DR47 DataRelease
Release Date: 02/24/2023
New Studies: 15
Updated Studies: 88
New Studies
| SDY2107: Tissue adaptation and clonal segregation of human memory T cells in barrier sites | ||||||||||
| Status: | New | |||||||||
| Description: | T lymphocytes migrate to barrier sites after exposure to pathogens providing localized immunity and long-term protection. Here, we obtained tissues from human organ donors to examine T cells across major barrier sites (skin, lung, jejunum), associated lymph nodes, lymphoid organs (spleen, bone marrow), and in circulation. By integrating single-cell protein and transcriptome profiling, we demonstrate that human barrier sites contain tissue-resident memory T cells (TRM) that exhibit site-adapted profiles for residency, homing, and function distinct from circulating memory T cells. Incorporating T cell receptor and transcriptome analysis, we show that circulating memory T cells are highly expanded, display extensive overlap between sites, and exhibit effector and cytolytic functional profiles, while TRM clones exhibit site-specific expansions and distinct functional capacities. Together, our findings indicate that circulating T cells are more disseminated and differentiated, while TRM exhibit tissue-specific adaptation and clonal segregation, suggesting that strategies to promote barrier immunity require tissue-targeting. | |||||||||
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| DOI: | 10.21430/M38TPFRMQI | |||||||||
| Subjects: | 7 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2157: 35th Multicenter Airway Research Collaboration (MARC-35): Genetic analysis of infants | ||||||||||
| Status: | New | |||||||||
| Description: | In a multicenter prospective cohort study of infants (age <1 year) hospitalized for bronchiolitis, we sought to identify genetic loci associated with asthma susceptibility and metabolites. We genotyped the whole genome from samples collected at hospitalization and conducted quantitative trait loci analyses. Using colocalization analysis, we confirmed the concordance between the identified loci and known asthma-susceptibility genes. We finally identified genetic loci and genetically driven metabolites that are associated with both genetic risk factors for asthma and childhood asthma development. | |||||||||
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| DOI: | 10.21430/M36N5NJVXZ | |||||||||
| Subjects: | 1 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2158: Immunity to seasonal coronavirus spike proteins does not protect from SARS-CoV-2 challenge in a mouse model | ||||||||||
| Status: | New | |||||||||
| Description: | Mice were vaccinated with the spike proteins of 229E, NL63, OC43, HKU1 and SARS-CoV-2 (expressed as soluble trimers) with an oil-in-water emulsion adjuvant in a prime-boost regimen. Control mice were vaccinated with an irrelevant recombinant antigen, recombinant influenza virus hemagglutinin (HA). Three weeks after boost, mice were transduced intranasally with a non-replicating adenovirus expressing human angiotensin converting enzyme 2 (ACE2) followed by a challenge with wild type SARS-CoV-2 strain Washington-1 five days later. Finally, this vaccination experiment was repeated. However, instead of a SARS-CoV-2 challenge, animals were vaccinated 3 weeks post boost with a lipid nanoparticle-formulated nucleoside-modified mRNA vaccine (mRNA-LNP) encoding the SARS-CoV-2 spike protein. | |||||||||
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| DOI: | 10.21430/M3GRS6DFE3 | |||||||||
| Subjects: | 186 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2166: mRNA vaccines induce rapid antibody responses in mice | |||||||||
| Status: | New | ||||||||
| Description: | mRNA vaccines can be developed and produced quickly, making them prime candidates for immediate outbreak responses. Furthermore, clinical trials have demonstrated rapid protection following mRNA vaccination. Thus, we sought to investigate how quickly mRNA vaccines elicit antibody responses compared to other vaccine modalities. We first compared the immune kinetics of mRNA and DNA vaccines expressing SARS-CoV-2 spike in mice. We observed rapid induction of antigen-specific binding and neutralizing antibodies by day 5 following mRNA (4??g/mouse), but not DNA (50??g/mouse), immunization. Comparing innate responses hours post immunization, the mRNA vaccine induced increased levels of IL-5, IL-6, and MCP-1 cytokines which maybe promoting humoral responses downstream. We then evaluated the immune kinetics of an HIV-1 mRNA vaccine in comparison to DNA, protein, and rhesus adenovirus 52 (RhAd52) vaccines of the same HIV-1 envelope antigen in mice. Again, induction of envelope-specific antibodies was observed by day 5 following mRNA vaccination, whereas antibodies were detected by day 7?14 following DNA, protein, and RhAd52 vaccination. Thus, eliciting rapid humoral immunity may be a unique and advantageous property of mRNA vaccines for controlling infectious disease outbreaks. | ||||||||
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| DOI: | 10.21430/M3BG3TEVVT | ||||||||
| Subjects: | 7 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY2167: Increased viral variants in children and young adults with impaired humoral immunity and persistent SARS-CoV-2 infection: A consecutive case series | |||||||||||
| Status: | New | ||||||||||
| Description: | There is increasing concern that persistent infection of SARS-CoV-2 within immunocompromised hosts could serve as a reservoir for mutation accumulation and subsequent emergence of novel strains with the potential to evade immune responses. We describe three patients with acute lymphoblastic leukemia who were persistently positive for SARS-CoV-2 by real-time polymerase chain reaction. Viral viability from longitudinally-collected specimens was assessed. Whole-genome sequencing and serological studies were performed to measure viral evolution and evidence of immune escape. We found compelling evidence of ongoing replication and infectivity for up to 162 days from initial positive by subgenomic RNA, single-stranded RNA, and viral culture analysis. Our results reveal a broad spectrum of infectivity, host immune responses, and accumulation of mutations, some with the potential for immune escape. Our results highlight the potential need to reassess infection control precautions in the management and care of immunocompromised patients. Routine surveillance of mutations and evaluation of their potential impact on viral transmission and immune escape should be considered. | ||||||||||
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| DOI: | 10.21430/M3ZE4KT4OU | ||||||||||
| Subjects: | 3 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2168: Adverse Events After SARS-CoV-2 mRNA Vaccination Among Patients With Inflammatory Bowel Disease | ||||||||||
| Status: | New | |||||||||
| Description: | Patients with immune-mediated inflammatory diseases such as inflammatory bowel disease (IBD) on immunosuppressive and biologic therapies were largely excluded from severe acute respiratory syndrome coronavirus-2 messenger RNA vaccine trials. We evaluated adverse events (AE) after messenger RNA vaccination in 246 adults with IBD participating in a longitudinal vaccine registry. In general, AE frequency was similar to that reported in the general population. AEs were more common among younger patients and those with previous COVID-19. AEs were less common in individuals receiving advanced therapies with biologics or small-molecule inhibitors. Those with IBD and other immune-mediated inflammatory diseases can be reassured that the AE risk is likely not increased, and may be reduced, while on advanced therapies. | |||||||||
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| DOI: | 10.21430/M3JRRVRSU4 | |||||||||
| Subjects: | 2 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2169: Nucleocapsid Antigenemia Is a Marker of Acute SARS-CoV-2 Infection | ||||||||||
| Status: | New | |||||||||
| Description: | Detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is essential for diagnosis, treatment, and infection control. Polymerase chain reaction (PCR) fails to distinguish acute from resolved infections, as RNA is frequently detected after infectiousness. We hypothesized that nucleocapsid in blood marks acute infection with the potential to enhance isolation and treatment strategies. In a retrospective serosurvey of inpatient and outpatient encounters, we categorized samples along an infection timeline using timing of SARS-CoV-2 testing and symptomatology. Among 1860 specimens from 1607 patients, the highest levels and frequency of antigenemia were observed in samples from acute SARS-CoV-2 infection. Antigenemia was higher in seronegative individuals and in those with severe disease. In our analysis, antigenemia exhibited 85.8% sensitivity and 98.6% specificity as a biomarker for acute coronavirus disease 2019 (COVID-19). Thus, antigenemia sensitively and specifically marks acute SARS-CoV-2 infection. Further study is warranted to determine whether antigenemia may aid individualized assessment of active COVID-19. | |||||||||
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| DOI: | 10.21430/M3V0UOMK3E | |||||||||
| Subjects: | 2 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2170: C57BL/6J Mice Are Not Suitable for Modeling Severe SARS-CoV-2 Beta and Gamma Variant Infection | |||||||
| Status: | New | ||||||
| Description: | SARS-CoV-2 variants, including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) variants, have displayed increased transmissibility and, therefore, have been categorized as variants of concern (VOCs). The pervasiveness of VOCs suggests a high probability of future mutations that may lead to increased virulence. Prior reports have shown that VOC infection without expression of human angiotensin converting enzyme-2 receptor (hACE2) in mice is possible. We sought to understand if the increased transmissibility of VOCs can infect C57BL/6 mice without expression of hACE2 receptor required for entry of SARS-CoV-2 normally. We examined the ability of infection with Beta and Gamma variants to infect and cause both pathological and clinical changes consistent with severe COVID-19, including body weight changes, survival, subgenomic viral titer, lung histology on Hematoxylin and Eosin (H&E) staining, and viral protein expression as measured by immunohistochemistry staining of viral antigen (IHC). These methods were used to examine three groups of mice: C57BL6, Rag2-/-, and Ccr2-/- mice. We observed that these mice, infected with Beta and Gamma variants of SARS-CoV-2, did not show pathological changes as indicated by weight loss, altered survival, or significant lung pathology on H&E staining. Subgenomic qPCR and IHC staining for viral protein indicated that there was some evidence of infection but far below ACE2 transgenic mice, which showed clinical disease and pathologic changes consistent with ARDS. These data suggest that these variants replicate poorly even in the setting of profound immune deficiency | ||||||
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| DOI: | 10.21430/M3URLEFSYD | ||||||
| Subjects: | 8 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2171: Modeling the Impact of Vaccination Strategies for Nursing Homes in the Context of Increased Severe Acute Respiratory Syndrome Coronavirus 2 Community Transmission and Variants | |||||||
| Status: | New | ||||||
| Description: | Using an agent-based model, we examined the impact of community prevalence, the Delta variant, staff vaccination coverage, and booster vaccines for residents on outbreak dynamics in nursing homes. Increased staff coverage and high booster vaccine effectiveness leads to fewer infections, but cumulative incidence is highly dependent on community transmission. | ||||||
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| DOI: | 10.21430/M3T2140MM5 | ||||||
| Subjects: | 1 | ||||||
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| Assays: | None | ||||||
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| SDY2172: Variable cellular responses to SARS-CoV-2 in fully vaccinated patients with multiple myeloma | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | We wanted to determine whether MM patients without detectable anti-S IgG antibodies to SARS-CoV-2 immunization (seronegative) had detectable SARSCoV-2 B and T cell responses after SARS-CoV-2 vaccination, which would possibly provide some protection against severe disease even in the absence of anti-S antibodies. In order to assay quantitative and qualitative differences in T cell responses, we adopted a high-resolution flow cytometry assay that incorporates multiple cytokines and activation markers. Such data are urgently required to guide masking, social distancing, and passive antibody/booster vaccination strategies for potentially vulnerable MM patients treated with these anti-cancer agents as we enter the second fall season of the COVID-19 pandemic. | |||||||||||||||
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| DOI: | 10.21430/M3JLICY0TG | |||||||||||||||
| Subjects: | 3 | |||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||
| SDY2173: Sex Differences in Lung Imaging and SARS-CoV-2 Antibody Responses in a COVID-19 Golden Syrian Hamster Model | |||||||||
| Status: | New | ||||||||
| Description: | In the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more severe outcomes are reported in males than in females, including hospitalizations and deaths. Animal models can provide an opportunity to mechanistically interrogate causes of sex differences in the pathogenesis of SARS-CoV-2. Adult male and female golden Syrian hamsters (8 to 10 weeks of age) were inoculated intranasally with 105 50% tissue culture infective dose (TCID50) of SARS-CoV-2/USA-WA1/2020 and euthanized at several time points during the acute (i.e., virus actively replicating) and recovery (i.e., after the infectious virus has been cleared) phases of infection. There was no mortality, but infected male hamsters experienced greater morbidity, losing a greater percentage of body mass, developed more extensive pneumonia as noted on chest computed tomography, and recovered more slowly than females. Treatment of male hamsters with estradiol did not alter pulmonary damage. Virus titers in respiratory tissues, including nasal turbinates, trachea, and lungs, and pulmonary cytokine concentrations, including interferon-? (IFN-? | ||||||||
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| DOI: | 10.21430/M3JWMD4XHU | ||||||||
| Subjects: | 2 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY2174: A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants | ||||||||||
| Status: | New | |||||||||
| Description: | A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants | |||||||||
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| DOI: | 10.21430/M37RN5ILVC | |||||||||
| Subjects: | 3 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2175: Modeling in higher dimensions to improve diagnostic testing accuracy: theory and examples for multiplex saliva-based SARS-CoV-2 antibody assays | |||||||
| Status: | New | ||||||
| Description: | The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has emphasized the importance and challenges of correctly interpreting antibody test results. Identification of positive and negative samples requires a classification strategy with low error rates, which is hard to achieve when the corresponding measurement values overlap. Additional uncertainty arises when classification schemes fail to account for complicated structure in data. We address these problems through a mathematical framework that combines high dimensional data modeling and optimal decision theory. Specifically, we show that appropriately increasing the dimension of data better separates positive and negative populations and reveals nuanced structure that can be described in terms of mathematical models. We combine these models with optimal decision theory to yield a classification scheme that better separates positive and negative samples relative to traditional methods such as confidence intervals (CIs) and receiver operating characteristics. We validate the usefulness of this approach in the context of a multiplex salivary SARS-CoV-2 immunoglobulin G assay dataset. This example illustrates how our analysis: (i) improves the assay accuracy (e.g. lowers classification errors by up to 42 % compared to CI methods); (ii) reduces the number of indeterminate samples when an inconclusive class is permissible (e.g. by 40 % compared to the original analysis of the example multiplex dataset); and (iii) decreases the number of antigens needed to classify samples. Our work showcases the power of mathematical modeling in diagnostic classification and highlights a method that can be adopted broadly in public health and clinical settings. | ||||||
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| DOI: | 10.21430/M39EFSK7EI | ||||||
| Subjects: | 1 | ||||||
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| SDY2176: A safe and highly efficacious measles virus-based vaccine expressing SARS-CoV-2 stabilized prefusion spike | |||||||||||||||||
| Status: | New | ||||||||||||||||
| Description: | The current pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights an urgent need to develop a safe, efficacious, and durable vaccine. Using a measles virus (rMeV) vaccine strain as the backbone, we developed a series of recombinant attenuated vaccine candidates expressing various forms of the SARS-CoV-2 spike (S) protein and its receptor binding domain (RBD) and evaluated their efficacy in cotton rat, IFNAR-/-mice, IFNAR-/--hCD46 mice, and golden Syrian hamsters. We found that rMeV expressing stabilized prefusion S protein (rMeV-preS) was more potent in inducing SARS-CoV-2-specific neutralizing antibodies than rMeV expressing full-length S protein (rMeV-S), while the rMeVs expressing different lengths of RBD (rMeV-RBD) were the least potent. Animals immunized with rMeV-preS produced higher levels of neutralizing antibody than found in convalescent sera from COVID-19 patients and a strong Th1-biased T cell response. The rMeV-preS also provided complete protection of hamsters from challenge with SARS-CoV-2, preventing replication in lungs and nasal turbinates, body weight loss, cytokine storm, and lung pathology. These data demonstrate that rMeV-preS is a safe and highly efficacious vaccine candidate, supporting its further development as a SARS-CoV-2 vaccine | ||||||||||||||||
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| DOI: | 10.21430/M39VJJKEMO | ||||||||||||||||
| Subjects: | 19 | ||||||||||||||||
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| SDY2177: Early Prediction and Longitudinal Modeling of Preeclampsia from Multiomics | ||||||||
| Status: | New | |||||||
