated. The correlation between IgG levels within the week before detection and Ct level was assessed. Findings: Reduced prevalence among fully vaccinated HCW was observed for (i) infections detected due to exposure, with asymptomatic presentation (VE(i)=65.1%, 95%CI 45-79%), (ii) the presumed infectious (Ct<30) subset of these (VE(ii)=69.6%, 95%CI 43-84%) (iii) never-symptomatic infections (VE(iii)=72.3%, 95%CI 48-86%), and (iv) the presumed infectious (Ct<30) subset (VE(iv)=83.0%, 95%CI 51-94%).Incidence of (v) symptomatic and (vi) symptomatic-infectious cases was significantly lower among fully vaccinated vs. unvaccinated individuals (VE(v)= 89.7%, 95%CI 84-94%, VE(vi)=88.1%, 95%CI 80-95%).The mean Ct-value was significantly higher in vaccinated vs. unvaccinated (27.3?1.2 vs. 22.2?1.0, p<0.001) and the proportion of positive SARS-CoV-2 antigen tests was also significantly lower among vaccinated vs. unvaccinated PCR-positive HCW (80% vs. 31%, p<0.001). Lower infectivity was correlated with higher IgG concentrations (R=0.36, p=0.01). Interpretation: These results suggest that BNT162b2 is moderately to highly effective in reducing infectivity, via preventing infection and through reducing viral shedding. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3VXVCH51N | |||||||||
| Subjects: | 4 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2118: Covid-19 Breakthrough Infections in Vaccinated Health Care Workers | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Background: Despite the high efficacy of the BNT162b2 messenger RNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rare breakthrough infections have been reported, including infections among health care workers. Data are needed to characterize these infections and define correlates of breakthrough and infectivity. Methods: At the largest medical center in Israel, we identified breakthrough infections by performing extensive evaluations of health care workers who were symptomatic (including mild symptoms) or had known infection exposure. These evaluations included epidemiologic investigations, repeat reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays, antigen-detecting rapid diagnostic testing (Ag-RDT), serologic assays, and genomic sequencing. Correlates of breakthrough infection were assessed in a case-control analysis. We matched patients with breakthrough infection who had antibody titers obtained within a week before SARS-CoV-2 detection (peri-infection period) with four to five uninfected controls and used generalized estimating equations to predict the geometric mean titers among cases and controls and the ratio between the titers in the two groups. We also assessed the correlation between neutralizing antibody titers and N gene cycle threshold (Ct) values with respect to infectivity. Results: Among 1497 fully vaccinated health care workers for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented. Neutralizing antibody titers in case patients during the peri-infection period were lower than those in matched uninfected controls (case-to-control ratio, 0.361; 95% confidence interval, 0.165 to 0.787). Higher peri-infection neutralizing antibody titers were associated with lower infectivity (higher Ct values). Most breakthrough cases were mild or asymptomatic, although 19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha) variant was found in 85% of samples tested. A total of 74% of case patients had a high viral load (Ct value, <30) at some point during their infection; however, of these patients, only 17 (59%) had a positive result on concurrent Ag-RDT. No secondary infections were documented. Conclusions: Among fully vaccinated health care workers, the occurrence of breakthrough infections with SARS-CoV-2 was correlated with neutralizing antibody titers during the peri-infection period. Most breakthrough infections were mild or asymptomatic, although persistent symptoms did occur. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3WCZ14DE2 | ||||||||||
| Subjects: | 2 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2119: Higher Proinflammatory Cytokines Are Associated With Increased Antibody Titer After a Third Dose of SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | Background: Solid organ transplant recipients (SOTRs) are at increased risk for severe COVID-19 and exhibit lower antibody responses to SARS-CoV-2 vaccines. This study aimed to determine if prevaccination cytokine levels are associated with antibody response to SARS-CoV-2 vaccination. Methods: A cross-sectional study was performed among 58 SOTRs before and after two-dose mRNA vaccine series, 35 additional SOTRs before and after a third vaccine dose, and comparison to 16 healthy controls (HCs). Antispike antibody was assessed