DR51 DataRelease
Release Date: March 2024
New Studies: 37
Updated Studies: 0
New Studies
| SDY2459: BP in irradiated NHPs | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | Because there is a link between high blood pressure and vascular disease in all these sites, we undertook a retrospective study to evaluate blood pressure and radiation in this cohort of animals. In this work, we utilized a cohort of nonhuman primates (rhesus macaques, Macaca mulatta) long-term survivors of high-dose total-body irradiation (1.1–8.5 Gy, N = 129) and controls (N = 37) to evaluate the effects of radiation on blood pressure and obesity. Subjects were between 3 and 22 years of age (median 9 years). Blood pressure (BP) was measured 1–14 years postirradiation (median 4 years). Subjects were sedated with a combination of ketamine HCl (15 mg/kg body weight, IM) and midazolam (0.1 mg/kg body weight, IM) and systolic, diastolic, and mean arterial pressures were measured using a high definition oscillometer. Obesity was defined by dual energy X-ray absorptiometry as a body fat percentage >35%. Statistical analysis of the collected data indicated significant increases in blood pressure with increasing age and obesity. However, radiation did not significantly alter blood pressure in irradiated animals relative to controls, radiation dose, or age of irradiation. | |||||||||||||||
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| DOI: | 10.21430/m3s3jtrmxm | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
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| Assays: | None | |||||||||||||||
| Clinical Assessments: | None | |||||||||||||||
| SDY2463: Altered immunity in HIV exposed uninfected infants | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | A longitudinal infant cohort that collected blood samples at birth, weeks 4, 15 and 36 was used to characterize the immunophenotype of NK cells and T cells, and TCR repertoire of naive and memory CD4 and CD8 T cells. These parameters were associated to vaccine specific antibody responses. | |||||||||||||||
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| DOI: | 10.21430/m3p9yuxo3y | |||||||||||||||
| Subjects: | 61 | |||||||||||||||
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| Publications: | None | |||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||
| SDY2466: SARS-CoV-2 BA.1 and BA.2 breakthrough infections boost antibody responses to early Omicron subvariants but not BQ.1.1 and XBB.1.5 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description: | Here, the authors describe the potency and breadth of neutralizing and binding antibody responses against a large panel of VOC following an Omicron BA.1 or BA.2 breakthrough infection in a heterogeneous cohort of individuals with diverse exposure histories. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| DOI: | 10.21430/m3qke0o5vy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Subjects: | 67 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Publications: | None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| SDY2484: Humoral correlates of protection against Mycobacterium tuberculosis following intravenous Bacille Calmette-Guerin vaccination in rhesus macaques | |||||||
| Status: | New | ||||||
| Description: | Altering the route of immunization of Bacille Calmette-Guerin (BCG) immunization from low-dose intradermal vaccination to high-dose intravenous (IV) injection resulted in a high level of protection against Mycobacterium tuberculosis (Mtb) infection, providing an opportunity to uncover immune correlates and mechanisms of protection. Beyond the traditionally accepted role for T cells in controlling Mtb infection, IV BCG vaccination was associated with a robust expansion of local humoral immune responses that tracked with bacterial control. However, given the near complete protection afforded by high-dose IV BCG immunization, a precise correlate of immune protection was difficult to define. Here we leveraged plasma and bronchoalveolar lavage fluid (BAL) from a cohort of rhesus macaques that received decreasing doses of IV BCG, and aimed to define the correlates of immunity across macaques that experienced immune protection or breakthrough infection following Mtb challenge. We show an IV BCG dose-dependent induction of Mtb-specific humoral immune responses, both in the plasma and the airways. Moreover, antibody responses at peak immunogenicity significantly predicted bacterial control following challenge. Multivariate analyses revealed antibody-mediated complement and NK cell activating humoral networks as key functional signatures associated with protective immunity. Collectively, this work extends our understanding of humoral biomarkers and potential mechanisms of IV BCG mediated protection against Mtb. | ||||||
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| DOI: | 10.21430/m3ulm1mkye | ||||||
| Subjects: | 35 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2500: DTU_SRH_001: Virus specific CD8 T cells in 10 healthy donors and 2 hepatitis donors | ||||||||||
| Status: | New | |||||||||
| Description: | This study served to verify up to 6 MHC-I-tetramer specificities for each of 12 donors (10 healthy blood donors and 2 hepatitis doors). Virus-derived epitopes were derived from CMV, EBV, VZV, HAdV-C, B19, HIV-1 and VACV along with one MART-1 tumor specifity. Each file is named according to the specific donor, epitope sequence and HLA-restriction used. Each tetramer-specificity was encoded as a combination of 1-2 fluorochromes; a list of combinations is present as a metadata file along with information of percieved reactivity to cognate peptide stimulation in a previous assay (see Pagh Kristensen et al 2023 BioRvix, https://doi.org/10.1101/2023.11.06.565606). This study also performed downsampling and computational analysis of virus-specific populations compared to bulk CD8 T cells from each donor. Maximum 5000 cells were exported from each population including bulk CD8 T cells and used as input for FlowSOM clustering and umap dimentionality reduction, 8 clusters were chosen to represent different phenptypic groups within the dataset. | |||||||||
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| DOI: | 10.21430/m317wx3a4q | |||||||||
| Subjects: | 12 | |||||||||