| Description: | Preeclampsia is a complex disease of pregnancy whose physiopathology remains unclear and that poses a threat to both mothers and fetus. Specific complex changes in women's physiology precede a diagnosis of preeclampsia. Understanding multiple aspects and interactions of such complex changes at different levels of biology can be enabled by simultaneous applications of multiple assays. We developed machine learning model for early prediction of preeclampsia (in first 16 weeks of pregnancy) and over gestation by analyzing six omics datasets from a longitudinal cohort of normotensive and preeclamptic pregnant women. The highest prediction accuracy in early pregnancy was observed in the urine metabolome followed by the plasma proteome. A prediction model using only nine urine metabolites had the highest predictive accuracy and was validated on an independent cohort (area under the receiver operating characteristics curve (AUC)=0.88, 95% confidence intervals (CI): [0.76, 0.99], cross-validated; AUC=0.83, 95% CI: [0.62,1], validated). Univariate analysis further confirmed statistical significance of all metabolites and proteins chosen by the prediction models. Several proteins identified as biomarkers in our prediction model have previously been established (e.g., LEP, VEGF-A) or indicated to be associated with preeclampsia, further validating our findings. To gain further insights into the trajectory and progression of preeclampsia, we performed longitudinal modeling by analyzing all samples collected over gestation. We developed an integrated multiomics model revealing high accuracy in profiling preeclampsia and demonstrating gain from integration (AUC = 0.94, 95% CI: [0.90, 0.99]). We identified several biological pathways associated with preeclampsia including steroid hormone biosynthesis (both early in pregnancy and over gestation), tryptophan and caffeine metabolisms (over gestation) and arachidonic acid metabolism (in early pregnancy). The findings derived from models were integrated with immune system cytometry data, confirming known pathological alterations associated with preeclampsia and suggesting novel associations between the immune and proteomic dynamics. Integration with clinical variables further improved prediction accuracy of the urine metabolome model (AUC=0.90, 95% CI: [0.80, 0.99], urine metabolome, validated). While further validation in a larger population is necessary, these encouraging results can serve as a basis for a simple, early diagnostic test for preeclampsia. | |||||||
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| DOI: | 10.21430/M36YYREGA0 | |||||||
| Subjects: | 0 | |||||||
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Updated Studies
| SDY1781: Proinflammatory IgG Fc structures in patients with severe COVID-19 | ||||||||||
| Status: | Updated | |||||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 infections can cause coronavirus disease 2019 (COVID-19), which manifests with a range of severities from mild illness to life-threatening pneumonia and multi-organ failure. Severe COVID-19 is characterized by an inflammatory signature, including high levels of inflammatory cytokines, alveolar inflammatory infiltrates and vascular microthrombi. Here we show that patients with severe COVID-19 produced a unique serologic signature, including an increased likelihood of IgG1 with afucosylated Fc glycans. This Fc modification on severe acute respiratory syndrome coronavirus 2 IgGs enhanced interactions with the activating Fc-Gamma receptor Fc-Gamma RIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including interleukin-6 and tumor necrosis factor. These results show that disease severity in COVID-19 correlates with the presence of proinflammatory IgG Fc structures, including afucosylated IgG1. | |||||||||
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| DOI: | 10.21430/M33D4Y9RTM | |||||||||
| Subjects: | 4 | |||||||||
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| SDY1798: Discovery and functional interrogation of SARS-CoV-2 RNA-host protein interactions | |||||||
| Status: | Updated | ||||||
| Description: | SARS-CoV-2 is the cause of a pandemic with growing global mortality. Using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS), we identified 309 host proteins that bind the SARS-CoV-2 RNA during active infection. Integration of this data with ChIRP-MS data from three other RNA viruses defined viral specificity of RNA-host protein interactions. Targeted CRISPR screens revealed that the majority of functional RNA-binding proteins protect the host from virus-induced cell death, and comparative CRISPR screens across seven RNA viruses revealed shared and SARS-specific antiviral factors. Finally, by combining the RNA-centric approach and functional CRISPR screens, we demonstrated a physical and functional connection between SARS-CoV-2 and mitochondria, highlighting this organelle as a general platform for antiviral activity. Altogether, these data provide a comprehensive catalog of functional SARS-CoV-2 RNA-host protein interactions, which may inform studies to understand the host-virus interface and nominate host pathways that could be targeted for therapeutic benefit. | ||||||
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| DOI: | 10.21430/M3NPEVXJWP | ||||||
| Subjects: | 2 | ||||||
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| SDY1800: Durable SARS-CoV-2 B cell immunity after mild or severe disease | ||||||||||
| Status: | Updated | |||||||||
| Description: | Multiple studies have shown loss of severe acute respiratory syndrome coronavirus 2-specific (SARS-CoV-2-specific) antibodies over time after infection, raising concern that humoral immunity against the virus is not durable. If immunity wanes quickly, millions of people may be at risk for reinfection after recovery from coronavirus disease 2019 (COVID-19). However, memory B cells (MBCs) could provide durable humoral immunity even if serum neutralizing antibody titers decline. We performed multidimensional flow cytometric analysis of S protein receptor binding domain-specific (S-RBD-specific) MBCs in cohorts of ambulatory patients with COVID-19 with mild disease (n = 7), and hospitalized patients with moderate to severe disease (n = 7), at a median of 54 days (range, 39-104 days) after symptom onset. We detected S-RBD-specific class-switched MBCs in 13 of 14 participants, failing only in the individual with the lowest plasma levels of anti-S-RBD IgG and neutralizing antibodies. Resting MBCs (rMBCs) made up the largest proportion of S-RBD-specific MBCs in both cohorts. FCRL5, a marker of functional memory on rMBCs, was more dramatically upregulated on S-RBD-specific rMBCs after mild infection than after severe infection. These data indicate that most SARS-CoV-2-infected individuals develop S-RBD-specific, class-switched rMBCs that resemble germinal center-derived B cells induced by effective vaccination against other pathogens, providing evidence for durable B cell-mediated immunity against SARS-CoV-2 after mild or severe disease. | |||||||||
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| DOI: | 10.21430/M3YQ1SXVS6 | |||||||||
| Subjects: | 3 | |||||||||
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| SDY1803: Neutralizing antibody against SARS-CoV-2 spike in COVID-19 patients, health care workers, and convalescent plasma donors | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | Rapid and specific antibody testing is crucial for improved understanding, control, and treatment of COVID-19 pathogenesis. Herein, we describe and apply a rapid, sensitive, and accurate virus neutralization assay for SARS-CoV-2 antibodies. The assay is based on an HIV-1 lentiviral vector that contains a secreted intron Gaussia luciferase (Gluc) or secreted nano-luciferase reporter cassette, pseudotyped with the SARS-CoV-2 spike (S) glycoprotein, and is validated with a plaque-reduction assay using an authentic, infectious SARS-CoV-2 strain. The assay was used to evaluate SARS-CoV-2 antibodies in serum from individuals with a broad range of COVID-19 symptoms; patients included those in the intensive care unit (ICU), health care workers (HCWs), and convalescent plasma donors. The highest neutralizing antibody titers were observed among ICU patients, followed by general hospitalized patients, HCWs, and convalescent plasma donors. Our study highlights a wide phenotypic variation in human antibody responses against SARS-CoV-2 and demonstrates the efficacy of a potentially novel lentivirus pseudotype assay for high-throughput serological surveys of neutralizing antibody titers in large cohorts. | ||||||||||||||
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| DOI: | 10.21430/M3BAM4CN94 | ||||||||||||||
| Subjects: | 5 | ||||||||||||||
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| SDY1809: Efficacy of clinical evaluations for COVID-19 on the front line | ||||||||||
| Status: | Updated | |||||||||
| Description: | We conducted a retrospective review of patients assessed for possible COVID-19 illness at our urban medical center in Los Angeles, California. We carefully reviewed all clinical records to ascertain the provider's level of clinical suspicion for COVID-19 illness and compared these assessments with available results of SARS-CoV-2 testing, in addition to longitudinal data on clinical outcomes. We found that the vast majority of patients (96% of N = 25) clinically assessed to have a low probability of COVID-19 illness were subsequently confirmed to have either a negative SARS-CoV-2 test result or, in the absence of testing, clinical stability without any further concern for COVID-19 illness. All clinical assessments were performed by a physician, with some (16%) conducted by a nurse practitioner or physician assistant in conjunction with physician supervision. | |||||||||
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| DOI: | 10.21430/M39YVOOYSV | |||||||||
| Subjects: | 1 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY1810: Pseudo-safety in a cohort of patients with COVID-19 discharged home from the emergency department | ||||||||||
| Status: | Updated | |||||||||
| Description: | Introduction: Emergency Departments (ED) are often the first line of contact with individuals infected with COVID-19 and play a key role in triage. However, there is currently little specific guidance for deciding when patients with COVID-19 require hospitalisation and when they may be safely observed as an outpatient. Methods: In this retrospective study, we characterised all patients with COVID-19 discharged home from EDs in our US multisite healthcare system from March 2020 to August 2020, focusing on individuals who returned within 2 weeks and required hospital admission. We restricted analyses to first-encounter data that do not depend on laboratory or imaging diagnostics in order to inform point-of-care assessments in resource-limited environments. Vitals and comorbidities were extracted from the electronic health record. We performed ordinal logistic regression analyses to identify predictors of inpatient admission, intensive care and intubation. Results: Of n=923 patients who were COVID-19 positive discharged from the ED, n=107 (11.6%) returned within 2 weeks and were admitted. In a multivariable-adjusted model including n=788 patients with complete risk factor information, history of hypertension increased odds of hospitalisation and severe illness by 1.92-fold (95% CI 1.07 to 3.41), diabetes by 2.20-fold (1.18 to 4.02), chronic lung disease by 2.21-fold (1.22 to 3.92) and fever by 2.89-fold (1.71 to 4.82). Having at least two of these risk factors increased the odds of future hospitalisation by 6.68-fold (3.54 to 12.70). Patients with hypertension, diabetes, chronic lung disease or fever had significantly longer hospital stays (median 5.92 days, 3.08-10.95 vs 3.21, 1.10-5.75, p<0.01) with numerically higher but not significantly different rates of intensive care unit admission (27.02% vs 14.30%, p=0.27) and intubation (12.16% vs 7.14%, p=0.71). Discussion: Patients infected with COVID-19 may appear clinically safe for home convalescence. However, those with hypertension, diabetes, chronic lung disease and fever may in fact be only 'pseudo-safe' and are most at risk for subsequent hospitalisation with more severe illness and longer hospital stays. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3OOUUIKO5 | |||||||||
| Subjects: | 1 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY1812: Repeated cross-sectional sero-monitoring of SARS-CoV-2 in New York City | |||||||
| Status: | Updated | ||||||
| Description: | In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first detected in China and has since caused a pandemic of coronavirus disease 2019 (COVID-19). The first case of COVID-19 in New York City was officially confirmed on 1 March 2020 followed by a severe local epidemic1. Here, to understand seroprevalence dynamics, we conduct a retrospective, repeated cross-sectional analysis of anti-SARS-CoV-2 spike antibodies in weekly intervals from the beginning of February to July 2020 using more than 10,000 plasma samples from patients at Mount Sinai Hospital in New York City. We describe the dynamics of seroprevalence in an 'urgent care' group, which is enriched in cases of COVID-19 during the epidemic, and a 'routine care' group, which more closely represents the general population. Seroprevalence increased at different rates in both groups; seropositive samples were found as early as mid-February, and levelled out at slightly above 20% in both groups after the epidemic wave subsided by the end of May. From May to July, seroprevalence remained stable, suggesting lasting antibody levels in the population. Our data suggest that SARS-CoV-2 was introduced in New York City earlier than previously documented and describe the dynamics of seroconversion over the full course of the first wave of the pandemic in a major metropolitan area. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3ZV06EAM0 | ||||||
| Subjects: | 6 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY1813: Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | T cells are involved in control of SARS-CoV-2 infection. To establish the patterns of immunodominance of different SARS-CoV-2 antigens and precisely measure virus-specific CD4+ and CD8+ T cells, we study epitope-specific T cell responses of 99 convalescent coronavirus disease 2019 (COVID-19) cases. The SARS-CoV-2 proteome is probed using 1,925 peptides spanning the entire genome, ensuring an unbiased coverage of human leukocyte antigen (HLA) alleles for class II responses. For HLA class I, we study an additional 5,600 predicted binding epitopes for 28 prominent HLA class I alleles, accounting for wide global coverage. We identify several hundred HLA-restricted SARS-CoV-2-derived epitopes. Distinct patterns of immunodominance are observed, which differ for CD4+ T cells, CD8+ T cells, and antibodies. The class I and class II epitopes are combined into epitope megapools to facilitate identification and quantification of SARS-CoV-2-specific CD4+ and CD8+ T cells. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3F1F8OJDN | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Assays: | None | ||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY1815: Functional characterization of CD4+ T cell receptors crossreactive for SARS-CoV-2 and endemic coronaviruses | |||||||
| Status: | Updated | ||||||
| Description: | Recent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unexposed donors, possibly due to crossrecognition by T cells specific for common cold coronaviruses (CCCs). True T cell crossreactivity, defined as the recognition by a single TCR of more than one distinct peptide-MHC ligand, has never been shown in the context of SARS-CoV-2.METHODS: We used the viral functional expansion of specific T cells (ViraFEST) platform to identify T cell responses crossreactive for the spike (S) glycoproteins of SARS-CoV-2 and CCCs at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2-unexposed donors. Confirmation of SARS-CoV-2/CCC crossreactivity and assessments of functional avidity were performed using a TCR cloning and transfection system.RESULTS: Memory CD4+ T cell clonotypes that crossrecognized the S proteins of SARS-CoV-2 and at least one other CCC were detected in 65% of CCPs and unexposed donors. Several of these TCRs were shared among multiple donors. Crossreactive T cells demonstrated significantly impaired SARS-CoV-2-specific proliferation in vitro relative to monospecific CD4+ T cells, which was consistent with lower functional avidity of their TCRs for SARS-CoV-2 relative to CCC.CONCLUSIONSOur data confirm, for what we believe is the first time, the existence of unique memory CD4+ T cell clonotypes crossrecognizing SARS-CoV-2 and CCCs. The lower avidity of crossreactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that preexisting CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these crossreactive T cell responses affect clinical outcomes in COVID-19 patients. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3C1CZ1MF2 | ||||||
| Subjects: | 2 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1816: Vascular Disease and Thrombosis in SARS-CoV-2-Infected Rhesus Macaques | |||||||||
| Status: | Updated | ||||||||
| Description: | The COVID-19 pandemic has led to extensive morbidity and mortality throughout the world. Clinical features that drive SARS-CoV-2 pathogenesis in humans include inflammation and thrombosis, but the mechanistic details underlying these processes remain to be determined. In this study, we demonstrate endothelial disruption and vascular thrombosis in histopathologic sections of lungs from both humans and rhesus macaques infected with SARS-CoV-2. To define key molecular pathways associated with SARS-CoV-2 pathogenesis in macaques, we performed transcriptomic analyses of bronchoalveolar lavage and peripheral blood and proteomic analyses of serum. We observed macrophage infiltrates in lung and upregulation of macrophage, complement, platelet activation, thrombosis, and proinflammatory markers, including C-reactive protein, MX1, IL-6, IL-1, IL-8, TNF-Alpha, and NF-KappaB. These results suggest a model in which critical interactions between inflammatory and thrombosis pathways lead to SARS-CoV-2-induced vascular disease. Our findings suggest potential therapeutic targets for COVID-19. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3ZINJ9X7N | ||||||||
| Subjects: | 2 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY1818: Correlates of Protection Against SARS-CoV-2 in Rhesus Macaques | |||||||||
| Status: | Updated | ||||||||
| Description: | Recent studies have reported protective efficacy of both natural immunity and vaccine-induced immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge in rhesus macaques. However, the importance of humoral and cellular immunity for protection against SARS-CoV-2 infection remains to be determined. Here we show that adoptive transfer of purified IgG from convalescent macaques protects naive recipient rhesus macaques against SARS-CoV-2 challenge in a dose dependent fashion. Depletion of CD8+ T cells in convalescent animals partially abrogated the protective efficacy of natural immunity against SARS-CoV-2 re-challenge, suggesting the importance of cellular immunity in the context of waning or subprotective antibody titers. These data demonstrate that relatively low antibody titers are sufficient for protection against SARS-CoV-2 in rhesus macaques, and that cellular immune responses may also contribute to protection if antibody responses are suboptimal. We also show that higher antibody titers are required for therapy of SARS-CoV-2 infection in macaques. These findings have important implications for the development of SARS-CoV-2 vaccines and immune-based therapeutics. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3MW65JZHD | ||||||||
| Subjects: | 7 | ||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||
| SDY1819: Comparison of Subgenomic and Total RNA in SARS-CoV-2 Challenged Rhesus Macaques | |||||||
| Status: | Updated | ||||||