using the IgG Euroimmun ELISA. Electrochemiluminescence detection-based multiplexed sandwich immunoassays (Meso Scale Diagnostics) were used to quantify plasma cytokine and chemokine concentrations (n = 20 analytes) and compare concentrations between SOTRs and HCs, stratified by ultimate antibody response to the vaccine using Wilcoxon-rank-sum test with false discovery rates computed to correct for multiple comparisons. Results: In the study population, 100% of HCs, 59% of SOTRs after 2 doses and 63% of SOTRs after 3 doses had a detectable antibody response. Multiple baseline cytokines were elevated in SOTRs versus HCs. There was no significant difference in baseline cytokine levels between SOTRs with high versus low-titer antibodies after 2 doses of vaccine. However, as compared with poor antibody responders, SOTRs who went on to develop a high-titer antibody response to a third dose of vaccine had significantly higher prethird dose levels of several innate immune cytokines including IL-17, IL-2Ra, IL-6, IP-10, MIP-1?, and TNF-? (false discovery rates < 0.05). Conclusions: A specific inflammatory profile may be associated with developing higher antibodies in response to a third dose of SARS-CoV-2 vaccine in SOTRs. | |||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3ERSVMISI | |||||||||||||||
| Subjects: | 3 | |||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||
| SDY2121: CD4+ T cells from COVID-19 mRNA vaccine recipients recognize a conserved epitope present in diverse coronaviruses | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Recent studies have shown that vaccinated individuals harbor T cells that can cross-recognize SARS-CoV-2 and endemic human common cold coronaviruses. However, it is still unknown whether CD4+ T cells from vaccinated individuals recognize peptides from bat coronaviruses that may have the potential of causing future pandemics. In this study, we identified a SARS-CoV-2 spike protein epitope (S815-827) that is conserved in coronaviruses from different genera and subgenera, including SARS-CoV, MERS-CoV, multiple bat coronaviruses, and a feline coronavirus. Our results showed that S815-827 was recognized by 42% of vaccinated participants in our study who received the Pfizer-BioNTech (BNT162b2) or Moderna (mRNA-1273) COVID-19 vaccines. Using T cell expansion and T cell receptor sequencing assays, we demonstrated that S815-827-reactive CD4+ T cells from the majority of responders cross-recognized homologous peptides from at least 6 other diverse coronaviruses. Our results support the hypothesis that the current mRNA vaccines elicit T cell responses that can cross-recognize bat coronaviruses and thus might induce some protection against potential zoonotic outbreaks. Furthermore, our data provide important insights that inform the development of T cell?based pan-coronavirus vaccine strategies. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3HBH1BBQV | ||||||||||
| Subjects: | 2 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2122: Neutralization of the SARS-CoV-2 Omicron BA.4/5 and BA.2.12.1 Subvariants | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Emerging subvariants of the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have reignited concern about further immune escape. Specifically, BA.2.12.1, which is on the rise in the United States, has two more mutations (L452Q and S704L) than BA.2 (Fig. S1A in the Supplementary Appendix, available with the full text of this letter at NEJM.org). In addition, BA.4 and BA.5 (hereafter, BA.4/5), which bear identical spike proteins, have become the dominant strains in South Africa. Here, we examine neutralizing-antibody titers in serum samples obtained from vaccinated persons who had received a single booster dose of the same vaccine used in the two-dose series and who had been previously infected with SARS-CoV-2. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3UUW8F1FT | ||||||||||||
| Subjects: | 4 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY2124: Risk of severe clinical outcomes among persons with SARS-CoV-2 infection with differing levels of vaccination during widespread Omicron (B.1.1.529) and Delta (B.1.617.2) variant circulation in Northern California: A retrospective cohort study | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | Background: The incidence of and risk factors for severe clinical outcomes with the Omicron (B.1.1.529) SARS-CoV-2 variant have not been well-defined. Methods: We conducted a retrospective cohort study to assess risks of severe clinical outcomes within 21 days after SARS-CoV-2 diagnosis in a large, diverse, integrated health system. Findings: Among 118,078 persons with incident SARS-CoV-2 infection, 48,101 (41%) were during the Omicron period and 