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| Publications: | None | |||||||||
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| SDY2543: The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-β pathway | |||||||||||||||
| Status: | New | ||||||||||||||
| Description: | Evasion of host immunity is a hallmark of cancer; however, mechanisms linking oncogenic mutations and immune escape are incompletely understood. Through loss-of-function screening of 1,001 tumor suppressor genes, we identified death-associated protein kinase 3 (DAPK3) as a previously unrecognized driver of anti-tumor immunity through the stimulator of interferon genes (STING) pathway of cytosolic DNA sensing. Loss of DAPK3 expression or kinase activity impaired STING activation and interferon (IFN)-β-stimulated gene induction. DAPK3 deficiency in IFN-β-producing tumors drove rapid growth and reduced infiltration of CD103+CD8α+ dendritic cells and cytotoxic lymphocytes, attenuating the response to cancer chemo-immunotherapy. Mechanistically, DAPK3 coordinated post-translational modification of STING. In unstimulated cells, DAPK3 inhibited STING K48-linked poly-ubiquitination and proteasome-mediated degradation. After cGAMP stimulation, DAPK3 was required for STING K63-linked poly-ubiquitination and STING-TANK-binding kinase 1 interaction. Comprehensive phospho-proteomics uncovered a DAPK3-specific phospho-site on the E3 ligase LMO7, critical for LMO7-STING interaction and STING K63-linked poly-ubiquitination. Thus, DAPK3 is an essential kinase for STING activation that drives tumor-intrinsic innate immunity and tumor immune surveillance. | ||||||||||||||
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| DOI: | 10.21430/m35a7n55c9 | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
| SDY2544: Low-dose Ad26.COV2.S protection against SARS-CoV-2 challenge in rhesus macaques | |||||||||||||
| Status: | New | ||||||||||||
| Description: | We previously reported that a single immunization with an adenovirus serotype 26 (Ad26)-vector-based vaccine expressing an optimized SARS-CoV-2 spike (Ad26.COV2.S) protected rhesus macaques against SARS-CoV-2 challenge. To evaluate reduced doses of Ad26.COV2.S, 30 rhesus macaques were immunized once with 1 × 1011, 5 × 1010, 1.125 × 1010, or 2 × 109 viral particles (vp) Ad26.COV2.S or sham and were challenged with SARS-CoV-2. Vaccine doses as low as 2 × 109 vp provided robust protection in bronchoalveolar lavage, whereas doses of 1.125 × 1010 vp were required for protection in nasal swabs. Activated memory B cells and binding or neutralizing antibody titers following vaccination correlated with protective efficacy. At suboptimal vaccine doses, viral breakthrough was observed but did not show enhancement of disease. These data demonstrate that a single immunization with relatively low dose of Ad26.COV2.S effectively protected against SARS-CoV-2 challenge in rhesus macaques, although a higher vaccine dose may be required for protection in the upper respiratory tract. | ||||||||||||
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| DOI: | 10.21430/m3via6os0t | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2545: Humoral and cellular immune memory to four COVID-19 vaccines | |||||||||||
| Status: | New | ||||||||||
| Description: | Multiple COVID-19 vaccines, representing diverse vaccine platforms, successfully protect against symptomatic COVID-19 cases and deaths. Head-to-head comparisons of T cell, B cell, and antibody responses to diverse vaccines in humans are likely to be informative for understanding protective immunity against COVID-19, with particular interest in immune memory. Here, SARS-CoV-2-spike-specific immune responses to Moderna mRNA-1273, Pfizer/BioNTech BNT162b2, Janssen Ad26.COV2.S, and Novavax NVX-CoV2373 were examined longitudinally for 6 months 100% of individuals made memory CD4+ T cells, with cTfh and CD4-CTL highly represented after mRNA or NVX-CoV2373 vaccination. mRNA vaccines and Ad26.COV2.S induced comparable CD8+ T cell frequencies, though only detectable in 60–67% of subjects at 6 months. A differentiating feature of Ad26.COV2.S immunization was a high frequency of CXCR3+ memory B cells. mRNA vaccinees had substantial declines in antibodies, while memory T and B cells were comparatively stable. These results may also be relevant for insights against other pathogens. | ||||||||||
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| DOI: | 10.21430/m3yhxnn6ia | ||||||||||
| Subjects: | 0 | ||||||||||
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| SDY2546: COVID-19 vaccine booster dose needed to achieve Omicron-specific neutralisation in nursing home residents | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Methods: We longitudinally enrolled 85 NH residents (median age 77) and 48 HCWs (median age 51), and sampled them after the initial vaccination series; and just before and 2 weeks after booster vaccination. Anti-spike, anti-receptor binding domain (RBD) and neutralisation titres to the original Wuhan strain and neutralisation to the Omicron strain were obtained. Findings: Booster vaccination significantly increased vaccine-specific anti-spike, anti-RBD, and neutralisation levels above the pre-booster levels in NH residents and HCWs, both in those with and without prior SARS-CoV-2 infection. Omicron-specific neutralisation activity was low after the initial 2 dose series with only 28% of NH residents' and 28% HCWs' titres above the assay's lower limit of detection. Omicron neutralising activity following the booster lifted 86% of NH residents and 93% of HCWs to the detectable range. | ||||||||||||
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| DOI: | 10.21430/m3r5h37fu9 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2547: Use of Outpatient-Derived COVID-19 Convalescent Plasma in COVID-19 Patients Before Seroconversion | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | Transfusion of COVID-19 convalescent plasma (CCP) containing high titers of anti-SARS-CoV-2 antibodies serves as therapy for COVID-19 patients. Transfusions early during disease course was found to be beneficial. Lessons from the SARS-CoV-2 pandemic could inform early responses to future pandemics and may continue to be relevant in lower resource settings. We sought to identify factors correlating to high antibody titers in convalescent plasma donors and understand the magnitude and pharmacokinetic time course of both transfused antibody titers and the endogenous antibody titers in transfused recipients. | ||||||||||||||||||
