DR46 DataRelease
Release Date: 12/15/2022
| SDY1394: Blood and tissue studies of Tick-borne diseases in adults. Blood and tissue studies of Tick-borne diseases in children. Year1 | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | The study is designed to look at how the body responds to infection with Lyme disease spirochete and how this response relates to clinical symptoms and infection outcomes. | ||||||||||||||||||
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| DOI: | 10.21430/M3XL8X77T6 | ||||||||||||||||||
| Subjects: | 2 | ||||||||||||||||||
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| Publications: | None | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY1395: Blood and tissue studies of Tick-borne diseases in adults. Blood and tissue studies of Tick-borne diseases in children. Year2 | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | The study is designed to look at how the body responds to infection with Lyme disease spirochete and how this response relates to clinical symptoms and infection outcomes. | ||||||||||||||||||
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| DOI: | 10.21430/M3PVMO2ISJ | ||||||||||||||||||
| Subjects: | 29 | ||||||||||||||||||
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| Publications: | None | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY1396: Systems Immune Profiling of Divergent Responses to Infection | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | Our ongoing studies investigate mechanisms of individual susceptibility and resistance to infection in order to identify biomarkers of severe disease or potential therapeutic approaches. | ||||||||||||||||||
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| DOI: | 10.21430/M3OPV1DVTB | ||||||||||||||||||
| Subjects: | 1 | ||||||||||||||||||
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| Publications: | None | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY1397: Systems Immune Profiling of Divergent Responses to Infection - Year2 | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | Our ongoing studies investigate mechanisms of individual susceptibility and resistance to infection in order to identify biomarkers of severe disease or potential therapeutic approaches. | ||||||||||||||||||
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| DOI: | 10.21430/M3OKZI2ZXD | ||||||||||||||||||
| Subjects: | 16 | ||||||||||||||||||
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| Publications: | None | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY1530: ZIKV ex vivo PBMCs study | |||||||
| Status: | New | ||||||
| Description: | Ex vivo infections of human PBMCs were infected with ZIKV (PRVABC59) and DENV2 (Nicaragua 172-06) and analysis was performed to study the innate immune profile upon infection using CyTOF and a multiplexed beads array assay (MBAA). | ||||||
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| DOI: | 10.21430/M316LYQMUG | ||||||
| Subjects: | 5 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1538: Systems Biology to Identify Biomarkers of Neonatal Vaccine Immunogenicity | ||||||||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||||||||
| 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. | |||||||||||||||||||||||||||
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| DOI: | 10.21430/M35PWV2M56 | |||||||||||||||||||||||||||
| Subjects: | 720 | |||||||||||||||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||||||||||||||
| SDY2011: A shift in lung macrophage composition is associated with COVID-19 severity and recovery | ||||||||||
| Status: | New | |||||||||
| Description: | The goal of our study was to identify drivers of COVID-19 severity and death in order to support the identification and development of tailored immunotherapy strategies to halt disease progression. We performed high dimensional immunophenotyping on hospitalized COVID-19 patients at the Mount Sinai Hospital from March 2020-December 2020. We characterized serum inflammation patterns using the Olink platform which allowed us to detect 92 different proteins in 583 COVID+ patients (1956 COVID+ and 45 COVID- volunteer serum samples). To understand the diversity of immune patterns, we performed unbiased clustering analysis and identified immune patterns that correlated with disease severity, comorbidities, and patient outcome. We grouped immune patterns based on these clinical parameters and calculated protein module scores based on the covariance patterns of different cytokines. Next, we characterized circulating immune cells using CyTOF on whole blood samples and scRNAseq on PBMC. We used unbiased clustering on PBMC scRNAseq to identify immune cell populations and compared the relative frequencies across Olink groups. Following this, we integrated our proteomics data with scRNAseq to identify 4 distinct patterns of immune response in COVID-19. To characterize local changes to the lung immune microenvironment, we obtained BAL samples from COVID+, COVID-, and convalescent patients and performed scRNAseq. We further expanded our characterization of the lung using MICSSS on lung autopsy samples and quantified changes in myeloid cell infiltration. | |||||||||