| Description: | Respiratory virus challenge studies involve administration of the challenge virus and sampling to assess for protection in the same anatomical locations. It can therefore be difficult to differentiate actively replicating virus from input challenge virus. For SARS-CoV-2, specific monitoring of actively replicating virus is critical for investigating the protective and therapeutic efficacy of vaccines, monoclonal antibodies, and antiviral drugs. We adapted a SARS-CoV-2 subgenomic RNA (sgRNA) RT-PCR assay to differentiate productive infection from inactivated or neutralized virus. Subgenomic RNAs are generated after cell entry and are poorly incorporated into mature virions, and thus may provide a marker for actively replicating virus. We show envelope (E) sgRNA was degraded by RNase in infected cell lysates, while genomic RNA (gRNA) was protected, presumably due to packaging into virions. To investigate the capacity of the sgRNA assay to distinguish input challenge virus from actively replicating virus in vivo, we compared the E sgRNA assay to a standard nucleoprotein (N) or E total (both gRNA and sgRNA) RNA in convalescent rhesus macaques and in antibody-treated rhesus macaques after experimental SARS-CoV-2 challenge. In both studies, the E sgRNA assay was negative, suggesting protective efficacy, whereas the N and E total RNA assays remained positive. These data suggest the potential utility of sgRNA to monitor actively replicating virus in prophylactic and therapeutic SARS-CoV-2 studies. Importance: Developing therapeutic and prophylactic countermeasures for the SARS-CoV-2 virus is a public health priority. During challenge studies, respiratory viruses are delivered and sampled from the same anatomical location. It is therefore important to distinguish actively replicating virus from input challenge virus. The most common assay for detecting SARS-CoV-2 virus, reverse transcription polymerase chain reaction (RT-PCR) targeting nucleocapsid total RNA, cannot distinguish neutralized input virus from replicating virus. In this study, we assess SARS-CoV-2 subgenomic RNA as a potential measure of replicating virus in rhesus macaques. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3DM6E1Y0R | ||||||
| Subjects: | 4 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY1821: MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Recent studies have profiled the innate immune signatures in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and suggest that cellular responses to viral challenge may affect disease severity. Yet the molecular events that underlie cellular recognition and response to SARS-CoV-2 infection remain to be elucidated. Here, we find that SARS-CoV-2 replication induces a delayed interferon (IFN) response in lung epithelial cells. By screening 16 putative sensors involved in sensing of RNA virus infection, we found that MDA5 and LGP2 primarily regulate IFN induction in response to SARS-CoV-2 infection. Further analyses revealed that viral intermediates specifically activate the IFN response through MDA5-mediated sensing. Additionally, we find that IRF3, IRF5, and NF-B/p65 are the key transcription factors regulating the IFN response during SARS-CoV-2 infection. In summary, these findings provide critical insights into the molecular basis of the innate immune recognition and signaling response to SARS-CoV-2. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M31F88A9QL | ||||||||||
| Subjects: | 3 | ||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||
| SDY1829: Severely ill COVID-19 patients display impaired exhaustion features in SARS-CoV-2-reactive CD8+ T cells | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | The molecular properties of CD8+ T cells that respond to SARS-CoV-2 infection are not fully known. Here, we report on the single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells, obtained using a modified Antigen-Reactive T cell Enrichment (ARTE) assay, from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patients segregated into two groups based on whether the dominant CD8+ T cell response to SARS-CoV-2 was 'exhausted' or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed lesser cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the dominant non-exhausted subset from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival NF-KappaB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8+ T cell memory responses in patients with severe COVID-19 illness. CD8+ T cells reactive to influenza and respiratory syncytial virus from healthy subjects displayed polyfunctional features and enhanced glycolysis. Cells with such features were largely absent in SARS-CoV-2-reactive cells from both COVID-19 patients and healthy controls non-exposed to SARS-CoV-2. Overall, our single-cell analysis revealed substantial diversity in the nature of CD8+ T cells responding to SARS-CoV-2. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3A57H738Q | ||||||||||||
| Subjects: | 4 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY1831: Serological analysis reveals an imbalanced IgG subclass composition associated with COVID-19 disease severity | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | Coronavirus disease 2019 (COVID-19) is associated with a wide spectrum of disease presentation, ranging from asymptomatic infection to acute respiratory distress syndrome (ARDS). Paradoxically, a direct relationship has been suggested between COVID-19 disease severity and the levels of circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies, including virus-neutralizing titers. A serological analysis of 536 convalescent healthcare workers reveals that SARS-CoV-2-specific and virus-neutralizing antibody levels are elevated in individuals that experience severe disease. The severity-associated increase in SARS-CoV-2-specific antibody is dominated by immunoglobulin G (IgG), with an IgG subclass ratio skewed toward elevated receptor binding domain (RBD)- and S1-specific IgG3. In addition, individuals that experience severe disease show elevated SARS-CoV-2-specific antibody binding to the inflammatory receptor Fc?RIIIa. Based on these correlational studies, we propose that spike-specific IgG subclass utilization may contribute to COVID-19 disease severity through potent Fc-mediated effector functions. These results may have significant implications for SARS-CoV-2 vaccine design and convalescent plasma therapy. | |||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3B6163WG1 | |||||||||||||||
| Subjects: | 5 | |||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | |||||||||||||||
| SDY1832: Immunological imprinting of the antibody response in COVID-19 patients | ||||||||||
| Status: | Updated | |||||||||
| Description: | In addition to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), humans are also susceptible to six other coronaviruses, for which consecutive exposures to antigenically related and divergent seasonal coronaviruses are frequent. Despite the prevalence of COVID-19 pandemic and ongoing research, the nature of the antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here we longitudinally profile the early humoral immune response against SARS-CoV-2 in hospitalized coronavirus disease 2019 (COVID-19) patients and quantify levels of pre-existing immunity to OC43, HKU1 and 229E seasonal coronaviruses, and find a strong back-boosting effect to conserved but not variable regions of OC43 and HKU1 betacoronaviruses spike protein. However, such antibody memory boost to human coronaviruses negatively correlates with the induction of IgG and IgM against SARS-CoV-2 spike and nucleocapsid protein. Our findings thus provide evidence of immunological imprinting by previous seasonal coronavirus infections that can potentially modulate the antibody profile to SARS-CoV-2 infection. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3EMGZH7G6 | |||||||||
| Subjects: | 3 | |||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | |||||||||
| SDY1835: Delayed Rise of Oral Fluid Antibodies, Elevated BMI, and Absence of Early Fever Correlate With Longer Time to SARS-CoV-2 RNA Clearance in a Longitudinally Sampled Cohort of COVID-19 Outpatients | ||||||||||
| Status: | Updated | |||||||||
| Description: | Sustained molecular detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in the upper respiratory tract (URT) in mild to moderate coronavirus disease 2019 (COVID-19) is common. We sought to identify host and immune determinants of prolonged SARS-CoV-2 RNA detection. Methods : Ninety-five symptomatic outpatients self-collected midturbinate nasal, oropharyngeal (OP), and gingival crevicular fluid (oral fluid) samples at home and in a research clinic a median of 6 times over 1-3 months. Samples were tested for viral RNA, virus culture, and SARS-CoV-2 and other human coronavirus antibodies, and associations were estimated using Cox proportional hazards models. Results : Viral RNA clearance, as measured by SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR), in 507 URT samples occurred a median (interquartile range) 33.5 (17-63.5) days post-symptom onset. Sixteen nasal-OP samples collected 2-11 days post-symptom onset were virus culture positive out of 183 RT-PCR-positive samples tested. All participants but 1 with positive virus culture were negative for concomitant oral fluid anti-SARS-CoV-2 antibodies. The mean time to first antibody detection in oral fluid was 8-13 days post-symptom onset. A longer time to first detection of oral fluid anti-SARS-CoV-2 S antibodies (adjusted hazard ratio [aHR], 0.96; 95% CI, 0.92-0.99; P = .020) and body mass index (BMI) >=25 kg/m2 (aHR, 0.37; 95% CI, 0.18-0.78; P = .009) were independently associated with a longer time to SARS-CoV-2 viral RNA clearance. Fever as 1 of first 3 COVID-19 symptoms correlated with shorter time to viral RNA clearance (aHR, 2.06; 95% CI, 1.02-4.18; P = .044). Conclusions : We demonstrate that delayed rise of oral fluid SARS-CoV-2-specific antibodies, elevated BMI, and absence of early fever are independently associated with delayed URT viral RNA clearance. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3NG59FFQ5 | |||||||||
| Subjects: | 3 | |||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | |||||||||
| SDY1840: Tissue-based SARS-CoV-2 detection in fatal COVID-19 infections: Sustained direct viral-induced damage is not necessary to drive disease progression | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Coronavirus disease 2019 (COVID-19) is an ongoing pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although viral infection is known to trigger inflammatory processes contributing to tissue injury and organ failure, it is unclear whether direct viral damage is needed to sustain cellular injury. An understanding of pathogenic mechanisms has been handicapped by the absence of optimized methods to visualize the presence and distribution of SARS-CoV-2 in damaged tissues. We first developed a positive control cell line (Vero E6) to validate SARS-CoV-2 detection assays. We then evaluated multiple organs (lungs, kidneys, heart, liver, brain, intestines, lymph nodes, and spleen) from fourteen COVID-19 autopsy cases using immunohistochemistry (IHC) for the spike and the nucleoprotein proteins, and RNA in situ hybridization (RNA ISH) for the spike protein mRNA. Tissue detection assays were compared with quantitative polymerase chain reaction (qPCR)-based detection. SARS-CoV-2 was histologically detected in the Vero E6 positive cell line control, 1 of 14 (7%) lungs, and none (0%) of the other 59 organs. There was perfect concordance between the IHC and RNA ISH results. qPCR confirmed high viral load in the SARS-CoV-2 ISH-positive lung tissue, and absent or low viral load in all ISH-negative tissues. In patients who die of COVID-19-related organ failure, SARS-CoV-2 is largely not detectable using tissue-based assays. Even in lungs showing widespread injury, SARS-CoV-2 viral RNA or proteins were detected in only a small minority of cases. This observation supports the concept that viral infection is primarily a trigger for multiple-organ pathogenic proinflammatory responses. Direct viral tissue damage is a transient phenomenon that is generally not sustained throughout disease progression. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3IDUI9TUU | ||||||||||
| Subjects: | 2 | ||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||
| SDY1849: Estimating SARS-CoV-2 seroprevalence and epidemiological parameters with uncertainty from serological surveys | ||||||||||
| Status: | Updated | |||||||||
| Description: | Establishing how many people have been infected by SARS-CoV-2 remains an urgent priority for controlling the COVID-19 pandemic. Serological tests that identify past infection can be used to estimate cumulative incidence, but the relative accuracy and robustness of various sampling strategies have been unclear. We developed a flexible framework that integrates uncertainty from test characteristics, sample size, and heterogeneity in seroprevalence across subpopulations to compare estimates from sampling schemes. Using the same framework and making the assumption that seropositivity indicates immune protection, we propagated estimates and uncertainty through dynamical models to assess uncertainty in the epidemiological parameters needed to evaluate public health interventions and found that sampling schemes informed by demographics and contact networks outperform uniform sampling. The framework can be adapted to optimize serosurvey design given test characteristics and capacity, population demography, sampling strategy, and modeling approach, and can be tailored to support decision-making around introducing or removing interventions. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3M73PFN8O | |||||||||
| Subjects: | 1 | |||||||||
| Study PI, contact: |
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY1850: Model-informed COVID-19 vaccine prioritization strategies by age and serostatus | |||||||
| Status: | Updated | ||||||
| Description: | Limited initial supply of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine raises the question of how to prioritize available doses. We used a mathematical model to compare five age-stratified prioritization strategies. A highly effective transmission-blocking vaccine prioritized to adults ages 20 to 49 years minimized cumulative incidence, but mortality and years of life lost were minimized in most scenarios when the vaccine was prioritized to adults greater than 60 years old. Use of individual-level serological tests to redirect doses to seronegative individuals improved the marginal impact of each dose while potentially reducing existing inequities in COVID-19 impact. Although maximum impact prioritization strategies were broadly consistent across countries, transmission rates, vaccination rollout speeds, and estimates of naturally acquired immunity, this framework can be used to compare impacts of prioritization strategies across contexts. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3NEXZIAC5 | ||||||
| Subjects: | 1 | ||||||
| Study PI, contact: |
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1851: Interpreting vaccine efficacy trial results for infection and transmission | |||||||
| Status: | Updated | ||||||
| Description: | Randomized controlled trials (RCTs) have shown high efficacy of multiple vaccines against SARS-CoV-2 disease (COVID-19), and recent studies have shown the vaccines are also effective against infection. Evidence for the effect of each of these vaccines on ability to transmit the virus is also beginning to emerge. We describe an approach to estimate these vaccines' effects on viral positivity, a prevalence measure which under the reasonable assumption that vaccinated individuals who become infected are no more infectious than unvaccinated individuals forms a lower bound on efficacy against transmission. Specifically, we recommend separate analysis of positive tests triggered by symptoms (usually the primary RCT outcome) and cross-sectional prevalence of positive tests obtained regardless of symptoms. The odds ratio of carriage for vaccine vs. placebo provides an unbiased estimate of vaccine effectiveness against viral positivity, under certain assumptions, and we show through simulations that likely departures from these assumptions will only modestly bias this estimate. Applying this approach to published data from the RCT of the Moderna vaccine, we estimate that one dose of vaccine reduces the potential for transmission by at least 61%, possibly considerably more. We describe how these approaches can be translated into observational studies of vaccine effectiveness. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3S4GR1BIO | ||||||
| Subjects: | 2 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY1852: Modeling the impact of racial and ethnic disparities on COVID-19 epidemic dynamics | ||||||||||
| Status: | Updated | |||||||||
| Description: | Background: The impact of variable infection risk by race and ethnicity on the dynamics of SARS-CoV-2 spread is largely unknown. Methods: Here, we fit structured compartmental models to seroprevalence data from New York State and analyze how herd immunity thresholds (HITs), final sizes, and epidemic risk change across groups. Results: A simple model where interactions occur proportionally to contact rates reduced the HIT, but more realistic models of preferential mixing within groups increased the threshold toward the value observed in homogeneous populations. Across all models, the burden of infection fell disproportionately on minority populations: in a model fit to Long Island serosurvey and census data, 81% of Hispanics or Latinos were infected when the HIT was reached compared to 34% of non-Hispanic whites. Conclusions: Our findings, which are meant to be illustrative and not best estimates, demonstrate how racial and ethnic disparities can impact epidemic trajectories and result in unequal distributions of SARS-CoV-2 infection. Funding: K.C.M. was supported by National Science Foundation GRFP grant DGE1745303. Y.H.G. and M.L. were funded by the Morris-Singer Foundation. M.L. was supported by SeroNet cooperative agreement U01 CA261277 | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M33DAWUEID | |||||||||
| Subjects: | 2 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY1868: Critical ACE2 Determinants of SARS-CoV-2 and Group 2B Coronavirus Infection and Replication | |||||||
| Status: | Updated | ||||||
| Description: | The angiotensin-converting enzyme 2 (ACE2) receptor is a major severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) host range determinant, and understanding SARS-CoV-2-ACE2 interactions will provide important insights into COVID-19 pathogenesis and animal model development. SARS-CoV-2 cannot infect mice due to incompatibility between its receptor binding domain and the murine ACE2 receptor. Through molecular modeling and empirical in vitro validation, we identified 5 key amino acid differences between murine and human ACE2 that mediate SARS-CoV-2 infection, generating a chimeric humanized murine ACE2. Additionally, we examined the ability of the humanized murine ACE2 receptor to permit infection by an additional preemergent group 2B coronavirus, WIV-1, providing evidence for the potential pan-virus capabilities of this chimeric receptor. Finally, we predicted the ability of these determinants to inform host range identification of preemergent coronaviruses by evaluating hot spot contacts between SARS-CoV-2 and additional potential host receptors. Our results identify residue determinants that mediate coronavirus receptor usage and host range for application in SARS-CoV-2 and emerging coronavirus animal model development. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3FE77I3XS | ||||||