69,977 (59%) during the Delta (B.1.617.2) period. Cumulative incidence of any hospitalization (2.4% versus 7.8%; adjusted hazard ratio [aHR] 0.55; 95% confidence interval [CI] (0.51-0.59), with low-flow oxygen support (1.6% versus 6.4%; aHR 0.46; CI 0.43-0.50), with high-flow oxygen support (0.6% versus 2.8%; aHR 0.47; CI 0.41-0.54), with invasive mechanical ventilation (0.1% versus 0.7%; aHR 0.43; CI 0.33-0.56), and death (0.2% versus 0.7%; aHR 0.54; CI 0.42-0.70) were lower in the Omicron than the Delta period. The risk of hospitalization was higher among unvaccinated persons (aHR 8.34; CI 7.25-9.60) and those who completed a primary COVID-19 vaccination series (aHR 1.72; CI 1.49-1.97) compared with those who completed a primary vaccination series and an additional dose. The strongest risk factors for all severe clinical outcomes were older age, higher body mass index and select comorbidities. Interpretation: Persons with SARS-CoV-2 infection were significantly less likely to develop severe clinical outcomes during the Omicron period compared with the Delta period. COVID-19 primary vaccination and additional doses were associated with reduced risk of severe clinical outcomes among those with SARS-CoV-2 infection. | |||||||||||||||
| Program/Contract: |
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| DOI: | None | |||||||||||||||
| Subjects: | 2 | |||||||||||||||
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| Assays: | None | |||||||||||||||
| 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 | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3310R6FVA | |||||||||
| Subjects: | 1 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2126: SARS-CoV-2 mRNA vaccine induces robust specific and cross-reactive IgG and unequal neutralizing antibodies in naive and previously infected people | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Understanding vaccine-mediated protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is critical to overcoming the global coronavirus disease 2019 (COVID-19) pandemic. We investigate mRNA-vaccine-induced antibody responses against the reference strain, seven variants, and seasonal coronaviruses in 168 healthy individuals at three time points: before vaccination, after the first dose, and after the second dose. Following complete vaccination, both naive and previously infected individuals developed comparably robust SARS-CoV-2 spike antibodies and variable levels of cross-reactive antibodies to seasonal coronaviruses. However, the strength and frequency of SARS-CoV-2 neutralizing antibodies in naive individuals were lower than in previously infected individuals. After the first vaccine dose, one-third of previously infected individuals lacked neutralizing antibodies; this was improved to one-fifth after the second dose. In all individuals, neutralizing antibody responses against the Alpha and Delta variants were weaker than against the reference strain. Our findings support future tailored vaccination strategies against emerging SARS-CoV-2 variants as mRNA-vaccine-induced neutralizing antibodies are highly variable among individuals. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3NGLEV4KG | ||||||||||||
| Subjects: | 1 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2127: Immunological memory to common cold coronaviruses assessed longitudinally over a three-year period pre-COVID19 pandemic | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | The immune memory to common cold coronaviruses (CCCs) influences SARS-CoV-2 infection outcome, and understanding its effect is crucial for pan-coronavirus vaccine development. We performed a longitudinal analysis of pre-COVID19-pandemic samples from 2016-2019 in young adults and assessed CCC-specific CD4+ T cell and antibody responses. Notably, CCC responses were commonly detected with comparable frequencies as with other common antigens and were sustained over time. CCC-specific CD4+ T cell responses were associated with low HLA-DR+CD38+ signals, and their magnitude did not correlate with yearly CCC infection prevalence. Similarly, CCC-specific and spike RBD-specific IgG responses were stable in time. Finally, high CCC-specific CD4+ T cell reactivity, but not antibody titers, was associated with pre-existing SARS-CoV-2 immunity. These results provide a valuable reference for understanding the immune response to endemic coronaviruses and suggest that steady and sustained CCC responses are likely from a stable pool of memory CD4+ T cells due to repeated earlier exposures and possibly occasional reinfections. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3X6ZK6H5X | ||||||||||||