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| DOI: | 10.21430/M3YKLKQ0MA | |||||||||
| Subjects: | 563 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2075: Deficiency of PD-L1+ Non-Immune Cells in Preterm Labor | ||||||||||
| Status: | New | |||||||||
| Description: | The mechanisms that underlie the timing of labor in humans are largely unknown. In most pregnancies, labor is initiated at term (38-40 weeks gestation), but for many women spontaneous labor occurs preterm and is associated with high fetal mortality and morbidity. The objective of this study was to characterize the cells at the maternal-fetal interface (MFI) in term and preterm pregnancies, each in the laboring and non-laboring state. Using mass cytometry to obtain single-cell resolution, we identified 31 cell populations at the MFI, including 25 immune cell types and six non-immune cell types. Among the immune cells, maternal PD1+ CD8 T cells subsets were less abundant in term laboring compared to term non-laboring. Among the non-immune cells, PD-L1+ maternal (stromal) and fetal (extravillous trophoblast) cells were more abundant in term laboring compared to preterm laboring pregnancies. Consistent with these observations, the expression of CD274, the gene encoding PD-L1, was significantly depressed and less responsive to fetal signaling molecules in cultured mesenchymal stromal cells from the decidua of preterm compared to term pregnancies. Overall, these results suggest that the PD1/PD-L1 pathway at the MFI may perturb the delicate balance between immune tolerance and rejection and contribute to the onset of spontaneous preterm labor. | |||||||||
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| DOI: | 10.21430/M300YTT71X | |||||||||
| Subjects: | 52 | |||||||||
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| Publications: | None | |||||||||
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| Assays: | None | |||||||||
| 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: | New | ||||||||||||||
| 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. | ||||||||||||||
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| DOI: | 10.21430/M3FS3Q3TG6 | ||||||||||||||
| Subjects: | 4 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
| SDY2111: Reduced COVID-19 Vaccine Response in Patients Treated with Biologic Therapies for Asthma | ||||||||||
| Status: | New | |||||||||
| 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). | |||||||||
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| DOI: | 10.21430/M3A944EBOX | |||||||||
| Subjects: | 2 | |||||||||
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| SDY2113: Augmentation of humoral and cellular immune responses after third-dose SARS-CoV-2 vaccination and viral neutralization in myeloma patients | ||||||||||||||||
| Status: | New | |||||||||||||||
| 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). | |||||||||||||||
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| DOI: | 10.21430/M3EEDBBP9C | |||||||||||||||
| Subjects: | 2 | |||||||||||||||
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| SDY2114: Longitudinal analysis of severe acute respiratory syndrome coronavirus 2 seroprevalence using multiple serology platforms | |||||||||||||
| Status: | New | ||||||||||||
| 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. | ||||||||||||
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| DOI: | 10.21430/M3S0T656KV | ||||||||||||
| Subjects: | 1 | ||||||||||||
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| 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: | New | ||||||||
| 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 | ||||||||
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| DOI: | 10.21430/M301KI6WVE | ||||||||
| Subjects: | 6 | ||||||||
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| SDY2116: Inflammasome activation in infected macrophages drives COVID-19 pathology | |||||||||||||
| Status: | New | ||||||||||||
| 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. | ||||||||||||
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| DOI: | 10.21430/M3UICFULPO | ||||||||||||
| Subjects: | 5 | ||||||||||||
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| SDY2117: Decreased infectivity following BNT162b2 vaccination: A prospective cohort study in Israel | ||||||||||
| Status: | New | |||||||||
| 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. | |||||||||
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| DOI: | 10.21430/M3VXVCH51N | |||||||||
| Subjects: | 4 | |||||||||
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| SDY2118: Covid-19 Breakthrough Infections in Vaccinated Health Care Workers | |||||||||||
| Status: | New | ||||||||||
| 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. | ||||||||||
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| DOI: | 10.21430/M3WCZ14DE2 | ||||||||||
| Subjects: | 2 | ||||||||||
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| 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: | New | |||||||||||||||
| 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. | |||||||||||||||