| Subjects: | 7 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1890: SARS-CoV-2 Spreads through Cell-to-Cell Transmission | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible coronavirus responsible for the global COVID-19 pandemic. Herein we provide evidence that SARS-CoV-2 spreads through cell-cell contact in cultures, mediated by the spike glycoprotein. SARS-CoV-2 spike is more efficient in facilitating cell-to-cell transmission than SARS-CoV spike, which reflects, in part, their differential cell-cell fusion activity. Interestingly, treatment of cocultured cells with endosomal entry inhibitors impairs cell-to-cell transmission, implicating endosomal membrane fusion as an underlying mechanism. Compared with cell-free infection, cell-to-cell transmission of SARS-CoV-2 is refractory to inhibition by neutralizing antibody or convalescent sera of COVID-19 patients. While ACE2 enhances cell-to-cell transmission, we find that it is not absolutely required. Notably, despite differences in cell-free infectivity, the variants of concern (VOC) B.1.1.7 and B.1.351 have similar cell-to-cell transmission capability. Moreover, B.1.351 is more resistant to neutralization by vaccinee sera in cell-free infection, whereas B.1.1.7 is more resistant to inhibition by vaccine sera in cell-to-cell transmission. Overall, our study reveals critical features of SARS-CoV-2 spike-mediated cell-to-cell transmission, with important implications for a better understanding of SARS-CoV-2 spread and pathogenesis. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3GSKYH5JH | ||||||||||
| Subjects: | 8 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY1916: Inhibition of elastase enhances the adjuvanticity of alum and promotes anti-SARS-CoV-2 systemic and mucosal immunity | ||||||||||
| Status: | Updated | |||||||||
| Description: | Alum, used as an adjuvant in injected vaccines, promotes T helper 2 (Th2) and serum antibody (Ab) responses. However, it fails to induce secretory immunoglobulin (Ig) A (SIgA) in mucosal tissues and is poor in inducing Th1 and cell-mediated immunity. Alum stimulates interleukin 1 (IL-1) and the recruitment of myeloid cells, including neutrophils. We investigated whether neutrophil elastase regulates the adjuvanticity of alum, and whether a strategy targeting neutrophil elastase could improve responses to injected vaccines. Mice coadministered a pharmacological inhibitor of elastase, or lacking elastase, developed high-affinity serum IgG and IgA antibodies after immunization with alum-adsorbed protein vaccines, including the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). These mice also developed broader antigen-specific CD4+ T cell responses, including high Th1 and T follicular helper (Tfh) responses. Interestingly, in the absence of elastase activity, mucosal SIgA responses were induced after systemic immunization with alum as adjuvant. Importantly, lack or suppression of elastase activity enhanced the magnitude of anti-SARS-CoV-2 spike subunit 1 (S1) antibodies, and these antibodies reacted with the same epitopes of spike 1 protein as sera from COVID-19 patients. Therefore, suppression of neutrophil elastase could represent an attractive strategy for improving the efficacy of alum-based injected vaccines for the induction of broad immunity, including mucosal immunity. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M38FW5ZQHE | |||||||||
| Subjects: | 6 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY1917: Impaired neutralizing antibody response to COVID-19 mRNA vaccines in cancer patients | ||||||||||
| Status: | Updated | |||||||||
| Description: | There is currently a critical need to determine the efficacy of SARS-CoV-2 vaccination for immunocompromised patients. In this study, we determined the neutralizing antibody response in 160 cancer patients diagnosed with chronic lymphocytic leukemia (CLL), lung cancer, breast cancer, and various non-Hodgkin's lymphomas (NHL), after they received two doses of mRNA vaccines. Serum from 46 mRNA vaccinated health care workers (HCWs) served as healthy controls. We discovered that (1) cancer patients exhibited reduced neutralizing antibody titer (NT50) compared to HCWs; (2) CLL and NHL patients exhibited the lowest NT50 levels, with 50-60% of them below the detection limit; (3) mean NT50 levels in patients with CLL and NHL was ~2.6 fold lower than those with solid tumors; and (4) cancer patients who received anti-B cell therapy exhibited significantly reduced NT50 levels. Our results demonstrate an urgent need for novel immunization strategies for cancer patients against SARS-CoV-2, particularly those with hematological cancers and those on anti-B cell therapies. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M383VCI57N | |||||||||
| Subjects: | 2 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY1927: Corticosteroid treatment in COVID-19 modulates host inflammatory responses and transcriptional signatures of immune dysregulation | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease-2019 (COVID-19), a respiratory disease that varies in severity from mild to severe/fatal. Several risk factors for severe disease have been identified, notably age, male sex, and pre-existing conditions such as diabetes, obesity, and hypertension. Several advancements in clinical care have been achieved over the past year, including the use of corticosteroids (e.g., corticosteroids) and other immune-modulatory treatments that have now become standard of care for patients with acute severe COVID-19. While the understanding of the mechanisms that underlie increased disease severity with age has improved over the past few months, it remains incomplete. Furthermore, the molecular impact of corticosteroid treatment on host response to acute SARS-CoV-2 infection has not been investigated. In this study, a cross-sectional and longitudinal analysis of Ab, soluble immune mediators, and transcriptional responses in young (< or = 65 years) and aged (> 65 years) diabetic males with obesity hospitalized with acute severe COVID-19 was conducted. Additionally, the transcriptional profiles in samples obtained before and after corticosteroids became standard of care were compared. The analysis indicates that severe COVID-19 is characterized by robust Ab responses, heightened systemic inflammation, increased expression of genes related to inflammatory and pro-apoptotic processes, and reduced expression of those important for adaptive immunity regardless of age. In contrast, COVID-19 patients receiving steroids did not show high levels of systemic immune mediators and lacked transcriptional indicators of heightened inflammatory and apoptotic responses. Overall, these data suggest that inflammation and cell death are key drivers of severe COVID-19 pathogenesis in the absence of corticosteroid therapy. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3WIUTT8OD | ||||||||||||
| Subjects: | 8 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY1932: Cross-Reactive Antibodies to SARS-CoV-2 and MERS-CoV in Pre-COVID-19 Blood Samples from Sierra Leoneans | ||||||||||
| Status: | Updated | |||||||||
| Description: | Many countries in sub-Saharan Africa have experienced lower COVID-19 caseloads and fewer deaths than countries in other regions worldwide. Under-reporting of cases and a younger population could partly account for these differences, but pre-existing immunity to coronaviruses is another potential factor. Blood samples from Sierra Leonean Lassa fever and Ebola survivors and their contacts collected before the first reported COVID-19 cases were assessed using enzyme-linked immunosorbent assays for the presence of antibodies binding to proteins of coronaviruses that infect humans. Results were compared to COVID-19 subjects and healthy blood donors from the United States. Prior to the pandemic, Sierra Leoneans had more frequent exposures than Americans to coronaviruses with epitopes that cross-react with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), SARS-CoV, and Middle Eastern respiratory syndrome coronavirus (MERS-CoV). The percentage of Sierra Leoneans with antibodies reacting to seasonal coronaviruses was also higher than for American blood donors. Serological responses to coronaviruses by Sierra Leoneans did not differ by age or sex. Approximately a quarter of Sierra Leonian pre-pandemic blood samples had neutralizing antibodies against SARS-CoV-2 pseudovirus, while about a third neutralized MERS-CoV pseudovirus. Prior exposures to coronaviruses that induce cross-protective immunity may contribute to reduced COVID-19 cases and deaths in Sierra Leone. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3T4B7MGV4 | |||||||||
| Subjects: | 3 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY1945: A humanized mouse model of chronic COVID-19 | ||||||||||
| Status: | Updated | |||||||||
| Description: | Coronavirus disease 2019 (COVID-19) is an infectious disease that can present as an uncontrolled, hyperactive immune response, causing severe immunological injury. Existing rodent models do not recapitulate the sustained immunopathology of patients with severe disease. Here we describe a humanized mouse model of COVID-19 that uses adeno-associated virus to deliver human ACE2 to the lungs of humanized MISTRG6 mice. This model recapitulates innate and adaptive human immune responses to severe acute respiratory syndrome coronavirus 2 infection up to 28 days after infection, with key features of chronic COVID-19, including weight loss, persistent viral RNA, lung pathology with fibrosis, a human inflammatory macrophage response, a persistent interferon-stimulated gene signature and T cell lymphopenia. We used this model to study two therapeutics on immunopathology, patient-derived antibodies and steroids and found that the same inflammatory macrophages crucial to containing early infection later drove immunopathology. This model will enable evaluation of COVID-19 disease mechanisms and treatments. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3S6CCM01K | |||||||||
| Subjects: | 2 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY1947: Function Is More Reliable Than Quantity to Follow Up the Humoral Response to the Receptor-Binding Domain of SARS-CoV-2-Spike Protein after Natural Infection or COVID-19 Vaccination | ||||||||||
| Status: | Updated | |||||||||
| Description: | Both the SARS-CoV-2 pandemic and emergence of variants of concern have highlighted the need for functional antibody assays to monitor the humoral response over time. Antibodies directed against the spike (S) protein of SARS-CoV-2 are an important component of the neutralizing antibody response. In this work, we report that in a subset of patients -despite a decline in total S-specific antibodies- neutralizing antibody titers remain at a similar level for an average of 98 days in longitudinal sampling of a cohort of 59 Hispanic/Latino patients exposed to SARS-CoV-2. Our data suggest that 100% of seroconverting patients make detectable neutralizing antibody responses which can be quantified by a surrogate viral neutralization test. Examination of sera from ten out of the 59 subjects which received mRNA-based vaccination revealed that both IgG titers and neutralizing activity of sera were higher after vaccination compared to a cohort of 21 SARS-CoV-2 naive subjects. One dose was sufficient for the induction of a neutralizing antibody, but two doses were necessary to reach 100% surrogate virus neutralization in subjects irrespective of previous SARS-CoV-2 natural infection status. Like the pattern observed after natural infection, the total anti-S antibodies titers declined after the second vaccine dose; however, neutralizing activity remained relatively constant for more than 80 days after the first vaccine dose. Furthermore, our data indicates that -compared with mRNA vaccination- natural infection induces a more robust humoral immune response in unexposed subjects. This work is an important contribution to understanding the natural immune response to the novel coronavirus in a population severely impacted by SARS-CoV-2. Furthermore, by comparing the dynamics of the immune response after the natural infection vs. the vaccination, these findings suggest that functional neutralizing antibody tests are more relevant indicators than the presence or absence of binding antibodies. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M337OBG0UC | |||||||||
| Subjects: | 3 | |||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | |||||||||
| SDY1962: Does a lack of vaccine side effects correlate with reduced BNT162b2 mRNA vaccine response among healthcare workers and nursing home residents? | |||||||
| Status: | Updated | ||||||
| Description: | Background: The BNT162b2 SARS-CoV-2 mRNA vaccination has mitigated the burden of COVID-19 among residents of long-term care facilities considerably, despite being excluded from the vaccine trials. Data on reactogenicity (vaccine side effects) in this population are limited.Aims: To assess reactogenicity among nursing home (NH) residents. To provide a plausible proxy for predicting vaccine response among this population.Methods: We enrolled and sampled NH residents and community-dwelling healthcare workers who received the BNT162b2 mRNA vaccine, to assess local or systemic reactogenicity and antibody levels (immunogenicity).Results: NH residents reported reactions at a much lower frequency and lesser severity than the community-dwelling healthcare workers. These reactions were mild and transient with all subjects experiencing more local than systemic reactions. Based on our reactogenicity and immunogenicity data, we developed a linear regression model predicting log-transformed anti-spike, anti-receptor-binding domain (RBD), and neutralizing titers, with a dichotomous variable indicating the presence or absence of reported reactions which revealed a statistically significant effect, with estimated shifts in log-transformed titers ranging from 0.32 to 0.37 (all p < 0.01) indicating greater immunogenicity in subjects with one or more reported reactions of varying severity.Discussion: With a significantly lower incidence of post-vaccination reactions among NH residents as reported in this study, the BNT162b2 mRNA vaccine appears to be well-tolerated among this vulnerable population. If validated in larger populations, absence of reactogenicity could help guide clinicians in prioritizing vaccine boosters.Conclusions: Reactogenicity is significantly mild among nursing home residents and overall, subjects who reported post-vaccination reactions developed higher antibody titers. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3KRZ9GLCR | ||||||
| Subjects: | 4 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY1963: Protective efficacy of Ad26.COV2.S against SARS-CoV-2 B.1.351 in macaques | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | The emergence of SARS-CoV-2 variants that partially evade neutralizing antibodies poses a threat to the efficacy of current COVID-19 vaccines1,2. The Ad26.COV2.S vaccine expresses a stabilized spike protein from the WA1/2020 strain of SARS-CoV-2, and has recently demonstrated protective efficacy against symptomatic COVID-19 in humans in several geographical regions?including in South Africa, where 95% of sequenced viruses in cases of COVID-19 were the B.1.351 variant3. Here we show that Ad26.COV2.S elicits humoral and cellular immune responses that cross-react with the B.1.351 variant and protects against B.1.351 challenge in rhesus macaques. Ad26.COV2.S induced lower binding and neutralizing antibodies against B.1.351 as compared to WA1/2020, but elicited comparable CD8 and CD4 T cell responses against the WA1/2020, B.1.351, B.1.1.7, P.1 and CAL.20C variants. B.1.351 infection of control rhesus macaques resulted in higher levels of virus replication in bronchoalveolar lavage and nasal swabs than did WA1/2020 infection. Ad26.COV2.S provided robust protection against both WA1/2020 and B.1.351, although we observed higher levels of virus in vaccinated macaques after B.1.351 challenge. These data demonstrate that Ad26.COV2.S provided robust protection against B.1.351 challenge in rhesus macaques. Our findings have important implications for vaccine control of SARS-CoV-2 variants of concern. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3I9MMZOGZ | ||||||||||||
| Subjects: | 6 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY1964: Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine | |||||||||||
| Status: | Updated | ||||||||||
| Description: | The CVnCoV (CureVac) mRNA vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was recently evaluated in a phase 2b/3 efficacy trial in humans1. CV2CoV is a second-generation mRNA vaccine containing non-modified nucleosides but with optimized non-coding regions and enhanced antigen expression. Here we report the results of a head-to-head comparison of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in non-human primates. We immunized 18 cynomolgus macaques with two doses of 12??g lipid nanoparticle-formulated CVnCoV or CV2CoV or with sham (n?=?6 per group). Compared with CVnCoV, CV2CoV induced substantially higher titres of binding and neutralizing antibodies, memory B cell responses and T cell responses as well as more potent neutralizing antibody responses against SARS-CoV-2 variants, including the Delta variant. Moreover, CV2CoV was found to be comparably immunogenic to the BNT162b2 (Pfizer) vaccine in macaques. Although CVnCoV provided partial protection against SARS-CoV-2 challenge, CV2CoV afforded more robust protection with markedly lower viral loads in the upper and lower respiratory tracts. Binding and neutralizing antibody titres were correlated with protective efficacy. These data demonstrate that optimization of non-coding regions can greatly improve the immunogenicity and protective efficacy of a non-modified mRNA SARS-CoV-2 vaccine in non-human primates. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3YD38IFGB | ||||||||||
| Subjects: | 3 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY1965: Virological Characteristics ofHospitalized Children WithSARS-CoV-2 Infection | ||||||||||
| Status: | Updated | |||||||||
| Description: | In children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, virological characteristics and correlation with disease severity have not been extensively studied. The primary objective in this study is to determine the correlation between SARS-CoV-2 viral load (VL) in infected children with age, disease severity, and underlying comorbidities.Children ,21 years, screened for SARS-CoV-2 at the time of hospitalization, who tested positive by polymerase chain reaction were included in this study. VL at different sites was determined and compared between groups. Of the 102 children included in this study, 44% of the cohort had asymptomatic infection, and children with .1 comorbidity were the most at risk for severe disease. VL in children with symptomatic infection was significantly higher than in children with asymptomatic infection (3.0 3 105 vs 7.2 3 103 copies per mL; P = .001). VL in the respiratory tract was significantly higher in children ,1 year, compared with older children (3.3 3 107 vs 1.3 3 104 copies per mL respectively; P , .0001), despite most infants presenting with milder illness. Besides the respiratory tract, SARS-CoV-2 RNA was also detectable in samples from the gastrointestinal tract (saliva and rectum) and blood. In 13 children for whom data on duration of polymerase chain reaction positivity was available, 12 of 13 tested positive 2 weeks after initial diagnosis, and 6 of 13 continued to test positive 4 weeks after initial diagnosis. In hospitalized children with SARS-CoV-2, those with .1 comorbid condition experienced severe disease. SARS-CoV-2 VL in the respiratory tract is significantly higher in children with symptomatic disease and children ,1 year of age. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3OBTZVHIQ | |||||||||
| Subjects: | 3 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY1966: A combination of two human neutralizing antibodies prevents SARS-CoV-2 infection in cynomolgus macaques | |||||||||