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| DOI: | 10.21430/m31n1mq1ft | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| SDY2548: Direct comparison of antibody responses to four SARS-CoV-2 vaccines in Mongolia | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Different SARS-CoV-2 vaccines are approved in various countries, but few direct comparisons of the antibody responses they stimulate have been reported. We collected plasma specimens in July 2021 from 196 Mongolian participants fully vaccinated with one of four COVID-19 vaccines: Pfizer/BioNTech, AstraZeneca, Sputnik V, and Sinopharm. Functional antibody testing with a panel of nine SARS-CoV-2 viral variant receptor binding domain (RBD) proteins revealed marked differences in vaccine responses, with low antibody levels and RBD-ACE2 blocking activity stimulated by the Sinopharm and Sputnik V vaccines in comparison to the AstraZeneca or Pfizer/BioNTech vaccines. The Alpha variant caused 97% of infections in Mongolia in June and early July 2021. Individuals who recover from SARS-CoV-2 infection after vaccination achieve high antibody titers in most cases. These data suggest that public health interventions such as vaccine boosting, potentially with more potent vaccine types, may be needed to control COVID-19 in Mongolia and worldwide. | ||||||||||||
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| DOI: | 10.21430/m3u8jr4ful | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2549: Human B Cell Clonal Expansion and Convergent Antibody Responses to SARS-CoV-2 | |||||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||||
| Description: | B cells are critical for the production of antibodies and protective immunity to viruses. Here we show that patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) display early recruitment of B cells expressing a limited subset of IGHV genes, progressing to a highly polyclonal response of B cells with broader IGHV gene usage and extensive class switching to IgG and IgA subclasses with limited somatic hypermutation in the initial weeks of infection. We identify convergence of antibody sequences across SARS-CoV-2-infected patients, highlighting stereotyped naive responses to this virus. Notably, sequence-based detection in COVID-19 patients of convergent B cell clonotypes previously reported in SARS-CoV infection predicts the presence of SARS-CoV/SARS-CoV-2 cross-reactive antibody titers specific for the receptor-binding domain. These findings offer molecular insights into shared features of human B cell responses to SARS-CoV-2 and SARS-CoV. | ||||||||||||||||||||||||
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| DOI: | 10.21430/m3rtb0hobg | ||||||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||||||||
| SDY2550: Differential T-Cell Reactivity to Endemic Coronaviruses and SARS-CoV-2 in Community and Health Care Workers | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Herein we measured CD4+ T-cell responses against common cold coronaviruses (CCC) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in high-risk health care workers (HCW) and community controls. We observed higher levels of CCC-reactive T cells in SARS-CoV-2-seronegative HCW compared to community donors, consistent with potential higher occupational exposure of HCW to CCC. We further show that SARS-CoV-2 T-cell reactivity of seronegative HCW was higher than community controls and correlation between CCC and SARS-CoV-2 responses is consistent with cross-reactivity and not associated with recent in vivo activation. Surprisingly, CCC T-cell reactivity was decreased in SARS-CoV-2-infected HCW, suggesting that exposure to SARS-CoV-2 might interfere with CCC responses, either directly or indirectly. This result was unexpected, but consistently detected in independent cohorts derived from Miami and San Diego. CD4+ T-cell responses against common cold coronaviruses (CCC) are elevated in SARS-CoV-2 seronegative high-risk health care workers (HCW) compared to COVID-19 convalescent HCW, suggesting that exposure to SARS-CoV-2 might interfere with CCC responses and/or cross-reactivity associated with a protective effect | ||||||||||||
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| DOI: | 10.21430/m3ixzp2qus | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2551: Evaluation of a COVID-19 convalescent plasma program at a U.S. academic medical center | |||||||||||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||||||||||
| Description: | Amidst the therapeutic void at the onset of the COVID-19 pandemic, a critical mass of scientific and clinical interest coalesced around COVID-19 convalescent plasma (CCP). To date, the CCP literature has focused largely on safety and efficacy outcomes, but little on implementation outcomes or experience. Expert opinion suggests that if CCP has a role in COVID-19 treatment, it is early in the disease course, and it must deliver a sufficiently high titer of neutralizing antibodies (nAb). Missing in the literature are comprehensive evaluations of how local CCP programs were implemented as part of pandemic preparedness and response, including considerations of the core components and personnel required to meet demand with adequately qualified CCP in a timely and sustained manner. To address this gap, we conducted an evaluation of a local CCP program at a large U.S. academic medical center, the University of North Carolina Medical Center (UNCMC), and patterned our evaluation around the dimensions of the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to systematically describe key implementation-relevant metrics. We aligned our evaluation with program goals of reaching the target population with severe or critical COVID-19, integrating into the structure of the hospital-wide pandemic response, adapting to shifting landscapes, and sustaining the program over time during a compassionate use expanded access program (EAP) era and a randomized controlled trial (RCT) era. During the EAP era, the UNCMC CCP program was associated with faster CCP infusion after admission compared with contemporaneous affiliate hospitals without a local program: median 29.6 hours (interquartile range, IQR: 21.2-48.1) for the UNCMC CCP program versus 47.6 hours (IQR 32.6-71.6) for affiliate hospitals; (P<0.0001). Sixty-eight of 87 CCP recipients in the EAP (78.2%) received CCP containing the FDA recommended minimum nAb titer of ≥1:160. CCP delivery to hospitalized patients operated with equal efficiency regardless of receiving treatment via a RCT or a compassionate-use mechanism. It was found that in a highly resourced academic medical center, rapid implementation of a local CCP collection, treatment, and clinical trial program could be achieved through re-deployment of highly trained laboratory and clinical personnel. These data provide important pragmatic considerations critical for health systems considering the use of CCP as part of an integrated pandemic response. | ||||||||||||||||||||||||||||||