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| DOI: | 10.21430/M3ERSVMISI | |||||||||||||||
| Subjects: | 3 | |||||||||||||||
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| SDY2120: Dense phenotyping from EHR enables machine learning-based prediction of PTB | |||||||
| Status: | New | ||||||
| Description: | BACKGROUND: Identifying pregnancies at risk for preterm birth, one of the leading causes of worldwide infant mortality, has the potential to improve prenatal care. However, we lack broadly applicable methods to accurately predict preterm birth risk. The dense longitudinal information present in electronic health records (EHRs) is enabling scalable and cost-efficient risk modeling of many diseases, but EHR resources have been largely untapped in the study of pregnancy. METHODs: Here, we apply machine learning to diverse data from EHRs with 35,282 deliveries to predict singleton preterm birth. RESULTS: We find that machine learning models based on billing codes alone can predict preterm birth risk at various gestational ages (e.g., ROC-AUC = 0.75, PR-AUC = 0.40 at 28 weeks of gestation) and outperform comparable models trained using known risk factors (e.g., ROC-AUC = 0.65, PR-AUC = 0.25 at 28 weeks). Examining the patterns learned by the model reveals it stratifies deliveries into interpretable groups, including high-risk preterm birth subtypes enriched for distinct comorbidities. Our machine learning approach also predicts preterm birth subtypes (spontaneous vs. indicated), mode of delivery, and recurrent preterm birth. Finally, we demonstrate the portability of our approach by showing that the prediction models maintain their accuracy on a large, independent cohort (5978 deliveries) from a different healthcare system. CONCLUSIONS: By leveraging rich phenotypic and genetic features derived from EHRs, we suggest that machine learning algorithms have great potential to improve medical care during pregnancy. However, further work is needed before these models can be applied in clinical settings. | ||||||
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| DOI: | 10.21430/M32KEU0EDF | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2121: CD4+ T cells from COVID-19 mRNA vaccine recipients recognize a conserved epitope present in diverse coronaviruses | |||||||||||
| Status: | New | ||||||||||
| 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. | ||||||||||
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| DOI: | 10.21430/M3HBH1BBQV | ||||||||||
| Subjects: | 2 | ||||||||||
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| SDY2122: Neutralization of the SARS-CoV-2 Omicron BA.4/5 and BA.2.12.1 Subvariants | |||||||||||||
| Status: | New | ||||||||||||
| 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. | ||||||||||||
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| DOI: | 10.21430/M3UUW8F1FT | ||||||||||||
| Subjects: | 4 | ||||||||||||
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| 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: | New | ||||||||||||
| 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. | ||||||||||||
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| DOI: | 10.21430/M3FXU7B7MZ | ||||||||||||
| Subjects: | 2 | ||||||||||||
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| Assays: | None | ||||||||||||
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| 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: | New | |||||||||
| 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: | New | ||||||||||||
| 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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| SDY2127: Immunological memory to common cold coronaviruses assessed longitudinally over a three-year period pre-COVID19 pandemic | |||||||||||||
| Status: | New | ||||||||||||
| 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: | New | ||||||||
| 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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| SDY2130: Identifying and Alleviating Bias Due to Differential Depletion of Susceptible People in Postmarketing Evaluations of COVID-19 Vaccines | |||||||
| Status: | New | ||||||
| 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: | New | ||||||
| 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 | ||||||
| Study PI, contact: |
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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: | New | ||||||
| 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 | ||||||
| Study PI, contact: |
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| Assays: | None | ||||||
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| SDY2133: Longitudinal metabolomics of human plasma reveals prognostic markers of COVID-19 disease severity | ||||||||||
| Status: | New | |||||||||
| 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. | |||||||||
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| DOI: | 10.21430/M3RMVB13M8 | |||||||||
| Subjects: | 5 | |||||||||
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| SDY2134: The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies | |||||||