| Subjects: | 1 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2129: Integrated plasma proteomic and single-cell immune signaling network signatures demarcate mild, moderate, and severe COVID-19 | |||||||||
| Status: | Updated | ||||||||
| Description: | The biological determinants underlying the range of coronavirus 2019 (COVID-19) clinical manifestations are not fully understood. Here, over 1,400 plasma proteins and 2,600 single-cell immune features comprising cell phenotype, endogenous signaling activity, and signaling responses to inflammatory ligands are cross-sectionally assessed in peripheral blood from 97 patients with mild, moderate, and severe COVID-19 and 40 uninfected patients. Using an integrated computational approach to analyze the combined plasma and single-cell proteomic data, we identify and independently validate a multi-variate model classifying COVID-19 severity (multi-class area under the curve [AUC]training = 0.799, p = 4.2e-6; multi-class AUCvalidation = 0.773, p = 7.7e-6). Examination of informative model features reveals biological signatures of COVID-19 severity, including the dysregulation of JAK/STAT, MAPK/mTOR, and nuclear factor ?B (NF-?B) immune signaling networks in addition to recapitulating known hallmarks of COVID-19. These results provide a set of early determinants of COVID-19 severity that may point to therapeutic targets for prevention and/or treatment of COVID-19 progression. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M32UYJZ33S | ||||||||
| Subjects: | 4 | ||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||
| SDY2130: Identifying and Alleviating Bias Due to Differential Depletion of Susceptible People in Postmarketing Evaluations of COVID-19 Vaccines | |||||||
| Status: | Updated | ||||||
| Description: | Recent studies have provided key information about SARS-CoV-2 vaccines' efficacy and effectiveness (VE). One important question that remains is whether the protection conferred by vaccines wanes over time. However, estimates over time are subject to bias from differential depletion of susceptible individuals between vaccinated and unvaccinated groups. We examined the extent to which biases occur under different scenarios and assessed whether serological testing has the potential to correct this bias. By identifying nonvaccine antibodies, these tests could identify individuals with prior infection. We found that in scenarios with high baseline VE, differential depletion of susceptible individuals created minimal bias in VE estimates, suggesting that any observed declines are likely not due to spurious waning alone. However, if baseline VE was lower, the bias for leaky vaccines (which reduce individual probability of infection given contact) was larger and should be corrected for by excluding individuals with past infection if the mechanism is known to be leaky. Conducting analyses both unadjusted and adjusted for past infection could give lower and upper bounds for the true VE. Studies of VE should therefore enroll individuals regardless of prior infection history but also collect information, ideally through serological testing, on this critical variable. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3A6AINWX6 | ||||||
| Subjects: | 1 | ||||||
| Study PI, contact: |
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2131: The molecular epidemiology of multiple zoonotic origins of SARS-CoV-2 | |||||||
| Status: | Updated | ||||||
| Description: | Understanding the circumstances that lead to pandemics is important for their prevention. Here, we analyze the genomic diversity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) early in the coronavirus disease 2019 (COVID-19) pandemic. We show that SARS-CoV-2 genomic diversity before February 2020 likely comprised only two distinct viral lineages, denoted A and B. Phylodynamic rooting methods, coupled with epidemic simulations, reveal that these lineages were the result of at least two separate cross-species transmission events into humans. The first zoonotic transmission likely involved lineage B viruses around 18 November 2019 (23 October-8 December), while the separate introduction of lineage A likely occurred within weeks of this event. These findings indicate that it is unlikely that SARS-CoV-2 circulated widely in humans prior to November 2019 and define the narrow window between when SARS-CoV-2 first jumped into humans and when the first cases of COVID-19 were reported. As with other coronaviruses, SARS-CoV-2 emergence likely resulted from multiple zoonotic events. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3OF1XHUND | ||||||
| Subjects: | 1 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2132: The Huanan Seafood Wholesale Market in Wuhan was the early epicenter of the COVID-19 pandemic | |||||||
| Status: | Updated | ||||||