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| DOI: | 10.21430/m3155jyk11 | ||||||||||||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||||||||||||
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| SDY2552: Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes | ||||||||||
| Status: | New | |||||||||
| Description: | The molecular composition and binding epitopes of the immunoglobulin G (IgG) antibodies that circulate in blood plasma after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are unknown. Proteomic deconvolution of the IgG repertoire to the spike glycoprotein in convalescent subjects revealed that the response is directed predominantly (greater than 80 percent) against epitopes residing outside the receptor binding domain (RBD). In one subject, just four IgG lineages accounted for 93.5 percent of the response, including an amino (N)-terminal domain (NTD)-directed antibody that was protective against lethal viral challenge. Genetic, structural, and functional characterization of a multidonor class of public antibodies revealed an NTD epitope that is recurrently mutated among emerging SARS-CoV-2 variants of concern. These data show that public NTD-directed and other non-RBD plasma antibodies are prevalent and have implications for SARS-CoV-2 protection and antibody escape. | |||||||||
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| DOI: | 10.21430/m3yhp9kyvl | |||||||||
| Subjects: | 4 | |||||||||
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| SDY2553: Pregnancy alters interleukin-1 beta expression and antiviral antibody responses during severe acute respiratory syndrome coronavirus 2 infection | |||||||||||
| Status: | New | ||||||||||
| Description: | Background: Severe acute respiratory syndrome coronavirus 2, the disease-causing pathogen of the coronavirus disease 2019 pandemic, has resulted in morbidity and mortality worldwide. Pregnant women are more susceptible to severe coronavirus disease 2019 and are at higher risk of preterm birth than uninfected pregnant women. Despite this evidence, the immunologic effects of severe acute respiratory syndrome coronavirus 2 infection during pregnancy remain understudied. Objective: This study aimed to assess the impact of severe acute respiratory syndrome coronavirus 2 infection during pregnancy on inflammatory and humoral responses in maternal and fetal samples and compare antibody responses to severe acute respiratory syndrome coronavirus 2 among pregnant and nonpregnant women. Study design: Immune responses to severe acute respiratory syndrome coronavirus 2 were analyzed using samples from pregnant (n=33) and nonpregnant (n=17) women who tested either positive (pregnant, 22; nonpregnant, 17) or negative for severe acute respiratory syndrome coronavirus 2 (pregnant, 11) at Johns Hopkins Hospital. We measured proinflammatory and placental cytokine messenger RNAs, neonatal Fc receptor expression, and tetanus antibody transfer in maternal and cord blood samples. In addition, we evaluated antispike immunoglobulin G, antispike receptor-binding domain immunoglobulin G, and neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 in serum or plasma collected from nonpregnant women, pregnant women, and cord blood. Results: Pregnant women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection expressed more interleukin-1 beta, but not interleukin 6, in blood samples collected within 14 days vs >14 days after performing severe acute respiratory syndrome coronavirus 2 test. Pregnant women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection also had reduced antispike receptor-binding domain immunoglobulin G titers and were less likely to have detectable neutralizing antibody than nonpregnant women. Although severe acute respiratory syndrome coronavirus 2 infection did not disrupt neonatal Fc receptor expression in the placenta, maternal transfer of severe acute respiratory syndrome coronavirus 2 neutralizing antibody was inhibited by infection during pregnancy. Conclusion: Severe acute respiratory syndrome coronavirus 2 infection during pregnancy was characterized by placental inflammation and reduced antiviral antibody responses, which may impact the efficacy of coronavirus disease 2019 treatment in pregnancy. In addition, the long-term implications of placental inflammation for neonatal health require greater consideration. | ||||||||||
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| DOI: | 10.21430/m375nmdbkg | ||||||||||
| Subjects: | 0 | ||||||||||
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| SDY2554: A third dose of SARS-CoV-2 vaccine increases neutralizing antibodies against variants of concern in solid organ transplant recipients | ||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||