| Status: | Updated | ||||||||
| Description: | Background: Human monoclonal antibody (mAb) treatments are promising for COVID-19 prevention or therapy. The pre-exposure prophylactic efficacy of neutralizing antibodies that are engineered with mutations to extend their persistence in human serum and the neutralizing antibody titer in serum required for protection against SARS-CoV-2 infection remain poorly characterized.Methods: The Fc region of two neutralizing mAbs (COV2-2130 and COV2-2381) targeting non-overlapping epitopes on the receptor binding domain of SARS-CoV-2 spike protein was engineered to extend their persistence in humans and reduce interactions with Fc gamma receptors. We assessed protection by individual antibodies or a combination of the two antibodies (designated ADM03820) given prophylactically by an intravenous or intramuscular route in a non-human primate (NHP) model of SARS-CoV-2 infection.Findings: Passive transfer of individual mAbs or ADM03820 conferred virological protection in the NHP respiratory tract in a dose-dependent manner, and ADM03820 potently neutralized SARS-CoV-2 variants of concern in vitro. We defined a protective serum-neutralizing antibody titer and concentration in NHPs for passively transferred human antibodies that acted by direct viral neutralization.Conclusions: In summary, we demonstrate that neutralizing antibodies with extended half-life and lacking Fc-mediated effector functions are efficient for pre-exposure prophylaxis of SARS-CoV-2 infection in NHPs. These results support clinical development of ADM03820 for COVID-19 prevention. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3G3GC8IIZ | ||||||||
| Subjects: | 6 | ||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||
| SDY1967: Longitudinal SARS-CoV-2 mRNA Vaccine-Induced Humoral Immune Responses in Patients with Cancer | ||||||||||
| Status: | Updated | |||||||||
| Description: | Longitudinal studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced immune responses in patients with cancer are needed to optimize clinical care. In a prospective cohort study of 366 (291 vaccinated) patients, we measured antibody levels [anti-spike (IgG-(S-RBD) and anti-nucleocapsid immunoglobulin] at three time points. Antibody level trajectories and frequency of breakthrough infections were evaluated by tumor type and timing of treatment relative to vaccination. IgG-(S-RBD) at peak response (median = 42 days after dose 2) was higher (P = 0.002) and remained higher after 4 to 6 months (P = 0.003) in patients receiving mRNA-1273 compared with BNT162b2. Patients with solid tumors attained higher peak levels (P = 0.001) and sustained levels after 4 to 6 months (P < 0.001) compared with those with hematologic malignancies. B-cell targeted treatment reduced peak (P = 0.001) and sustained antibody responses (P = 0.003). Solid tumor patients receiving immune checkpoint inhibitors before vaccination had lower sustained antibody levels than those who received treatment after vaccination (P = 0.043). Two (0.69%) vaccinated and one (1.9%) unvaccinated patient had severe COVID-19 illness during follow-up. Our study shows variation in sustained antibody responses across cancer populations receiving various therapeutic modalities, with important implications for vaccine booster timing and patient selection. SIGNIFICANCE: Long-term studies of immunogenicity of SARS-CoV-2 vaccines in patients with cancer are needed to inform evidence-based guidelines for booster vaccinations and to tailor sequence and timing of vaccinations to elicit improved humoral responses. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3BGVPR3CN | |||||||||
| Subjects: | 3 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY1969: Mathematical Modeling to Inform Vaccination Strategies and Testing Approaches for Coronavirus Disease 2019 (COVID-19) in Nursing Homes | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | Background: Nursing home residents and staff were included in the first phase of coronavirus disease 2019 vaccination in the United States. Because the primary trial endpoint was vaccine efficacy (VE) against symptomatic disease, there are limited data on the extent to which vaccines protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the ability to infect others (infectiousness). Assumptions about VE against infection and infectiousness have implications for changes to infection prevention guidance for vaccinated populations, including testing strategies.Methods: We use a stochastic agent-based Susceptible-Exposed-Infectious (Asymptomatic/Symptomatic)-Recovered model of a nursing home to simulate SARS-CoV-2 transmission. We model 3 scenarios, varying VE against infection, infectiousness, and symptoms, to understand the expected impact of vaccination in nursing homes, increasing staff vaccination coverage, and different screening testing strategies under each scenario.Results: Increasing vaccination coverage in staff decreases total symptomatic cases in the nursing home (among staff and residents combined) in each VE scenario. In scenarios with 50% and 90% VE against infection and infectiousness, increasing staff coverage reduces symptomatic cases among residents. If vaccination only protects against symptoms, and asymptomatic cases remain infectious, increased staff coverage increases symptomatic cases among residents. However, this is outweighed by the reduction in symptomatic cases among staff. Higher frequency testing-more than once weekly-is needed to reduce total symptomatic cases if the vaccine has lower efficacy against infection and infectiousness, or only protects against symptoms.Conclusions: Encouraging staff vaccination is not only important for protecting staff, but might also reduce symptomatic cases in residents if a vaccine confers at least some protection against infection or infectiousness. | |||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M31WZ81NLC | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
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| Assays: | None | |||||||||||||||
| Clinical Assessments: | None | |||||||||||||||
| SDY1972: Population impact of SARS-CoV-2 variants with enhanced transmissibility and/or partial immune escape | ||||||||||
| Status: | Updated | |||||||||
| Description: | SARS-CoV-2 variants of concern exhibit varying degrees of transmissibility and, in some cases, escape from acquired immunity. Much effort has been devoted to measuring these phenotypes, but understanding their impact on the course of the pandemic-especially that of immune escape-has remained a challenge. Here, we use a mathematical model to simulate the dynamics of wild-type and variant strains of SARS-CoV-2 in the context of vaccine rollout and nonpharmaceutical interventions. We show that variants with enhanced transmissibility frequently increase epidemic severity, whereas those with partial immune escape either fail to spread widely or primarily cause reinfections and breakthrough infections. However, when these phenotypes are combined, a variant can continue spreading even as immunity builds up in the population, limiting the impact of vaccination and exacerbating the epidemic. These findings help explain the trajectories of past and present SARS-CoV-2 variants and may inform variant assessment and response in the future. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3EWP60HPZ | |||||||||
| Subjects: | 0 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY1973: Reduced BNT162b2 Messenger RNA Vaccine Response in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-Naive Nursing Home Residents | ||||||||||
| Status: | Updated | |||||||||
| Description: | After BNT162b2 messenger RNA vaccination, antibody levels to spike, receptor-binding domain, and virus neutralization were examined in 149 nursing home residents and 110 healthcare worker controls. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-naive nursing home residents' median post-second vaccine dose antibody neutralization titers are one-quarter that of SARS-CoV-2-naive healthcare workers. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M31XBTVKKN | |||||||||
| Subjects: | 5 | |||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | |||||||||
| SDY1974: Generation of human long-lived plasma cells by developmentally regulated epigenetic imprinting | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Antibody secreting cells (ASCs) circulate after vaccination and infection and migrate to the BM where a subset known as long-lived plasma cells (LLPCs) persists and secrete antibodies for a lifetime. The mechanisms by which circulating ASCs become LLPCs are not well elucidated. Here, we show that human blood ASCs have distinct morphology, transcriptomes, and epigenetics compared with BM LLPCs. Compared with blood ASCs, BM LLPCs have decreased nucleus/cytoplasm ratio but increased endoplasmic reticulum and numbers of mitochondria. LLPCs up-regulate pro-survival genes MCL1, BCL2, and BCL-XL while simultaneously down-regulating pro-apoptotic genes HRK1, CASP3, and CASP8 Consistent with reduced gene expression, the pro-apoptotic gene loci are less accessible in LLPCs. Of the pro-survival genes, only BCL2 is concordant in gene up-regulation and loci accessibility. Using a novel in vitro human BM mimetic, we show that blood ASCs undergo similar morphological and molecular changes that resemble ex vivo BM LLPCs. Overall, our study demonstrates that early-minted blood ASCs in the BM microniche must undergo morphological, transcriptional, and epigenetic changes to mature into apoptotic-resistant LLPCs. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3W5SK65XI | ||||||||||
| Subjects: | 6 | ||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||
| SDY1975: Single-Dose Intranasal Administration of AdCOVID Elicits Systemic and Mucosal Immunity against SARS-CoV-2 and Fully Protects Mice from Lethal Challenge | ||||||||||
| Status: | Updated | |||||||||
| Description: | The coronavirus disease 2019 (COVID-19) pandemic has highlighted the urgent need for effective prophylactic vaccination to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Intranasal vaccination is an attractive strategy to prevent COVID-19 as the nasal mucosa represents the first-line barrier to SARS-CoV-2 entry. The current intramuscular vaccines elicit systemic immunity but not necessarily high-level mucosal immunity. Here, we tested a single intranasal dose of our candidate adenovirus type 5-vectored vaccine encoding the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (AdCOVID) in inbred, outbred, and transgenic mice. A single intranasal vaccination with AdCOVID elicited a strong and focused immune response against RBD through the induction of mucosal IgA in the respiratory tract, serum neutralizing antibodies, and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile. A single AdCOVID dose resulted in immunity that was sustained for over six months. Moreover, a single intranasal dose completely protected K18-hACE2 mice from lethal SARS-CoV-2 challenge, preventing weight loss and mortality. These data show that AdCOVID promotes concomitant systemic and mucosal immunity and represents a promising vaccine candidate. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3O55DEMO6 | |||||||||
| Subjects: | 5 | |||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | |||||||||
| SDY1976: Shared B cell memory to coronaviruses and other pathogens varies in human age groups and tissues | ||||||||||
| Status: | Updated | |||||||||
| Description: | Vaccination and infection promote the formation, tissue distribution, and clonal evolution of B cells, which encode humoral immune memory. We evaluated pediatric and adult blood and deceased adult organ donor tissues to determine convergent antigen-specific antibody genes of similar sequences shared between individuals. B cell memory varied for different pathogens. Polysaccharide antigenspecific clones were not exclusive to the spleen. Adults had higher clone frequencies and greater class switching in lymphoid tissues than blood, while pediatric blood had abundant class-switched convergent clones. Consistent with reported serology, prepandemic children had class-switched convergent clones to severe acute respiratory syndrome coronavirus 2 with weak cross-reactivity to other coronaviruses, while adult blood or tissues showed few such clones. These results highlight the prominence of early childhood B cell clonal expansions and cross-reactivity for future responses to novel pathogens. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3TGZSFQZZ | |||||||||
| Subjects: | 4 | |||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | |||||||||
| SDY1977: SARS-CoV-2 vaccine uptake, perspectives, and adverse reactions following vaccination in patients with cancer undergoing treatment | ||||||||||
| Status: | Updated | |||||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines were developed, tested, and approved in record time. As patients with cancer were excluded from vaccine trials, some patients may be hesitant,1 given unanswered questions around safety and adverse reactions, especially those undergoing treatment. One study conducted among 134 patients receiving immune checkpoint inhibitors (ICIs) reported an 81% BNT162b2 vaccine uptake rate with similar rates of acute adverse reactions as reported among healthy individuals, except for higher frequency of myalgias among patients with cancer.2 Further research is needed by tumor type and treatment to better inform clinicians and patients during the vaccine decision-making process.We report data on uptake and perspectives on SARS-CoV-2 vaccination and postvaccination adverse reactions in 208 recently diagnosed patients with cancer (median age 63 years, 52.4% women, 33.2% non-White minorities, Table 1 ) at a large healthcare system in Los Angeles spanning the timeline from limited vaccine availability to broader dissemination (November 2020 to July 2021). Vaccine hesitancy and perspectives were measured using a modified version of the World Health Organization Vaccine Hesitancy Scale (Supplementary Material, available at https://doi.org/10.1016/j.annonc.2021.10.005).3 A self-administered symptoms questionnaire was given to vaccinated recipients after dose 1 (D1) and D2 for messenger RNA (mRNA) SARS-CoV-2 vaccines. Electronic medical records provided correlative clinical information. Chi-square tests were used to assess differences for categorical variables and a Wilcoxon rank-sum test for continuous variables (Stata v. 15.1). All tests were two-sided and considered statistically significant at P < 0.05. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M36ER193HY | |||||||||
| Subjects: | 2 | |||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY1978: Roles of antiviral sensing and type I interferon signaling in the restriction of SARS-CoV-2 replication | |||||||
| Status: | Updated | ||||||
| Description: | We investigated the role of tissue type and antiviral genes during SARS-CoV-2 infection in nonhuman primate (kidney) and human (liver, respiratory epithelial, gastric) cell lines. We report different viral growth kinetics and release among the cell lines despite comparable ACE2 expression. Transcriptomics revealed that absence of STAT1 in nonhuman primate cells appeared to enhance inflammatory responses without effecting infectious viral titer. Deletion of RL-6 in respiratory epithelial cells increased viral replication. Impaired infectious virus release was detected in Huh7 but not Huh7.5 cells, suggesting a role for RIG1. Gastric cells MKN45 exhibited robust antiviral gene expression and supported viral replication. Data here provide insight into molecular pathogenesis of and alternative cell lines for studying SARS-CoV-2 infection. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M381LM05UM | ||||||
| Subjects: | 7 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY1990: Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection | |||||||||||
| Status: | Updated | ||||||||||
| Description: | SARS-CoV-2-specific antibodies, CD4+ T cells, and CD8+ T cells are made in response to SARS-CoV-2 infection. Understanding the kinetics and durability of immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines and assessing the likely future course of the COVID-19 pandemic. We assessed the immune memory of all three branches of adaptive immunity (CD4+ T cell, CD8+ T cell, and humoral immunity) in a predominantly cross-sectional study, including a longitudinal subset, extending for up to eight months post-infection. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M31TX0GFHU | ||||||||||
| Subjects: | 1 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY2012: Longitudinal COVID-19-vaccination-induced antibody responses and Omicron neutralization in patients with lung cancer | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | During the global pandemic with COVID19, early reports indicated that cancer patients in general, and lung cancer patients in particular, who were infected with SARS-CoV-2 had high mortality rates, with a reported 25%?40% case fatality rate (CFR) (Rolfo et al., 2022). The underlying clinical, demographic, and tumor-biologic factors contributing to the aggressive course of infection in this vulnerable cancer population have not been fully elucidated and could arise through multiple mechanisms, including the immunosuppressive activity of lung cancer therapeutics, lung cancer itself, or other co-morbidities particularly related to the respiratory system (Kuderer et al., 2020; Zhang et al., 2021; Lievre et al., 2020). In December 2020, phase III randomized clinical trials demonstrated strong clinical efficacy of SARS-CoV-2 mRNA vaccines, which subsequently became available to the public in the United States, but did not specifically evaluate lung cancer patients (Baden et al., 2021; Chavez-Macgregor et al., 2022). Additionally, the recently emergent Omicron variants largely evade vaccination-induced immunity. It has been shown that third mRNA vaccine doses increase Omicron antibody neutralization in the general population; however, the efficacy of this third dose remains unknown in patients with lung cancer (Planas et al., 2022; Wu et al., 2022; Nemet et al., 2022). Thus, there are major knowledge gaps for managing patients with lung cancer in the COVID-19 era which need to be filled | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3B4HT6SZU | ||||||||||||
| Subjects: | 5 | ||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||
| SDY2024: Durability and Cross-Reactivity of SARS-CoV-2 mRNA Vaccine in Adolescent Children | |||||||||
| Status: | Updated | ||||||||
| Description: | Emergent SARS-CoV-2 variants and waning humoral immunity in vaccinated individuals have resulted in increased infections and hospitalizations. Children are not spared from infection nor complications of COVID-19, and the recent recommendation for boosters in individuals ages 12 years or older calls for broader understanding of the adolescent immune profile after mRNA vaccination. We tested the durability and cross-reactivity of anti-SARS-CoV-2 serologic responses over a six-month time course in vaccinated adolescents against the SARS-CoV-2 D614G (""wild type"") and Omicron antigens. Serum from 77 adolescents showed that anti-Spike antibodies wane significantly over six months. After completion of a two-vaccine series, cross-reactivity against Omicron-specific receptor-binding domain (RBD) was seen. Functional humoral activation against wild type and Omicron SARS-CoV-2 also declines over time in vaccinated adolescent children. Evidence of waning mRNA-induced vaccine immunity underscores vulnerabilities in long-term pediatric protection against SARS-CoV-2 infection, while cross-reactivity highlights the additional benefits of vaccination. Characterization of adolescent immune signatures post-vaccination will inform guidance on vaccine platforms and timelines, and ultimately optimize immunoprotection of children. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M31M7VL89N | ||||||||