| Description: | Understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 is critical to preventing zoonotic outbreaks before they become the next pandemic. The Huanan Seafood Wholesale Market in Wuhan, China, was identified as a likely source of cases in early reports but later this conclusion became controversial. We show the earliest known COVID-19 cases from December 2019, including those without reported direct links, were geographically centered on this market. We report that live SARS-CoV-2 susceptible mammals were sold at the market in late 2019 and, within the market, SARS-CoV-2-positive environmental samples were spatially associated with vendors selling live mammals. While there is insufficient evidence to define upstream events, and exact circumstances remain obscure, our analyses indicate that the emergence of SARS-CoV-2 occurred via the live wildlife trade in China, and show that the Huanan market was the epicenter of the COVID-19 pandemic. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3LANTY5MI | ||||||
| Subjects: | 1 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2133: Longitudinal metabolomics of human plasma reveals prognostic markers of COVID-19 disease severity | ||||||||||
| Status: | Updated | |||||||||
| Description: | There is an urgent need to identify which COVID-19 patients will develop life-threatening illness so that med- ical resources can be optimally allocated and rapid treatment can be administered early in the disease course, when clinical management is most effective. To aid in the prognostic classification of disease severity, we perform untargeted metabolomics on plasma from 339 patients, with samples collected at six longitudinal time points. Using the temporal metabolic profiles and machine learning, we build a predictive model of disease severity. We discover that a panel of metabolites measured at the time of study entry suc- cessfully determines disease severity. Through analysis of longitudinal samples, we confirm that most of these markers are directly related to disease progression and that their levels return to baseline upon disease recovery. Finally, we validate that these metabolites are also altered in a hamster model of COVID-19. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3RMVB13M8 | |||||||||
| Subjects: | 5 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2134: The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies | |||||||
| Status: | Updated | ||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-?, IFN-?, and/or IFN-? are found in ~20% of deceased patients across age groups, and in ~1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-?2 or IFN-?, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ?70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ?80 y old for autoantibodies neutralizing IFN-?2 or IFN-?, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-?2 and IFN-?. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M32LEYGFC5 | ||||||
| Subjects: | 2 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2135: Infectious disease dynamics and restrictions on social gathering size | |||||||
| Status: | Updated | ||||||
| Description: | Social gatherings can be an important locus of transmission for many pathogens including SARS-CoV-2. During an outbreak, restricting the size of these gatherings is one of several non-pharmaceutical interventions available to policy-makers to reduce transmission. Often these restrictions take the form of prohibitions on gatherings above a certain size. While it is generally agreed that such restrictions reduce contacts, the specific size threshold separating ""allowed"" from ""prohibited"" gatherings often does not have a clear scientific basis, which leads to dramatic differences in guidance across location and time. Building on the observation that gathering size distributions are often heavy-tailed, we develop a theoretical model of transmission during gatherings and their contribution to general disease dynamics. We find that a key, but often overlooked, determinant of the optimal threshold is the distribution of gathering sizes. Using data on pre-pandemic contact patterns from several sources as well as empirical estimates of transmission parameters for SARS-CoV-2, we apply our model to better understand the relationship between restriction threshold and reduction in cases. We find that, under reasonable transmission parameter ranges, restrictions may have to be set quite low to have any demonstrable effect on cases due to relative frequency of smaller gatherings. We compare our conceptual model with observed changes in reported contacts during lockdown in March of 2020 | ||||||
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| DOI: | 10.21430/M3N4SFTBH9 | ||||||