| Description: | Vaccine-induced SARS-CoV-2 antibody responses are attenuated in solid organ transplant recipients (SOTRs) and breakthrough infections are more common. Additional SARS-CoV-2 vaccine doses increase anti-spike IgG in some SOTRs, but it is uncertain whether neutralization of variants of concern (VOCs) is enhanced. We tested 47 SOTRs for clinical and research anti-spike IgG, pseudoneutralization (ACE2 blocking), and live-virus neutralization (nAb) against VOCs before and after a third SARS-CoV-2 vaccine dose (70% mRNA, 30% Ad26.COV2.S) with comparison to 15 healthy controls after two mRNA vaccine doses. We used correlation analysis to compare anti-spike IgG assays and focused on thresholds associated with neutralization. A third SARS-CoV-2 vaccine dose increased median total anti-spike (1.6-fold), pseudoneutralization against VOCs (2.5-fold vs. Delta), and neutralizing antibodies (1.4-fold against Delta). However, neutralization activity was significantly lower than healthy controls (p < .001); 32% of SOTRs had zero detectable nAb against Delta after third vaccination compared to 100% for controls. Correlation with nAb was seen at anti-spike IgG >4 Log10 (AU/ml) on the Euroimmun ELISA and >4 Log10 (AU/ml) on the MSD research assay. These findings highlight benefits of a third vaccine dose for some SOTRs and the need for alternative strategies to improve protection in a significant subset of this population. | |||||||||||||||||||||
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| DOI: | 10.21430/m3mva0vylw | |||||||||||||||||||||
| Subjects: | 0 | |||||||||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||||||||
| SDY2555: Circulating Spike Protein Detected in Post-COVID-19 mRNA Vaccine Myocarditis | |||||||||||||||
| Status: | New | ||||||||||||||
| Description: | Background: Cases of adolescents and young adults developing myocarditis after vaccination with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-targeted mRNA vaccines have been reported globally, but the underlying immunoprofiles of these individuals have not been described in detail. Methods: From January 2021 through February 2022, we prospectively collected blood from 16 patients who were hospitalized at Massachusetts General for Children or Boston Children's Hospital for myocarditis, presenting with chest pain with elevated cardiac troponin T after SARS-CoV-2 vaccination. We performed extensive antibody profiling, including tests for SARS-CoV-2-specific humoral responses and assessment for autoantibodies or antibodies against the human-relevant virome, SARS-CoV-2-specific T-cell analysis, and cytokine and SARS-CoV-2 antigen profiling. Results were compared with those from 45 healthy, asymptomatic, age-matched vaccinated control subjects. Results: Extensive antibody profiling and T-cell responses in the individuals who developed postvaccine myocarditis were essentially indistinguishable from those of vaccinated control subjects, despite a modest increase in cytokine production. A notable finding was that markedly elevated levels of full-length spike protein (33.9±22.4 pg/mL), unbound by antibodies, were detected in the plasma of individuals with postvaccine myocarditis, whereas no free spike was detected in asymptomatic vaccinated control subjects (unpaired t test; P<0.0001). Conclusions: Immunoprofiling of vaccinated adolescents and young adults revealed that the mRNA vaccine-induced immune responses did not differ between individuals who developed myocarditis and individuals who did not. However, free spike antigen was detected in the blood of adolescents and young adults who developed post-mRNA vaccine myocarditis, advancing insight into its potential underlying cause. | ||||||||||||||
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| DOI: | 10.21430/m3sjr04zkv | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
| SDY2556: Longitudinal characterization of circulating neutrophils uncovers phenotypes associated with severity in hospitalized COVID-19 patients. | |||||||||||||||||
| Status: | New | ||||||||||||||||
| Description: | Mechanisms of neutrophil involvement in severe coronavirus disease 2019 (COVID-19) remain incompletely understood. Here, we collect longitudinal blood samples from 306 hospitalized COVID-19+ patients and 86 controls and perform bulk RNA sequencing of enriched neutrophils, plasma proteomics, and high-throughput antibody profiling to investigate relationships between neutrophil states and disease severity. We identify dynamic switches between six distinct neutrophil subtypes. At days 3 and 7 post-hospitalization, patients with severe disease display a granulocytic myeloid-derived suppressor cell-like gene expression signature, while patients with resolving disease show a neutrophil progenitor-like signature. Humoral responses are identified as potential drivers of neutrophil effector functions, with elevated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulin G1 (IgG1)-to-IgA1 ratios in plasma of severe patients who survived. In vitro experiments confirm that while patient-derived IgG antibodies induce phagocytosis in healthy donor neutrophils, IgA antibodies predominantly induce neutrophil cell death. Overall, our study demonstrates a dysregulated myelopoietic response in severe COVID-19 and a potential role for IgA-dominant responses contributing to mortality. | ||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/m3m32vv26r | ||||||||||||||||
| Subjects: | 0 | ||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||
| SDY2557: Targeting spike glycans to inhibit SARS-CoV2 viral entry | |||||||||||||
| Status: | New | ||||||||||||
| Description: | SARS-CoV-2 spike harbors glycans which function as ligands for lectins. Therefore, it should be possible to exploit lectins to target SARS-CoV-2 and inhibit cellular entry by binding glycans on the spike protein. Burkholderia oklahomensis agglutinin (BOA) is an antiviral lectin that interacts with viral glycoproteins via N-linked high mannose glycans. Here, we show that BOA binds to the spike protein and is a potent inhibitor of SARS-CoV-2 viral entry at nanomolar concentrations. Using a variety of biophysical approaches, we demonstrate that the interaction is avidity driven and that BOA cross-links the spike protein into soluble aggregates. Furthermore, using virus neutralization assays, we demonstrate that BOA effectively inhibits all tested variants of concern as well as SARS-CoV 2003, establishing that multivalent glycan-targeting molecules have the potential to act as pan-coronavirus inhibitors. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/m3e6knnyvq | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2558: Omicron spike function and neutralizing activity elicited by a comprehensive panel of vaccines | |||||||||||
| Status: | New | ||||||||||