| Subjects: | 1 | ||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||
| SDY2026: SARS-CoV-2 transmission and impacts of unvaccinated-only screening in populations of mixed vaccination status | ||||||||||
| Status: | Updated | |||||||||
| Description: | Screening programs that test only the unvaccinated population have been proposed and implemented to mitigate SARS-CoV-2 spread, implicitly assuming that the unvaccinated population drives transmission. To evaluate this premise and quantify the impact of unvaccinated-only screening programs, we introduce a model for SARS-CoV-2 transmission through which we explore a range of transmission rates, vaccine effectiveness scenarios, rates of prior infection, and screening programs. We find that, as vaccination rates increase, the proportion of transmission driven by the unvaccinated population decreases, such that most community spread is driven by vaccine-breakthrough infections once vaccine coverage exceeds 55% (omicron) or 80% (delta), points which shift lower as vaccine effectiveness wanes. Thus, we show that as vaccination rates increase, the transmission reductions associated with unvaccinated-only screening decline, identifying three distinct categories of impact on infections and hospitalizations. More broadly, these results demonstrate that effective unvaccinated-only screening depends on population immunity, vaccination rates, and variant. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3T90LW0CA | |||||||||
| Subjects: | 2 | |||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2033: Vaccine protection against the SARS-CoV-2 Omicron variant in macaques | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | The rapid spread of the SARS-CoV-2 Omicron (B.1.1.529) variant, including in highly vaccinated populations, has raised important questions about the efficacy of current vaccines. In this study, we show that the mRNA-based BNT162b2 vaccine and the adenovirus-vector-based Ad26.COV2.S vaccine provide robust protection against high-dose challenge with the SARS-CoV-2 Omicron variant in cynomolgus macaques. We vaccinated 30 macaques with homologous and heterologous prime-boost regimens with BNT162b2 and Ad26.COV2.S. Following Omicron challenge, vaccinated macaques demonstrated rapid control of virus in bronchoalveolar lavage, and most vaccinated animals also controlled virus in nasal swabs. However, 4 vaccinated animals that had moderate Omicron-neutralizing antibody titers and undetectable Omicron CD8+ T cell responses failed to control virus in the upper respiratory tract. Moreover, virologic control correlated with both antibody and T cell responses. These data suggest that both humoral and cellular immune responses contribute to vaccine protection against a highly mutated SARS-CoV-2 variant. | ||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M36QZ9VXR6 | ||||||||||||||
| Subjects: | 5 | ||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||||
| SDY2034: mRNA-1273 and BNT162b2 COVID-19 vaccines elicit antibodies with differences in Fc-mediated effector functions | |||||||||||
| Status: | Updated | ||||||||||
| Description: | The successful development of several coronavirus disease 2019 (COVID-19) vaccines has substantially reduced morbidity and mortality in regions of the world where the vaccines have been deployed. However, in the wake of the emergence of viral variants that are able to evade vaccine-induced neutralizing antibodies, real-world vaccine efficacy has begun to show differences across the two approved mRNA platforms, BNT162b2 and mRNA-1273; these findings suggest that subtle variation in immune responses induced by the BNT162b2 and mRNA-1273 vaccines may confer differential protection. Given our emerging appreciation for the importance of additional antibody functions beyond neutralization, we profiled the postboost binding and functional capacity of humoral immune responses induced by the BNT162b2 and mRNA-1273 vaccines in a cohort of hospital staff. Both vaccines induced robust humoral immune responses to wild-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to variants of concern. However, differences emerged across epitope-specific responses, with higher concentrations of receptor binding domain (RBD)- and N-terminal domain-specific IgA observed in recipients of mRNA-1273. Antibodies eliciting neutrophil phagocytosis and natural killer cell activation were also increased in mRNA-1273 vaccine recipients as compared to BNT162b2 recipients. RBD-specific antibody depletion highlighted the different roles of non-RBD-specific antibody effector functions induced across the mRNA vaccines. These data provide insights into potential differences in protective immunity conferred by these vaccines. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3KWASU913 | ||||||||||
| Subjects: | 3 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY2035: SARS-CoV-2 antibodies protect against reinfection for at least 6 months in a multicentre seroepidemiological workplace cohort | |||||||
| Status: | Updated | ||||||
| Description: | Identifying the potential for SARS-CoV-2 reinfection is crucial for understanding possible long-term epidemic dynamics. We analysed longitudinal PCR and serological testing data from a prospective cohort of 4,411 United States employees in 4 states between April 2020 and February 2021. We conducted a multivariable logistic regression investigating the association between baseline serological status and subsequent PCR test result in order to calculate an odds ratio for reinfection. We estimated an odds ratio for reinfection ranging from 0.14 (95% CI: 0.019 to 0.63) to 0.28 (95% CI: 0.05 to 1.1), implying that the presence of SARS-CoV-2 antibodies at baseline is associated with around 72% to 86% reduced odds of a subsequent PCR positive test based on our point estimates. This suggests that primary infection with SARS-CoV-2 provides protection against reinfection in the majority of individuals, at least over a 6-month time period. We also highlight 2 major sources of bias and uncertainty to be considered when estimating the relative risk of reinfection, confounders and the choice of baseline time point, and show how to account for both in reinfection analysis. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3AJI51QL1 | ||||||
| Subjects: | 1 | ||||||
| Study PI, contact: |
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| Publications: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY2036: Durability of Anti-Spike Antibodies in Infants After Maternal COVID-19 Vaccination or Natural Infection | ||||||||||
| Status: | Updated | |||||||||
| Description: | Understanding the persistence of maternal antibody levels in infants is important because COVID-19 infections in this age group account for a disproportionate burden of pediatric SARS-CoV-2?associated morbidity6 and because COVID-19 vaccines are not currently planned for administration to infants younger than 6 months. Study limitations include the small number of infants, the longer mean time to follow-up in the infected group (due to pragmatic constraints related to timing of COVID-19 surges in Boston and the availability of participants for timely follow-up), and the reporting of antibody titers rather than clinical outcomes. Although the antibody titer known to be protective against COVID-19 in infants isunknown, these findings provide further incentive for pregnant individuals to pursue COVID-19 vaccination. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3CK1F3HPK | |||||||||
| Subjects: | 2 | |||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | |||||||||
| SDY2037: Passive transfer of Ad26.COV2.S-elicited IgG from humans attenuates SARS-CoV-2 disease in hamsters | |||||||
| Status: | Updated | ||||||
| Description: | SARS-CoV-2 Spike-specific binding and neutralizing antibodies, elicited either by natural infection or vaccination, have emerged as potential correlates of protection. An important question, however, is whether vaccine-elicited antibodies in humans provide direct, functional protection from SARS-CoV-2 infection and disease. In this study, we explored directly the protective efficacy of human antibodies elicited by Ad26.COV2.S vaccination by adoptive transfer studies. IgG from plasma of Ad26.COV2.S vaccinated individuals was purified and transferred into naive golden Syrian hamster recipients, followed by intra-nasal challenge of the hamsters with SARS-CoV-2. IgG purified from Ad26.COV2.S-vaccinated individuals provided dose-dependent protection in the recipient hamsters from weight loss following challenge. In contrast, IgG purified from placebo recipients provided no protection in this adoptive transfer model. Attenuation of weight loss correlated with binding and neutralizing antibody titers of the passively transferred IgG. This study suggests that Ad26.COV2.S-elicited antibodies in humans are mechanistically involved in protection against SARS-CoV-2. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3IX6DB4Q8 | ||||||
| Subjects: | 12 | ||||||
| Study PI, contact: |
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| Publications: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY2038: Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | A damaging inflammatory response is implicated in the pathogenesis of severe coronavirus disease 2019 (COVID-19), but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated immunoglobulin G (IgG) antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. To study the biology of afucosylated IgG immune complexes, we developed an in vivo model that revealed that human IgG-Fc-gamma receptor (Fc?R) interactions could regulate inflammation in the lung. Afucosylated IgG immune complexes isolated from patients with COVID-19 induced inflammatory cytokine production and robust infiltration of the lung by immune cells. In contrast to the antibody structures that were associated with disease progression, antibodies that were elicited by messenger RNA SARS-CoV-2 vaccines were highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. Vaccine-elicited IgG did not promote an inflammatory lung response. These results show that human IgG-Fc?R interactions regulate inflammation in the lung and define distinct lung activities mediated by the IgG that are associated with protection against, or progression to, severe COVID-19. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3V1ZYUVBN | ||||||||||||
| Subjects: | 9 | ||||||||||||
| Study PI, contact: |
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| Publications: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||
| SDY2039: Antibodies elicited by SARS-CoV-2 infection or mRNA vaccines have reduced neutralizing activity against Beta and Omicron pseudoviruses | ||||||||||
| Status: | Updated | |||||||||
| Description: | Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that have mutations associated with increased transmission and antibody escape have arisen over the course of the current pandemic. Although the current vaccines have largely been effective against past variants, the number of mutations found on the Omicron (B.1.1.529) spike protein appear to diminish the protection conferred by preexisting immunity. Using vesicular stomatitis virus (VSV) pseudoparticles expressing the spike protein of several SARS-CoV-2 variants, we evaluated the magnitude and breadth of the neutralizing antibody response over time in individuals after infection and in mRNA-vaccinated individuals. We observed that boosting increases the magnitude of the antibody response to wild-type (D614), Beta, Delta, and Omicron variants; however, the Omicron variant was the most resistant to neutralization. We further observed that vaccinated healthy adults had robust and broad antibody responses, whereas responses may have been reduced in vaccinated pregnant women, underscoring the importance of learning how to maximize mRNA vaccine responses in pregnant populations. Findings from this study show substantial heterogeneity in the magnitude and breadth of responses after infection and mRNA vaccination and may support the addition of more conserved viral antigens to existing SARS-CoV-2 vaccines. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3BG02P6RE | |||||||||
| Subjects: | 3 | |||||||||
| Study PI, contact: |
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| Assays: |
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| Clinical Assessments: | None | |||||||||
| SDY2040: Durable Humoral and Cellular Immune Responses 8 Months after Ad26.COV2.S Vaccination | |||||||||
| Status: | Updated | ||||||||
| Description: | These data show that the Ad26.COV2.S vaccine elicited durable humoral and cellular immune responses with minimal decreases for at least 8 months after immunization. In addition, we observed an expansion of neutralizing antibody breadth against SARS-CoV-2 variants over this time period, including against the more transmissible B.1.617.2 variant and the partially neutralization-resistant B.1.351 and P.1 variants, which suggests maturation of B-cell responses even without further boosting. The durability of immune responses elicited by the Ad26.COV2.S vaccine was consistent with the durability recently reported for an Ad26-based Zika vaccine.4 Longitudinal antibody responses to mRNA Covid-19 vaccines have also been reported for 6 months but with different kinetics of decreasing titers.5 The durability of humoral and cellular immune responses 8 months after Ad26.COV2.S vaccination with increased neutralizing antibody responses to SARS-CoV-2 variants over time, including after single-shot vaccination, further supports the use of the Ad26.COV2.S vaccine to combat the global Covid-19 pandemic. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M385J155ZW | ||||||||
| Subjects: | 3 | ||||||||
| Study PI, contact: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||
| SDY2041: Immunogenicity of Ad26.COV2.S vaccine against SARS-CoV-2 variants in humans | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | The Ad26.COV2.S vaccine1-3 has demonstrated clinical efficacy against symptomatic COVID-19, including against the B.1.351 variant that is partially resistant to neutralizing antibodies1. However, the immunogenicity of this vaccine in humans against SARS-CoV-2 variants of concern remains unclear. Here we report humoral and cellular immune responses from 20 Ad26.COV2.S vaccinated individuals from the COV1001 phase I-IIa clinical trial2 against the original SARS-CoV-2 strain WA1/2020 as well as against the B.1.1.7, CAL.20C, P.1 and B.1.351 variants of concern. Ad26.COV2.S induced median pseudovirus neutralizing antibody titres that were 5.0-fold and 3.3-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020 on day 71 after vaccination. Median binding antibody titres were 2.9-fold and 2.7-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020. Antibody-dependent cellular phagocytosis, complement deposition and natural killer cell activation responses were largely preserved against the B.1.351 variant. CD8 and CD4 T cell responses, including central and effector memory responses, were comparable among the WA1/2020, B.1.1.7, B.1.351, P.1 and CAL.20C variants. These data show that neutralizing antibody responses induced by Ad26.COV2.S were reduced against the B.1.351 and P.1 variants, but functional non-neutralizing antibody responses and T cell responses were largely preserved against SARS-CoV-2 variants. These findings have implications for vaccine protection against SARS-CoV-2 variants of concern. | ||||||||||||||||||
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| DOI: | 10.21430/M3RLFPEUYM | ||||||||||||||||||
| Subjects: | 5 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2042: Omicron variant Spike-specific antibody binding and Fc activity are preserved in recipients of mRNA or inactivated COVID-19 vaccines | ||||||||||
| Status: | Updated | |||||||||
| Description: | The Omicron variant of SARS-CoV-2 has been shown to evade neutralizing antibodies elicited by vaccination or infection. Despite the global spread of the Omicron variant, even among highly vaccinated populations, death rates have not increased concomitantly. These data suggest that immune mechanisms beyond antibody-mediated virus neutralization may protect against severe disease. In addition to neutralizing pathogens, antibodies contribute to control and clearance of infections through Fc effector mechanisms. Here, we probed the ability of vaccine-induced antibodies to drive Fc effector activity against the Omicron variant using samples from individuals receiving one of three SARS-CoV-2 vaccines. Despite a substantial loss of IgM, IgA, and IgG binding to the Omicron variant receptor binding domain (RBD) in samples from individuals receiving BNT162b2, mRNA-1273, and CoronaVac vaccines, stable binding was maintained against the full-length Omicron Spike protein. Compromised RBD binding IgG was accompanied by a loss of RBD-specific antibody Fc? receptor (Fc?R) binding in samples from individuals who received the CoronaVac vaccine, but RBD-specific Fc?R2a and Fc?R3a binding was preserved in recipients of mRNA vaccines. Conversely, Spike protein-specific antibodies exhibited persistent but reduced binding to Fc?Rs across all three vaccines, although higher binding was observed in samples from recipients of mRNA vaccines. This was associated with preservation of Fc?R2a and Fc?R3a binding antibodies and maintenance of Spike protein-specific antibody-dependent natural killer cell activation. Thus, despite the loss of Omicron neutralization, vaccine-induced Spike protein-specific antibodies continue to drive Fc effector functions, suggesting a capacity for extraneutralizing antibodies to contribute to disease control. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3LUE504P0 | |||||||||
| Subjects: | 4 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2043: One-Stop Serum Assay Identifies COVID-19 Disease Severity and Vaccination Responses | |||||||
| Status: | Updated | ||||||
| Description: | We developed a multiplex immunoassay from serum/plasma of acutely infected and convalescent COVID-19 patients and prepandemic and postpandemic healthy adults. We measured IgA, IgG, and/or IgM against SARS-CoV-2 nucleocapsid (N), spike domain 1 (S1), S1-receptor binding domain (RBD) and S1-N-terminal domain. For diagnosis, the combined [IgA + IgG + IgM] or IgG levels measured for N, S1, and S1-RBD yielded area under the curve values ?0.90. Virus-specific Ig levels were higher in patients with severe/critical compared with mild/moderate infections. A strong prozone effect was observed in sera from severe/critical patients-a possible source of underestimated Ab concentrations in previous studies. Mild/moderate patients displayed a slower rise and lower peak in anti-N and anti-S1 IgG levels compared with severe/critical patients, but anti-RBD IgG and neutralization responses reached similar levels at 2-4 mo after symptom onset. Measurement of the Ab responses in sera from 18 COVID-19-vaccinated patients revealed specific responses for the S1-RBD Ag and none against the N protein. This highly sensitive, SARS-CoV-2-specific, multiplex immunoassay measures the magnitude, complexity, and kinetics of the Ab response and can distinguish serum Ab responses from natural SARS-CoV-2 infections (mild or severe) and mRNA COVID-19 vaccines. | ||||||
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| DOI: | 10.21430/M3FRD03J1F | ||||||