| Subjects: | 1 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2141: Household Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 in the United States: Living Density, Viral Load, and Disproportionate Impact on Communities of Color | ||||||||||
| Status: | Updated | |||||||||
| Description: | Background: Households are hot spots for severe acute respiratory syndrome coronavirus 2 transmission. Methods: This prospective study enrolled 100 coronavirus disease 2019 (COVID-19) cases and 208 of their household members in North Carolina though October 2020, including 44% who identified as Hispanic or non-White. Households were enrolled a median of 6 days from symptom onset in the index case. Incident secondary cases within the household were detected using quantitative polymerase chain reaction of weekly nasal swabs (days 7, 14, 21) or by seroconversion at day 28. Results: Excluding 73 household contacts who were PCR-positive at baseline, the secondary attack rate (SAR) among household contacts was 32% (33 of 103; 95% confidence interval [CI], 22%-44%). The majority of cases occurred by day 7, with later cases confirmed as household-acquired by viral sequencing. Infected persons in the same household had similar nasopharyngeal viral loads (intraclass correlation coefficient = 0.45; 95% CI, .23-.62). Households with secondary transmission had index cases with a median viral load that was 1.4 log10 higher than those without transmission (P = .03), as well as higher living density (more than 3 persons occupying fewer than 6 rooms; odds ratio, 3.3; 95% CI, 1.02-10.9). Minority households were more likely to experience high living density and had a higher risk of incident infection than did White households (SAR, 51% vs 19%; P = .01). Conclusions: Household crowding in the context of high-inoculum infections may amplify the spread of COVID-19, potentially contributing to disproportionate impact on communities of color. | |||||||||
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| DOI: | 10.21430/M31ZDULPAH | |||||||||
| Subjects: | 2 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2157: 35th Multicenter Airway Research Collaboration (MARC-35): Genetic analysis of infants | ||||||||||
| Status: | Updated | |||||||||
| Description: | In a multicenter prospective cohort study of infants (age <1 year) hospitalized for bronchiolitis, we sought to identify genetic loci associated with asthma susceptibility and metabolites. We genotyped the whole genome from samples collected at hospitalization and conducted quantitative trait loci analyses. Using colocalization analysis, we confirmed the concordance between the identified loci and known asthma-susceptibility genes. We finally identified genetic loci and genetically driven metabolites that are associated with both genetic risk factors for asthma and childhood asthma development. | |||||||||
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| DOI: | 10.21430/M36N5NJVXZ | |||||||||
| Subjects: | 1 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2158: Immunity to seasonal coronavirus spike proteins does not protect from SARS-CoV-2 challenge in a mouse model | ||||||||||
| Status: | Updated | |||||||||
| Description: | Mice were vaccinated with the spike proteins of 229E, NL63, OC43, HKU1 and SARS-CoV-2 (expressed as soluble trimers) with an oil-in-water emulsion adjuvant in a prime-boost regimen. Control mice were vaccinated with an irrelevant recombinant antigen, recombinant influenza virus hemagglutinin (HA). Three weeks after boost, mice were transduced intranasally with a non-replicating adenovirus expressing human angiotensin converting enzyme 2 (ACE2) followed by a challenge with wild type SARS-CoV-2 strain Washington-1 five days later. Finally, this vaccination experiment was repeated. However, instead of a SARS-CoV-2 challenge, animals were vaccinated 3 weeks post boost with a lipid nanoparticle-formulated nucleoside-modified mRNA vaccine (mRNA-LNP) encoding the SARS-CoV-2 spike protein. | |||||||||
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| DOI: | 10.21430/M3GRS6DFE3 | |||||||||
| Subjects: | 186 | |||||||||
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| 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: | 7 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY2167: Increased viral variants in children and young adults with impaired humoral immunity and persistent SARS-CoV-2 infection: A consecutive case series | |||||||||||
| Status: | Updated | ||||||||||