| Description: | The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern comprises several sublineages, with BA.2 and BA.2.12.1 having replaced the previously dominant BA.1 and with BA.4 and BA.5 increasing in prevalence worldwide. We show that the large number of Omicron sublineage spike mutations leads to enhanced angiotensin-converting enzyme 2 (ACE2) binding, reduced fusogenicity, and severe dampening of plasma neutralizing activity elicited by infection or seven clinical vaccines relative to the ancestral virus. Administration of a homologous or heterologous booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1, BA.2, BA.2.12.1, BA.4, and BA.5 across all vaccines evaluated. Our data suggest that although Omicron sublineages evade polyclonal neutralizing antibody responses elicited by primary vaccine series, vaccine boosters may provide sufficient protection against Omicron-induced severe disease. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/m3fjy3o5gg | ||||||||||
| Subjects: | 0 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2559: Vaccines elicit highly conserved cellular immunity to SARS-CoV-2 Omicron | |||||||||||||
| Status: | New | ||||||||||||
| Description: | The highly mutated SARS-CoV-2 Omicron (B.1.1.529) variant has been shown to evade a substantial fraction of neutralizing antibody responses elicited by current vaccines that encode the WA1/2020 spike protein1. Cellular immune responses, particularly CD8+ T cell responses, probably contribute to protection against severe SARS-CoV-2 infection2-6. Here we show that cellular immunity induced by current vaccines against SARS-CoV-2 is highly conserved to the SARS-CoV-2 Omicron spike protein. Individuals who received the Ad26.COV2.S or BNT162b2 vaccines demonstrated durable spike-specific CD8+ and CD4+ T cell responses, which showed extensive cross-reactivity against both the Delta and the Omicron variants, including in central and effector memory cellular subpopulations. Median Omicron spike-specific CD8+ T cell responses were 82-84% of the WA1/2020 spike-specific CD8+ T cell responses. These data provide immunological context for the observation that current vaccines still show robust protection against severe disease with the SARS-CoV-2 Omicron variant despite the substantially reduced neutralizing antibody responses | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/m32bp19s8x | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2561: Longitudinal nucleocapsid antibody testing reveals undocumented SARS-CoV-2 infections in patients with lung cancer | ||||||||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||||||||
| Description: | Patients diagnosed with lung cancer (LC) exhibit increased susceptibility to SARS-CoV-2 infection. Rodilla et al. monitor the levels of plasma anti-nucleocapsid antibodies within a cohort of fully vaccinated LC patients and reveal that the actual infection rate is nearly twice the documented rate, indicating a significant prevalence of unreported cases. | |||||||||||||||||||||||||||
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| DOI: | 10.21430/m3rh6zv08i | |||||||||||||||||||||||||||
| Subjects: | 0 | |||||||||||||||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||||||||||||||
| SDY2562: SARS-CoV-2 IgG Spike antibody levels and avidity in natural infection or following vaccination with mRNA-1273 or BNT162b2 vaccines | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Certain aspects of the immunogenicity and effectiveness of the messenger ribonucleic acid (mRNA) vaccines (mRNA-1273 and BNT162b2) developed in response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are still uncharacterized. Serum or plasma samples from healthy donor recipients of either vaccine (BNT162b2 n = 53, mRNA-1273 n = 49; age 23-67), and individuals naturally infected with SARS-CoV-2 (n = 106; age 18-82) were collected 0-2 months post-infection or 1- and 4 months after second dose of vaccination. Anti-Spike antibody levels and avidity were measured via an enzyme-linked immunosorbent assay (ELISA). Overall, vaccination induced higher circulating anti-Spike protein immunoglobulin G (IgG) antibody levels and avidity compared to infection at similar time intervals. Both vaccines produced similar anti-Spike IgG concentrations at 1 month, while mRNA-1273 demonstrated significantly higher circulating antibody concentrations after 4 months. mRNA-1273 induced significantly higher avidity at month 1 compared to BNT162b2 across all age groups. However, the 23-34 age group was the only group to maintain statistical significance by 4 months. Male BNT162b2 recipients were approaching statistically significant lower anti-Spike IgG avidity compared to females by month 4. These findings demonstrate enhanced anti-Spike IgG levels and avidity following vaccination compared to natural infection. In addition, the mRNA-1273 vaccine induced higher antibody levels by 4 months compared to BNT162b2. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/m3la0cdz9l | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2563: SARS-CoV-2 RNAemia in a Healthy Blood Donor 40 Days After Respiratory Illness Resolution | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | Asymptomatic donors infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may pose a risk to the safety of the blood supply (1). Although a previous report described detection of viral RNA in donor plasma, these donors tested positive for SARS-CoV-2 in a respiratory specimen or developed fever shortly after donation, suggesting that the donation occurred early in the course of their infection (2). To our knowledge, the persistence of SARS-CoV-2 RNA in plasma from an eligible donor after recovery from illness has not yet been described. | |||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/m3ionfjdrz | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||
| SDY2564: SARS-CoV-2 Spike-Binding Antibody Longevity and Protection from Reinfection with Antigenically Similar SARS-CoV-2 Variants. | |||||||
| Status: | New | ||||||