| Subjects: | 5 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2044: Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection with persisting antibody responses and memory B and T cells | ||||||||||
| Status: | Updated | |||||||||
| Description: | Ending the COVID-19 pandemic will require long-lived immunity to SARS-CoV-2. Here, we evaluate 254 COVID-19 patients longitudinally up to 8 months and find durable broad-based immune responses. SARS-CoV-2 spike binding and neutralizing antibodies exhibit a bi-phasic decay with an extended half-life of >200 days suggesting the generation of longer-lived plasma cells. SARS-CoV-2 infection also boosts antibody titers to SARS-CoV-1 and common betacoronaviruses. In addition, spike-specific IgG+ memory B cells persist, which bodes well for a rapid antibody response upon virus re-exposure or vaccination. Virus-specific CD4+ and CD8+ T cells are polyfunctional and maintained with an estimated half-life of 200 days. Interestingly, CD4+ T cell responses equally target several SARS-CoV-2 proteins, whereas the CD8+ T cell responses preferentially target the nucleoprotein, highlighting the potential importance of including the nucleoprotein in future vaccines. Taken together, these results suggest that broad and effective immunity may persist long-term in recovered COVID-19 patients. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3ONST24P3 | |||||||||
| Subjects: | 3 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2045: Maternal immune response and placental antibody transfer after COVID-19 vaccination across trimester and platforms | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Here, we characterize the antibody profile after Ad26.COV2.S, mRNA-1273 or BNT162b2 vaccination in 158 pregnant individuals and evaluate transplacental antibody transfer by profiling maternal and umbilical cord blood in 175 maternal-neonatal dyads. These analyses reveal lower vaccine-induced functions and Fc receptor-binding after Ad26.COV2.S compared to mRNA vaccination and subtle advantages in titer and function with mRNA-1273 versus BN162b2. mRNA vaccines have higher titers and functions against SARS-CoV-2 variants of concern. First and third trimester vaccination results in enhanced maternal antibody-dependent NK-cell activation, cellular and neutrophil phagocytosis, and complement deposition relative to second trimester. Higher transplacental transfer ratios following first and second trimester vaccination may reflect placental compensation for waning maternal titers. | ||||||||||
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| DOI: | 10.21430/M3JP0UEVB0 | ||||||||||
| Subjects: | 5 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2047: Protective efficacy of rhesus adenovirus COVID-19 vaccines against mouse-adapted SARS-CoV-2 | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | The global COVID-19 pandemic has sparked intense interest in the rapid development of vaccines as well as animal models to evaluate vaccine candidates and to define immune correlates of protection. We recently reported a mouse-adapted SARS-CoV-2 virus strain (MA10) with the potential to infect wild-type laboratory mice, driving high levels of viral replication in respiratory tract tissues as well as severe clinical and respiratory symptoms, aspects of COVID-19 disease in humans that are important to capture in model systems. We evaluated the immunogenicity and protective efficacy of novel rhesus adenovirus serotype 52 (RhAd52) vaccines against MA10 challenge in mice. Baseline seroprevalence is lower for rhesus adenovirus vectors than for human or chimpanzee adenovirus vectors, making these vectors attractive candidates for vaccine development. We observed that RhAd52 vaccines elicited robust binding and neutralizing antibody titers, which inversely correlated with viral replication after challenge. These data support the development of RhAd52 vaccines and the use of the MA10 challenge virus to screen novel vaccine candidates and to study the immunologic mechanisms that underscore protection from SARS-CoV-2 challenge in wild-type mice. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M31B69O6UL | ||||||||||||
| Subjects: | 3 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2052: Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19 | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Randomized, double-blind, placebo-controlled clinical trial of Ad26.COV2.S on 25 participants. Participants were randomized to receive single-shot and 2-shot vaccine regimens with either 5 X 1010 or 1 X 1011 viral particles of Ad26.COV2.S or placebo in healthy adults 18 to 55 years of age. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M364XZ81G8 | ||||||||||
| Subjects: | 5 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2053: Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including third-dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is lower after infection compared with all vaccines evaluated but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks postvaccination in some cases. SARS-CoV-2 antibody specificity, breadth, and maturation are affected by imprinting from exposure history and distinct histological and antigenic contexts in infection compared with vaccination. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M36A5Z1XU9 | ||||||||||||
| Subjects: | 8 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2075: Deficiency of PD-L1+ Non-Immune Cells in Preterm Labor | ||||||||||
| Status: | Updated | |||||||||
| 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. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M300YTT71X | |||||||||
| Subjects: | 52 | |||||||||
| Study PI, contact: |
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| Publications: | None | |||||||||
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| SDY2108: Prior infection with SARS-CoV-2 WA1/2020 partially protects rhesus macaques against reinfection with B.1.1.7 and B.1.351 variants | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that result in increased transmissibility and partial evasion of neutralizing antibodies have recently emerged. Whether natural immunity induced by the original SARS-CoV-2 WA1/2020 strain protects against rechallenge with these SARS-CoV-2 variants remains a critical unresolved question. In this study, we show that natural immunity induced by the WA1/2020 strain leads to partial but incomplete protection against the SARS-CoV-2 variants B.1.1.7 (alpha) and B.1.351 (beta) in rhesus macaques. We challenged rhesus macaques with B.1.1.7 and B.1.351 and showed that infection with these variants resulted in high viral replication in the upper and lower respiratory tract. We then infected rhesus macaques with the WA1/2020 strain and rechallenged them on day 35 with the WA1/2020, B.1.1.7, or B.1.351 variants. Natural immunity to WA1/2020 led to robust protection against rechallenge with WA1/2020 but only partial protection against rechallenge with B.1.351. An intermediate degree of protection was observed in rhesus macaques against rechallenge with B.1.1.7. These data demonstrate partial but incomplete protective efficacy of natural immunity induced by WA1/2020 against SARS-CoV-2 variants of concern. Our findings have important implications for both vaccination and public health strategies in the context of emerging SARS-CoV-2 variants of concern. | ||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3FS3Q3TG6 | ||||||||||||||
| Subjects: | 4 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
| SDY2111: Reduced COVID-19 Vaccine Response in Patients Treated with Biologic Therapies for Asthma | ||||||||||
| Status: | Updated | |||||||||
| Description: | It is unclear if patients with severe asthma and atopic dermatit is on biologic therapies have an adequate and durable humoral immune response after vaccination to SARS-CoV-2. To address these questions, we conducted a prospective observational trial from February 2021 to September 2021 with adults who had severe asthma or atopic dermatitis treated with benralizumab (IL-5 receptor antagonist), mepolizumab(IL-5 antagonist), or dupilumab (IL-4 receptor a antagonist). | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3A944EBOX | |||||||||
| Subjects: | 2 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2113: Augmentation of humoral and cellular immune responses after third-dose SARS-CoV-2 vaccination and viral neutralization in myeloma patients | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | Despite the efficacy of COVID-19 vaccines in healthy individuals, multiple myeloma (MM) patients are immunocompromised and mount suboptimal humoral and cellular responses after two doses of mRNA vaccine (Addeo et al., 2021; Aleman et al., 2021; Van Oekelen et al., 2021). A broader observation of limited vaccine responses in cancer patients, particularly those with hematologic malignancies (Thakkar et al., 2021), has led to the implementation of additional (i.e., third dose) vaccine administration as a way to increase protection for patients with immune suppression. A third dose of BNT162b2 (Pfizer-BioNTech) COVID19 vaccine has shown to be effective in preventing severe COVID-19 caused by the SARS-CoV-2 B.1.617.2 (Delta) variant in the general population (Bar-On et al., 2021; Barda et al., 2021). Furthermore, third-dose administration of either the BNT162b2 (Pfizer-BioNTech) or mRNA1273 (Moderna) COVID-19 vaccine was associated with augmented immune responses in a diverse cohort of cancer patients (Shapiro et al., 2022). However, the real-world effectiveness of additional dosing in myeloma patients and viral neutralization have not been reported. Additionally, the impact of the currently dominant SARS-CoV-2 B.1.1.529 (Omicron) variant on efficacy of the third dose is largely unknown in patients with hematologic malignancies (Zeng et al., 2022). | |||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3EEDBBP9C | |||||||||||||||
| Subjects: | 2 | |||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||
| SDY2114: Longitudinal analysis of severe acute respiratory syndrome coronavirus 2 seroprevalence using multiple serology platforms | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological tests are based on the full-length spike (S), the receptor-binding domain (RBD), or the nucleoprotein (NP) as substrates. Here, we used samples from healthcare workers (HCWs) to perform a longitudinal analysis of the antibody responses using a research-grade RBD and spike-based enzyme-linked immunosorbent assay (ELISA), a commercial RBD and spike-based ELISA, and a commercial NP-based chemiluminescent microparticle immunoassay. Seroprevalence ranged around 28% early during the pandemic and a good correlation was observed between RBD and spike-based ELISAs. Modest correlations were observed between NP and both RBD and spike-based assays. The antibody levels in HCWs declined over time; however, the overall seroprevalence measured by RBD and spike-based assays remained unchanged, while the seroprevalence of NP-reactive antibodies significantly declined. Moreover, RBD and spike-based assays effectively detected seroconversion in vaccinees. Overall, our results consolidate the strength of different serological assays to assess the magnitude and duration of antibodies to SARS-CoV-2. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3S0T656KV | ||||||||||||
| Subjects: | 1 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2115: Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomised, placebo-controlled, phase 1 trial | |||||||||
| Status: | Updated | ||||||||
| Description: | Background: Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It's being developed by public sector manufacturers in Thailand, Vietnam, and Brazil; herein are initial results from Thailand. Methods: This phase 1 stage of a randomised, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial was conducted at the Vaccine Trial Centre, Mahidol University (Bangkok). Healthy males and non-pregnant females, aged 18-59 years and negative for SARS-CoV-2 antibodies, were eligible. Participants were randomised to receive one of six treatments by intramuscular injection twice, 28 days apart: 1 ?g, 1 ?g+CpG1018 (a toll-like receptor 9 agonist), 3 ?g, 3 ?g+CpG1018, 10 ?g, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited and spontaneously reported adverse events (AEs) during 7 and 28 days after each vaccination, respectively. Secondary outcomes were immunogenicity measures (anti-S IgG and pseudotyped virus neutralisation). An interim analysis assessed safety at day 57 in treatment-exposed individuals and immunogenicity through day 43 per protocol. ClinicalTrials.gov (NCT04764422). Findings: Between March 20 and April 23, 2021, 377 individuals were screened and 210 were enroled (35 per group); all received dose one; five missed dose two. The most common solicited AEs among vaccinees, all predominantly mild, were injection site pain (<63%), fatigue (<35%), headache (<32%), and myalgia (<32%). The proportion reporting a vaccine-related AE ranged from 5?7% to 17?1% among vaccine groups and was 2?9% in controls; there was no vaccine-related serious adverse event. The 10 ?g formulation's immunogenicity ranked best, followed by 3 ?g+CpG1018, 3 ?g, 1 ?g+CpG1018, and 1 ?g formulations. On day 43, the geometric mean concentrations of 50% neutralising antibody ranged from 122?23 international units per mL (IU/mL; 1 ?g, 95% confidence interval (CI) 86?40-172?91) to 474?35 IU/mL (10 ?g, 95% CI 320?90-701?19), with 93?9% to 100% of vaccine groups attaining a ? 4-fold increase over baseline. Interpretation: NDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 ?g and 3 ?g+CpG1018 formulations advanced to phase 2 | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M301KI6WVE | ||||||||
| Subjects: | 6 | ||||||||
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| SDY2116: Inflammasome activation in infected macrophages drives COVID-19 pathology | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA, and sustained interferon (IFN) response all of which are recapitulated and required for pathology in the SARS-CoV-2 infected MISTRG6-hACE2 humanized mouse model of COVID-19 with a human immune system. Blocking either viral replication with Remdesivir or the downstream IFN stimulated cascade with anti-IFNAR2 in vivo in the chronic stages of disease attenuated the overactive immune-inflammatory response, especially inflammatory macrophages. Here, we show SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release IL-1 and IL-18 and undergo pyroptosis thereby contributing to the hyperinflammatory state of the lungs. Inflammasome activation and its accompanying inflammatory response is necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. Remarkably, this same blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Thus, inflammasomes oppose host infection by SARS-CoV-2 by production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle. | ||||||||||||
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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: | Updated | |||||||||
| Description: | Background: BNT162b2 was shown to be 92% effective in preventing COVID-19. Prioritizing vaccine rollout, and achievement of herd immunity depend on SARS-CoV-2 transmission reduction. The vaccine's effect on infectivity is thus a critical priority. Methods: Among all 9650 HCW of a large tertiary medical center in Israel, we calculated the prevalence of positive SARS-CoV-2 qRT-PCR cases with asymptomatic presentation, tested following known or presumed exposure and the infectious subset (N-gene-Ct-value<30) of these. Additionally, infection incidence rates were calculated for symptomatic cases and infectious (Ct<30) cases. Vaccine effectiveness within three months of vaccine rollout was measured as one minus the relative risk or rate ratio, respectively. To further assess infectiousness, we compared the mean Ct-value and the proportion of infections with a positive SARS-CoV-2 antigen test of vaccinated vs. unvaccinated. The correlation between IgG levels within the week before detection and Ct level was assessed. Findings: Reduced prevalence among fully vaccinated HCW was observed for (i) infections detected due to exposure, with asymptomatic presentation (VE(i)=65.1%, 95%CI 45-79%), (ii) the presumed infectious (Ct<30) subset of these (VE(ii)=69.6%, 95%CI 43-84%) (iii) never-symptomatic infections (VE(iii)=72.3%, 95%CI 48-86%), and (iv) the presumed infectious (Ct<30) subset (VE(iv)=83.0%, 95%CI 51-94%).Incidence of (v) symptomatic and (vi) symptomatic-infectious cases was significantly lower among fully vaccinated vs. unvaccinated individuals (VE(v)= 89.7%, 95%CI 84-94%, VE(vi)=88.1%, 95%CI 80-95%).The mean Ct-value was significantly higher in vaccinated vs. unvaccinated (27.3?1.2 vs. 22.2?1.0, p<0.001) and the proportion of positive SARS-CoV-2 antigen tests was also significantly lower among vaccinated vs. unvaccinated PCR-positive HCW (80% vs. 31%, p<0.001). Lower infectivity was correlated with higher IgG concentrations (R=0.36, p=0.01). Interpretation: These results suggest that BNT162b2 is moderately to highly effective in reducing infectivity, via preventing infection and through reducing viral shedding. | |||||||||
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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: | Updated | ||||||||||
| Description: | Background: Despite the high efficacy of the BNT162b2 messenger RNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rare breakthrough infections have been reported, including infections among health care workers. Data are needed to characterize these infections and define correlates of breakthrough and infectivity. Methods: At the largest medical center in Israel, we identified breakthrough infections by performing extensive evaluations of health care workers who were symptomatic (including mild symptoms) or had known infection exposure. These evaluations included epidemiologic investigations, repeat reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays, antigen-detecting rapid diagnostic testing (Ag-RDT), serologic assays, and genomic sequencing. Correlates of breakthrough infection were assessed in a case-control analysis. We matched patients with breakthrough infection who had antibody titers obtained within a week before SARS-CoV-2 detection (peri-infection period) with four to five uninfected controls and used generalized estimating equations to predict the geometric mean titers among cases and controls and the ratio between the titers in the two groups. We also assessed the correlation between neutralizing antibody titers and N gene cycle threshold (Ct) values with respect to infectivity. Results: Among 1497 fully vaccinated health care workers for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented. Neutralizing antibody titers in case patients during the peri-infection period were lower than those in matched uninfected controls (case-to-control ratio, 0.361; 95% confidence interval, 0.165 to 0.787). Higher peri-infection neutralizing antibody titers were associated with lower infectivity (higher Ct values). Most breakthrough cases were mild or asymptomatic, although 19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha) variant was found in 85% of samples tested. A total of 74% of case patients had a high viral load (Ct value, <30) at some point during their infection; however, of these patients, only 17 (59%) had a positive result on concurrent Ag-RDT. No secondary infections were documented. Conclusions: Among fully vaccinated health care workers, the occurrence of breakthrough infections with SARS-CoV-2 was correlated with neutralizing antibody titers during the peri-infection period. Most breakthrough infections were mild or asymptomatic, although persistent symptoms did occur. | ||||||||||