| Description: | There is increasing concern that persistent infection of SARS-CoV-2 within immunocompromised hosts could serve as a reservoir for mutation accumulation and subsequent emergence of novel strains with the potential to evade immune responses. We describe three patients with acute lymphoblastic leukemia who were persistently positive for SARS-CoV-2 by real-time polymerase chain reaction. Viral viability from longitudinally-collected specimens was assessed. Whole-genome sequencing and serological studies were performed to measure viral evolution and evidence of immune escape. We found compelling evidence of ongoing replication and infectivity for up to 162 days from initial positive by subgenomic RNA, single-stranded RNA, and viral culture analysis. Our results reveal a broad spectrum of infectivity, host immune responses, and accumulation of mutations, some with the potential for immune escape. Our results highlight the potential need to reassess infection control precautions in the management and care of immunocompromised patients. Routine surveillance of mutations and evaluation of their potential impact on viral transmission and immune escape should be considered. | ||||||||||
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| DOI: | 10.21430/M3ZE4KT4OU | ||||||||||
| Subjects: | 3 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2168: Adverse Events After SARS-CoV-2 mRNA Vaccination Among Patients With Inflammatory Bowel Disease | ||||||||||
| Status: | Updated | |||||||||
| Description: | Patients with immune-mediated inflammatory diseases such as inflammatory bowel disease (IBD) on immunosuppressive and biologic therapies were largely excluded from severe acute respiratory syndrome coronavirus-2 messenger RNA vaccine trials. We evaluated adverse events (AE) after messenger RNA vaccination in 246 adults with IBD participating in a longitudinal vaccine registry. In general, AE frequency was similar to that reported in the general population. AEs were more common among younger patients and those with previous COVID-19. AEs were less common in individuals receiving advanced therapies with biologics or small-molecule inhibitors. Those with IBD and other immune-mediated inflammatory diseases can be reassured that the AE risk is likely not increased, and may be reduced, while on advanced therapies. | |||||||||
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| DOI: | 10.21430/M3JRRVRSU4 | |||||||||
| Subjects: | 2 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2169: Nucleocapsid Antigenemia Is a Marker of Acute SARS-CoV-2 Infection | ||||||||||
| Status: | Updated | |||||||||
| Description: | Detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is essential for diagnosis, treatment, and infection control. Polymerase chain reaction (PCR) fails to distinguish acute from resolved infections, as RNA is frequently detected after infectiousness. We hypothesized that nucleocapsid in blood marks acute infection with the potential to enhance isolation and treatment strategies. In a retrospective serosurvey of inpatient and outpatient encounters, we categorized samples along an infection timeline using timing of SARS-CoV-2 testing and symptomatology. Among 1860 specimens from 1607 patients, the highest levels and frequency of antigenemia were observed in samples from acute SARS-CoV-2 infection. Antigenemia was higher in seronegative individuals and in those with severe disease. In our analysis, antigenemia exhibited 85.8% sensitivity and 98.6% specificity as a biomarker for acute coronavirus disease 2019 (COVID-19). Thus, antigenemia sensitively and specifically marks acute SARS-CoV-2 infection. Further study is warranted to determine whether antigenemia may aid individualized assessment of active COVID-19. | |||||||||
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| DOI: | 10.21430/M3V0UOMK3E | |||||||||
| Subjects: | 2 | |||||||||
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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 | ||||||
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| DOI: | 10.21430/M3URLEFSYD | ||||||
| Subjects: | 8 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2171: Modeling the Impact of Vaccination Strategies for Nursing Homes in the Context of Increased Severe Acute Respiratory Syndrome Coronavirus 2 Community Transmission and Variants | |||||||
| Status: | Updated | ||||||
| Description: | Using an agent-based model, we examined the impact of community prevalence, the Delta variant, staff vaccination coverage, and booster vaccines for residents on outbreak dynamics in nursing homes. Increased staff coverage and high booster vaccine effectiveness leads to fewer infections, but cumulative incidence is highly dependent on community transmission. | ||||||
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| DOI: | 10.21430/M3T2140MM5 | ||||||