| Description: | SARS-CoV-2 is the cause of one of the largest noninfluenza pandemics of this century. This exceptional public health crisis highlights the urgent need for better understanding of the correlates of protection from infection and severe COVID-19. We established the PARIS cohort to determine durability and effectiveness of SARS-CoV-2 immune responses. Here, we report on the kinetics of SARS-CoV-2 spike-binding antibody after SARS-CoV-2 infection as well as reinfection rates using data collected between April 2020 and August 2021. We found that antibody levels stabilized at individual steady state levels after an initial decrease with seroreversion being found in only 6% of the convalescent participants. SARS-CoV-2 infections only occurred in participants without detectable spike-binding antibodies, indicating significant protection from reinfection with antigenically similar viruses. Our data indicate the importance of spike-binding antibody titers in protection prior to vaccination and the wide circulation of antigenically diverse variants of concern. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/m3o55f20tz | ||||||
| Subjects: | 137 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY2565: Evidence for retained spike-binding and neutralizing activity against emerging SARS-CoV-2 variants in serum of COVID-19 mRNA vaccine recipients | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Background: Highly efficacious vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed. However, the emergence of viral variants that are more infectious than the earlier SARS-CoV-2 strains is concerning. Several of these viral variants have the potential to partially escape neutralizing antibody responses, warranting continued immune-monitoring. Methods: We used a panel of 30 post-mRNA vaccination sera to determine neutralization and RBD and spike binding activity against a number of emerging viral variants. The virus neutralization was determined using authentic SARS-CoV-2 clinical isolates in an assay format that mimics physiological conditions. Findings: We tested seven currently circulating viral variants of concern/interest, including the three Iota sublineages, Alpha (E484K), Beta, Delta and Lambda in neutralization assays. We found only small decreases in neutralization against Iota and Delta. The reduction was stronger against a sub-variant of Lambda, followed by Beta and Alpha (E484K). Lambda is currently circulating in parts of Latin America and was detected in Germany, the US and Israel. Of note, reduction in a receptor binding domain and spike binding assay that also included Gamma, Kappa and A.23.1 was negligible. Interpretation: Taken together, these findings suggest that mRNA SARS-CoV-2 vaccines may remain effective against these viral variants of concern/interest and that spike binding antibody tests likely retain specificity in the face of evolving SARS-CoV-2 diversity. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/m35sd2inua | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2566: Evolution of enhanced innate immune evasion by SARS-CoV-2 | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission1,2. Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant3 suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6-all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection4. The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/m3u1qa6vz8 | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2574: Dissecting Functional Antibody Activity Against Influenza Virus | ||||||||||
| Status: | New | |||||||||
| Description: | Not Provided | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/m3butykv0a | |||||||||
| Subjects: | 51 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2575: Neutralizing Antibodies Against Influenza B Viruses from Both Lineages | ||||||||||
| Status: | New | |||||||||
| Description: | To develop more effective influenza B virus vaccines, three novel IBV hemagglutinin (HA) vaccines were designed using a computationally optimized broadly reactive antigen (COBRA) methodology. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/m3v9i0ulq8 | |||||||||
| Subjects: | 100 | |||||||||
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| SDY2576: Directed evolution of and structural insights into antibody-mediated disruption of a stable receptor-ligand complex | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Antibody drugs exert therapeutic effects via a range of mechanisms, including competitive inhibition, allosteric modulation, and immune effector mechanisms. Facilitated dissociation is an additional mechanism where antibody-mediated ""disruption"" of stable high-affinity macromolecular complexes can potentially enhance therapeutic efficacy. However, this mechanism is not well understood or utilized therapeutically. Here, we investigate and engineer the weak disruptive activity of an existing therapeutic antibody, omalizumab, which targets IgE antibodies to block the allergic response. We develop a yeast display approach to select for and engineer antibody disruptive efficiency and generate potent omalizumab variants that dissociate receptor-bound IgE. We determine a low resolution cryo-EM structure of a transient disruption intermediate containing the IgE-Fc, its partially dissociated receptor and an antibody inhibitor. Our results provide a conceptual framework for engineering disruptive inhibitors for other targets, insights into the failure in clinical trials of the previous high affinity omalizumab HAE variant and anti-IgE antibodies that safely and rapidly disarm allergic effector cells. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/m344a57hws | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2577: IgG-like bispecific antibodies with potent and synergistic neutralization against circulating SARS-CoV-2 variants of concern | |||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||
| Description: | Monoclonal antibodies are a promising approach to treat COVID-19, however the emergence of SARS-CoV-2 variants has challenged the efficacy and future of these therapies. Antibody cocktails are being employed to mitigate these challenges, but neutralization escape remains a major challenge and alternative strategies are needed. Here we present two anti-SARS-CoV-2 spike binding antibodies, one Class 1 and one Class 4, selected from our non-immune human single-chain variable fragment (scFv) phage library, that are engineered into four, fully-human IgG-like bispecific antibodies (BsAb). Prophylaxis of hACE2 mice and post-infection treatment of golden hamsters demonstrates the efficacy of the monospecific antibodies against the original Wuhan strain, while promising in vitro results with the BsAbs demonstrate enhanced binding and distinct synergistic effects on neutralizing activity against circulating variants of concern. In particular, one BsAb engineered in a tandem scFv-Fc configuration shows synergistic neutralization activity against several variants of concern including B.1.617.2. This work provides evidence that synergistic neutralization can be achieved using a BsAb scaffold, and serves as a foundation for the future development of broadly reactive BsAbs against emerging variants of concern. | ||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/m35znooxj1 | ||||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||||||