| Status: | New | ||||||
| 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. | ||||||
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| DOI: | 10.21430/M32LEYGFC5 | ||||||
| Subjects: | 2 | ||||||
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| SDY2135: Infectious disease dynamics and restrictions on social gathering size | |||||||
| Status: | New | ||||||
| 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 | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3N4SFTBH9 | ||||||
| Subjects: | 1 | ||||||
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| Assays: | None | ||||||
| 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: | New | |||||||||
| 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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| SDY1515: Peanut Sublingual Immunotherapy (CoFAR4) | ||||||||||||||
| Status: | Updated | |||||||||||||
| Description: | Peanut allergy is a common ailment in the United States. Research suggests that the prevalence of peanut allergy in the United States has doubled over the last 5 years. Currently, the only effective treatment for peanut allergy is a peanut-free diet and quick access to self-injectable epinephrine in the event of peanut exposure. The sublingual route is a potential method to administer immunotherapy for the treatment of food allergies. The intent of this study is to induce desensitization and eventually tolerance to peanut protein and evaluate the safety and immunologic effects of daily sublingual immunotherapy (SLIT) for individuals with peanut allergy. The trial will enroll 40 participants. After the first 10 participants between the ages of 18 and 40 are enrolled, safety information will be reviewed. If there are no safety concerns, the study will continue to enroll the remaining participants between the ages of 12 and 40. This clinical trial will last 172 to 216 weeks. Participants will be randomly assigned to receive peanut SLIT or placebo SLIT. All participants will have an entry oral food challenge (OFC). The treatment group will receive gradual dosing escalations of peanut SLIT and maintenance therapy over a 44-week period, followed by another OFC. Following the OFC, participants will be unblinded, and the placebo group will receive peanut SLIT escalated to a higher maximum dose than the first treatment group. Maintenance therapy will continue for both groups for more than 2 years. Study visits will occur every 2 weeks during dosing escalations of peanut SLIT, followed by visits gradually spacing out during maintenance to every 12 weeks. At selected visits, a physical examination, skin prick tests, blood and urine collection, and atopic dermatitis and asthma evaluations will occur. Approximately 6 OFCs will be administered to each participant throughout the course of the study. Additionally, 10 participants will be enrolled as control participants who will not receive any study therapy and will only have blood drawn at 3 visits throughout the course of the trial. | |||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3UH9QGIY2 | |||||||||||||
| Subjects: | 62 | |||||||||||||
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| Assays: | None | |||||||||||||
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| SDY1642: Establishment of Vaginal Microbiota Composition in Early Pregnancy and its Association with Subsequent Preterm Prelabor Rupture of the Fetal Membrane | ||||||||||
| Status: | Updated | |||||||||
| Description: | Vaginal bacterial community composition influences pregnancy outcome. Preterm prelabor rupture of the fetal membranes (PPROM), which precedes 30% of all spontaneous preterm births, is associated with high vaginal bacterial diversity prior to rupture. The point at which vaginal bacterial diversity is established before PPROM is unknown. In this study, we use metataxonomics to longitudinally characterize the vaginal bacterial composition from as early as 6 weeks of gestation in women at high (n = 38) and low (n = 22) risk of preterm birth who subsequently experience PPROM and in women delivering at term without complications (n = 36). Reduced Lactobacillus spp. abundance and high diversity was observed prior to PPROM in 20% and 26% of women at low and high risk of preterm births respectively, but in only 3% of women who delivered at term. PPROM was associated with instability of bacterial community structure during pregnancy and a shift toward higher diversity predominately occurring during the second trimester. This was characterized by increased relative abundance of potentially pathogenic species including Prevotella, Peptoniphilus, Streptococcus, and Dialister. This study identifies reduced Lactobacillus spp. abundance and increasing vaginal bacterial diversity as an early risk factor for PPROM and highlights the need for interventional studies designed to assess the impact of modifying vaginal bacterial composition for the prevention of preterm birth. | |||||||||
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| DOI: | 10.21430/M3GL2SM9XS | |||||||||
| Subjects: | 0 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||