| Subjects: | 1 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2172: Variable cellular responses to SARS-CoV-2 in fully vaccinated patients with multiple myeloma | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | We wanted to determine whether MM patients without detectable anti-S IgG antibodies to SARS-CoV-2 immunization (seronegative) had detectable SARSCoV-2 B and T cell responses after SARS-CoV-2 vaccination, which would possibly provide some protection against severe disease even in the absence of anti-S antibodies. In order to assay quantitative and qualitative differences in T cell responses, we adopted a high-resolution flow cytometry assay that incorporates multiple cytokines and activation markers. Such data are urgently required to guide masking, social distancing, and passive antibody/booster vaccination strategies for potentially vulnerable MM patients treated with these anti-cancer agents as we enter the second fall season of the COVID-19 pandemic. | |||||||||||||||
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| DOI: | 10.21430/M3JLICY0TG | |||||||||||||||
| Subjects: | 3 | |||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||
| SDY2173: Sex Differences in Lung Imaging and SARS-CoV-2 Antibody Responses in a COVID-19 Golden Syrian Hamster Model | |||||||||
| Status: | Updated | ||||||||
| Description: | In the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more severe outcomes are reported in males than in females, including hospitalizations and deaths. Animal models can provide an opportunity to mechanistically interrogate causes of sex differences in the pathogenesis of SARS-CoV-2. Adult male and female golden Syrian hamsters (8 to 10 weeks of age) were inoculated intranasally with 105 50% tissue culture infective dose (TCID50) of SARS-CoV-2/USA-WA1/2020 and euthanized at several time points during the acute (i.e., virus actively replicating) and recovery (i.e., after the infectious virus has been cleared) phases of infection. There was no mortality, but infected male hamsters experienced greater morbidity, losing a greater percentage of body mass, developed more extensive pneumonia as noted on chest computed tomography, and recovered more slowly than females. Treatment of male hamsters with estradiol did not alter pulmonary damage. Virus titers in respiratory tissues, including nasal turbinates, trachea, and lungs, and pulmonary cytokine concentrations, including interferon-? (IFN-? | ||||||||
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| DOI: | 10.21430/M3JWMD4XHU | ||||||||
| Subjects: | 2 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY2174: A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants | ||||||||||
| Status: | Updated | |||||||||
| Description: | A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants | |||||||||
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| DOI: | 10.21430/M37RN5ILVC | |||||||||
| Subjects: | 3 | |||||||||
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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. | ||||||
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| DOI: | 10.21430/M39EFSK7EI | ||||||
| Subjects: | 1 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2176: A safe and highly efficacious measles virus-based vaccine expressing SARS-CoV-2 stabilized prefusion spike | |||||||||||||||||
| Status: | Updated | ||||||||||||||||
| Description: | The current pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights an urgent need to develop a safe, efficacious, and durable vaccine. Using a measles virus (rMeV) vaccine strain as the backbone, we developed a series of recombinant attenuated vaccine candidates expressing various forms of the SARS-CoV-2 spike (S) protein and its receptor binding domain (RBD) and evaluated their efficacy in cotton rat, IFNAR-/-mice, IFNAR-/--hCD46 mice, and golden Syrian hamsters. We found that rMeV expressing stabilized prefusion S protein (rMeV-preS) was more potent in inducing SARS-CoV-2-specific neutralizing antibodies than rMeV expressing full-length S protein (rMeV-S), while the rMeVs expressing different lengths of RBD (rMeV-RBD) were the least potent. Animals immunized with rMeV-preS produced higher levels of neutralizing antibody than found in convalescent sera from COVID-19 patients and a strong Th1-biased T cell response. The rMeV-preS also provided complete protection of hamsters from challenge with SARS-CoV-2, preventing replication in lungs and nasal turbinates, body weight loss, cytokine storm, and lung pathology. These data demonstrate that rMeV-preS is a safe and highly efficacious vaccine candidate, supporting its further development as a SARS-CoV-2 vaccine | ||||||||||||||||
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| DOI: | 10.21430/M39VJJKEMO | ||||||||||||||||
| Subjects: | 19 | ||||||||||||||||
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