| SDY2578: Influenza H3 hemagglutinin vaccine with scrambled immunodominant epitopes elicits antibodies directed toward immunosubdominant head epitopes. | ||||||||||
| Status: | New | |||||||||
| Description: | Here, the authors designed an H3 HA vaccine antigen with various amino acids at immunodominant epitopes of the HA head domain, termed scrambled HA (scrHA). | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/m3avxr3yfo | |||||||||
| Subjects: | 160 | |||||||||
| Study PI, contact: |
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| SDY2579: An immunostimulatory glycolipid that blocks SARS-CoV-2, RSV, and influenza infections in vivo | |||||||
| Status: | New | ||||||
| Description: | K18 human-ACE2 transgenic C57BL/6 mice administered 2ug of 7DW8-5. Infectious viral load determined 3 days after challenge in both lung and nasal tissues. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/m3n3wm4osp | ||||||
| Subjects: | 20 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY2580: Polymer delivery of Influenza Vaccine | |||||||
| Status: | New | ||||||
| Description: | Not Provided | ||||||
| Program/Contract: |
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| DOI: | 10.21430/m3c49tyd79 | ||||||
| Subjects: | 0 | ||||||
| Study PI, contact: |
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2581: Host Predictors of Broadly Cross-Reactive Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants of Concern Differ Between Infection and Vaccination | ||||||||||
| Status: | New | |||||||||
| Description: | Following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination there is significant variability between individuals in protective antibody levels against SARS-CoV-2, and within individuals against different virus variants. However, host demographic or clinical characteristics that predict variability in cross-reactive antibody levels are not well-described. These data could inform clinicians, researchers, and policymakers on the populations most likely to require vaccine booster in an institutional review board approved prospective observational cohort study of staff at St. Jude Childrens Research Hospital, we identified participants with plasma samples collected after SARS-CoV-2 infection, after mRNA vaccination, and after vaccination following infection, and quantitated immunoglobulin G (IgG) levels by enzyme-linked immunosorbent assay to the spike receptor binding domain (RBD) from 5 important SARS-CoV-2 variants (Wuhan Hu-1, B.1.1.7, B.1.351, P.1, and B.1.617.2). We used regression models to identify factors that contributed to cross-reactive IgG against 1 or multiple viral variants. Following infection, a minority of the cohort generated cross-reactive antibodies, IgG antibodies that bound all tested variants. Those who did had increased disease severity, poor metabolic health, and were of a particular ancestry. Vaccination increased the levels of cross-reactive IgG levels in all populations, including immunocompromised, elderly, and persons with poor metabolic health. Younger people with a healthy weight mounted the highest responses.Our findings provide important new information on individual antibody responses to infection/vaccination that could inform clinicians on populations that may require follow-on immunization. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/m3f139urpw | |||||||||
| Subjects: | 0 | |||||||||
| Study PI, contact: |
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2582: Large-scale proteomics in the first trimester of pregnancy predict psychopathology and temperament in preschool children | |||||||
| Status: | New | ||||||
| Description: | Background: Understanding the prenatal origins of children’s psychopathology is a fundamental goal in developmental and clinical science. Recent research suggests that inflammation during pregnancy can trigger a cascade of fetal programming changes that contribute to vulnerability for the emergence of psychopathology. Most studies, however, have focused on a handful of proinflammatory cytokines and have not explored a range of prenatal biological pathways that may be involved in increasing postnatal risk for emotional and behavioral difficulties. Methods: Using extreme gradient boosted machine learning models, we explored large-scale proteomics, considering over 1,000 proteins from first trimester blood samples, to predict behavior in early childhood. Mothers reported on their 3- to 5-year-old children’s (N = 89, 51% female) temperament (Child Behavior Questionnaire) and psychopathology (Child Behavior Checklist). Results: We found that machine learning models of prenatal proteomics predict 5%–10% of the variance in children’s sadness, perceptual sensitivity, attention problems, and emotional reactivity. Enrichment analyses identified immune function, nervous system development, and cell signaling pathways as being particularly important in predicting children’s outcomes. Conclusions: Our findings, though exploratory, suggest processes in early pregnancy that are related to functioning in early childhood. Predictive features included far more proteins than have been considered in prior work. Specifically, proteins implicated in inflammation, in the development of the central nervous system, and in key cell-signaling pathways were enriched in relation to child temperament and psychopathology measures. Keywords: Biomarkers; child development; machine learning; prenatal; prediction. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/m34sax8sjb | ||||||
| Subjects: | 0 | ||||||
| Study PI, contact: |
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||