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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: | Updated | |||||||||||||||
| Description: | Background: Solid organ transplant recipients (SOTRs) are at increased risk for severe COVID-19 and exhibit lower antibody responses to SARS-CoV-2 vaccines. This study aimed to determine if prevaccination cytokine levels are associated with antibody response to SARS-CoV-2 vaccination. Methods: A cross-sectional study was performed among 58 SOTRs before and after two-dose mRNA vaccine series, 35 additional SOTRs before and after a third vaccine dose, and comparison to 16 healthy controls (HCs). Antispike antibody was assessed using the IgG Euroimmun ELISA. Electrochemiluminescence detection-based multiplexed sandwich immunoassays (Meso Scale Diagnostics) were used to quantify plasma cytokine and chemokine concentrations (n = 20 analytes) and compare concentrations between SOTRs and HCs, stratified by ultimate antibody response to the vaccine using Wilcoxon-rank-sum test with false discovery rates computed to correct for multiple comparisons. Results: In the study population, 100% of HCs, 59% of SOTRs after 2 doses and 63% of SOTRs after 3 doses had a detectable antibody response. Multiple baseline cytokines were elevated in SOTRs versus HCs. There was no significant difference in baseline cytokine levels between SOTRs with high versus low-titer antibodies after 2 doses of vaccine. However, as compared with poor antibody responders, SOTRs who went on to develop a high-titer antibody response to a third dose of vaccine had significantly higher prethird dose levels of several innate immune cytokines including IL-17, IL-2Ra, IL-6, IP-10, MIP-1?, and TNF-? (false discovery rates < 0.05). Conclusions: A specific inflammatory profile may be associated with developing higher antibodies in response to a third dose of SARS-CoV-2 vaccine in SOTRs. | |||||||||||||||
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| DOI: | 10.21430/M3ERSVMISI | |||||||||||||||
| Subjects: | 3 | |||||||||||||||
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| SDY2121: CD4+ T cells from COVID-19 mRNA vaccine recipients recognize a conserved epitope present in diverse coronaviruses | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Recent studies have shown that vaccinated individuals harbor T cells that can cross-recognize SARS-CoV-2 and endemic human common cold coronaviruses. However, it is still unknown whether CD4+ T cells from vaccinated individuals recognize peptides from bat coronaviruses that may have the potential of causing future pandemics. In this study, we identified a SARS-CoV-2 spike protein epitope (S815-827) that is conserved in coronaviruses from different genera and subgenera, including SARS-CoV, MERS-CoV, multiple bat coronaviruses, and a feline coronavirus. Our results showed that S815-827 was recognized by 42% of vaccinated participants in our study who received the Pfizer-BioNTech (BNT162b2) or Moderna (mRNA-1273) COVID-19 vaccines. Using T cell expansion and T cell receptor sequencing assays, we demonstrated that S815-827-reactive CD4+ T cells from the majority of responders cross-recognized homologous peptides from at least 6 other diverse coronaviruses. Our results support the hypothesis that the current mRNA vaccines elicit T cell responses that can cross-recognize bat coronaviruses and thus might induce some protection against potential zoonotic outbreaks. Furthermore, our data provide important insights that inform the development of T cell?based pan-coronavirus vaccine strategies. | ||||||||||
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| DOI: | 10.21430/M3HBH1BBQV | ||||||||||
| Subjects: | 2 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2122: Neutralization of the SARS-CoV-2 Omicron BA.4/5 and BA.2.12.1 Subvariants | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Emerging subvariants of the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have reignited concern about further immune escape. Specifically, BA.2.12.1, which is on the rise in the United States, has two more mutations (L452Q and S704L) than BA.2 (Fig. S1A in the Supplementary Appendix, available with the full text of this letter at NEJM.org). In addition, BA.4 and BA.5 (hereafter, BA.4/5), which bear identical spike proteins, have become the dominant strains in South Africa. Here, we examine neutralizing-antibody titers in serum samples obtained from vaccinated persons who had received a single booster dose of the same vaccine used in the two-dose series and who had been previously infected with SARS-CoV-2. | ||||||||||||
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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: | Updated | ||||||||||||
| Description: | Background: The incidence of and risk factors for severe clinical outcomes with the Omicron (B.1.1.529) SARS-CoV-2 variant have not been well-defined. Methods: We conducted a retrospective cohort study to assess risks of severe clinical outcomes within 21 days after SARS-CoV-2 diagnosis in a large, diverse, integrated health system. Findings: Among 118,078 persons with incident SARS-CoV-2 infection, 48,101 (41%) were during the Omicron period and 69,977 (59%) during the Delta (B.1.617.2) period. Cumulative incidence of any hospitalization (2.4% versus 7.8%; adjusted hazard ratio [aHR] 0.55; 95% confidence interval [CI] (0.51-0.59), with low-flow oxygen support (1.6% versus 6.4%; aHR 0.46; CI 0.43-0.50), with high-flow oxygen support (0.6% versus 2.8%; aHR 0.47; CI 0.41-0.54), with invasive mechanical ventilation (0.1% versus 0.7%; aHR 0.43; CI 0.33-0.56), and death (0.2% versus 0.7%; aHR 0.54; CI 0.42-0.70) were lower in the Omicron than the Delta period. The risk of hospitalization was higher among unvaccinated persons (aHR 8.34; CI 7.25-9.60) and those who completed a primary COVID-19 vaccination series (aHR 1.72; CI 1.49-1.97) compared with those who completed a primary vaccination series and an additional dose. The strongest risk factors for all severe clinical outcomes were older age, higher body mass index and select comorbidities. Interpretation: Persons with SARS-CoV-2 infection were significantly less likely to develop severe clinical outcomes during the Omicron period compared with the Delta period. COVID-19 primary vaccination and additional doses were associated with reduced risk of severe clinical outcomes among those with SARS-CoV-2 infection. | ||||||||||||
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| DOI: | 10.21430/M3FXU7B7MZ | ||||||||||||
| Subjects: | 2 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2125: Production of the Receptor-binding Domain of the Viral Spike Proteins from 2003 and 2019 SARS CoVs and the Four Common Human Coronaviruses for Serologic Assays and Inhibitor Screening | ||||||||||
| Status: | Updated | |||||||||
| Description: | The recombinant receptor-binding domain (RBD) of the viral spike protein from SARS-CoV-1 and 2 are reliable antigens for detecting viral-specific antibodies in humans. We and others have shown that the levels of RBD-binding antibodies and SARS-CoV-2 neutralizing antibodies in patients are correlated. Here, we report the expression and purification of properly folded RBD proteins from SARS and common-cold HCoVs in mammalian cells. RBD proteins were produced with cleavable tags for affinity purification from the cell culture medium and to support multiple immunoassay platforms and drug discovery efforts. Graphic abstract: High-Yield Production of Viral Spike RBDs for Diagnostics and Drug Discovery | |||||||||
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| DOI: | 10.21430/M3310R6FVA | |||||||||
| Subjects: | 1 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2126: SARS-CoV-2 mRNA vaccine induces robust specific and cross-reactive IgG and unequal neutralizing antibodies in naive and previously infected people | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Understanding vaccine-mediated protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is critical to overcoming the global coronavirus disease 2019 (COVID-19) pandemic. We investigate mRNA-vaccine-induced antibody responses against the reference strain, seven variants, and seasonal coronaviruses in 168 healthy individuals at three time points: before vaccination, after the first dose, and after the second dose. Following complete vaccination, both naive and previously infected individuals developed comparably robust SARS-CoV-2 spike antibodies and variable levels of cross-reactive antibodies to seasonal coronaviruses. However, the strength and frequency of SARS-CoV-2 neutralizing antibodies in naive individuals were lower than in previously infected individuals. After the first vaccine dose, one-third of previously infected individuals lacked neutralizing antibodies; this was improved to one-fifth after the second dose. In all individuals, neutralizing antibody responses against the Alpha and Delta variants were weaker than against the reference strain. Our findings support future tailored vaccination strategies against emerging SARS-CoV-2 variants as mRNA-vaccine-induced neutralizing antibodies are highly variable among individuals. | ||||||||||||
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| DOI: | 10.21430/M3NGLEV4KG | ||||||||||||
| Subjects: | 1 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2127: Immunological memory to common cold coronaviruses assessed longitudinally over a three-year period pre-COVID19 pandemic | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | The immune memory to common cold coronaviruses (CCCs) influences SARS-CoV-2 infection outcome, and understanding its effect is crucial for pan-coronavirus vaccine development. We performed a longitudinal analysis of pre-COVID19-pandemic samples from 2016-2019 in young adults and assessed CCC-specific CD4+ T cell and antibody responses. Notably, CCC responses were commonly detected with comparable frequencies as with other common antigens and were sustained over time. CCC-specific CD4+ T cell responses were associated with low HLA-DR+CD38+ signals, and their magnitude did not correlate with yearly CCC infection prevalence. Similarly, CCC-specific and spike RBD-specific IgG responses were stable in time. Finally, high CCC-specific CD4+ T cell reactivity, but not antibody titers, was associated with pre-existing SARS-CoV-2 immunity. These results provide a valuable reference for understanding the immune response to endemic coronaviruses and suggest that steady and sustained CCC responses are likely from a stable pool of memory CD4+ T cells due to repeated earlier exposures and possibly occasional reinfections. | ||||||||||||
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| DOI: | 10.21430/M3X6ZK6H5X | ||||||||||||
| Subjects: | 1 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2129: Integrated plasma proteomic and single-cell immune signaling network signatures demarcate mild, moderate, and severe COVID-19 | |||||||||
| Status: | Updated | ||||||||
| Description: | The biological determinants underlying the range of coronavirus 2019 (COVID-19) clinical manifestations are not fully understood. Here, over 1,400 plasma proteins and 2,600 single-cell immune features comprising cell phenotype, endogenous signaling activity, and signaling responses to inflammatory ligands are cross-sectionally assessed in peripheral blood from 97 patients with mild, moderate, and severe COVID-19 and 40 uninfected patients. Using an integrated computational approach to analyze the combined plasma and single-cell proteomic data, we identify and independently validate a multi-variate model classifying COVID-19 severity (multi-class area under the curve [AUC]training = 0.799, p = 4.2e-6; multi-class AUCvalidation = 0.773, p = 7.7e-6). Examination of informative model features reveals biological signatures of COVID-19 severity, including the dysregulation of JAK/STAT, MAPK/mTOR, and nuclear factor ?B (NF-?B) immune signaling networks in addition to recapitulating known hallmarks of COVID-19. These results provide a set of early determinants of COVID-19 severity that may point to therapeutic targets for prevention and/or treatment of COVID-19 progression. | ||||||||
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| DOI: | 10.21430/M32UYJZ33S | ||||||||
| Subjects: | 4 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY2130: Identifying and Alleviating Bias Due to Differential Depletion of Susceptible People in Postmarketing Evaluations of COVID-19 Vaccines | |||||||
| Status: | Updated | ||||||
| Description: | Recent studies have provided key information about SARS-CoV-2 vaccines' efficacy and effectiveness (VE). One important question that remains is whether the protection conferred by vaccines wanes over time. However, estimates over time are subject to bias from differential depletion of susceptible individuals between vaccinated and unvaccinated groups. We examined the extent to which biases occur under different scenarios and assessed whether serological testing has the potential to correct this bias. By identifying nonvaccine antibodies, these tests could identify individuals with prior infection. We found that in scenarios with high baseline VE, differential depletion of susceptible individuals created minimal bias in VE estimates, suggesting that any observed declines are likely not due to spurious waning alone. However, if baseline VE was lower, the bias for leaky vaccines (which reduce individual probability of infection given contact) was larger and should be corrected for by excluding individuals with past infection if the mechanism is known to be leaky. Conducting analyses both unadjusted and adjusted for past infection could give lower and upper bounds for the true VE. Studies of VE should therefore enroll individuals regardless of prior infection history but also collect information, ideally through serological testing, on this critical variable. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3A6AINWX6 | ||||||
| Subjects: | 1 | ||||||
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| SDY2131: The molecular epidemiology of multiple zoonotic origins of SARS-CoV-2 | |||||||
| Status: | Updated | ||||||
| Description: | Understanding the circumstances that lead to pandemics is important for their prevention. Here, we analyze the genomic diversity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) early in the coronavirus disease 2019 (COVID-19) pandemic. We show that SARS-CoV-2 genomic diversity before February 2020 likely comprised only two distinct viral lineages, denoted A and B. Phylodynamic rooting methods, coupled with epidemic simulations, reveal that these lineages were the result of at least two separate cross-species transmission events into humans. The first zoonotic transmission likely involved lineage B viruses around 18 November 2019 (23 October-8 December), while the separate introduction of lineage A likely occurred within weeks of this event. These findings indicate that it is unlikely that SARS-CoV-2 circulated widely in humans prior to November 2019 and define the narrow window between when SARS-CoV-2 first jumped into humans and when the first cases of COVID-19 were reported. As with other coronaviruses, SARS-CoV-2 emergence likely resulted from multiple zoonotic events. | ||||||
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| DOI: | 10.21430/M3OF1XHUND | ||||||
| Subjects: | 1 | ||||||
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| SDY2132: The Huanan Seafood Wholesale Market in Wuhan was the early epicenter of the COVID-19 pandemic | |||||||
| Status: | Updated | ||||||
| Description: | Understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 is critical to preventing zoonotic outbreaks before they become the next pandemic. The Huanan Seafood Wholesale Market in Wuhan, China, was identified as a likely source of cases in early reports but later this conclusion became controversial. We show the earliest known COVID-19 cases from December 2019, including those without reported direct links, were geographically centered on this market. We report that live SARS-CoV-2 susceptible mammals were sold at the market in late 2019 and, within the market, SARS-CoV-2-positive environmental samples were spatially associated with vendors selling live mammals. While there is insufficient evidence to define upstream events, and exact circumstances remain obscure, our analyses indicate that the emergence of SARS-CoV-2 occurred via the live wildlife trade in China, and show that the Huanan market was the epicenter of the COVID-19 pandemic. | ||||||
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| DOI: | 10.21430/M3LANTY5MI | ||||||
| Subjects: | 1 | ||||||
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| SDY2133: Longitudinal metabolomics of human plasma reveals prognostic markers of COVID-19 disease severity | ||||||||||
| Status: | Updated | |||||||||
| Description: | There is an urgent need to identify which COVID-19 patients will develop life-threatening illness so that med- ical resources can be optimally allocated and rapid treatment can be administered early in the disease course, when clinical management is most effective. To aid in the prognostic classification of disease severity, we perform untargeted metabolomics on plasma from 339 patients, with samples collected at six longitudinal time points. Using the temporal metabolic profiles and machine learning, we build a predictive model of disease severity. We discover that a panel of metabolites measured at the time of study entry suc- cessfully determines disease severity. Through analysis of longitudinal samples, we confirm that most of these markers are directly related to disease progression and that their levels return to baseline upon disease recovery. Finally, we validate that these metabolites are also altered in a hamster model of COVID-19. | |||||||||
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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: | Updated | ||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-?, IFN-?, and/or IFN-? are found in ~20% of deceased patients across age groups, and in ~1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-?2 or IFN-?, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ?70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ?80 y old for autoantibodies neutralizing IFN-?2 or IFN-?, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-?2 and IFN-?. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death. | ||||||
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| DOI: | 10.21430/M32LEYGFC5 | ||||||
| Subjects: | 2 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2135: Infectious disease dynamics and restrictions on social gathering size | |||||||
| Status: | Updated | ||||||
| Description: | Social gatherings can be an important locus of transmission for many pathogens including SARS-CoV-2. During an outbreak, restricting the size of these gatherings is one of several non-pharmaceutical interventions available to policy-makers to reduce transmission. Often these restrictions take the form of prohibitions on gatherings above a certain size. While it is generally agreed that such restrictions reduce contacts, the specific size threshold separating ""allowed"" from ""prohibited"" gatherings often does not have a clear scientific basis, which leads to dramatic differences in guidance across location and time. Building on the observation that gathering size distributions are often heavy-tailed, we develop a theoretical model of transmission during gatherings and their contribution to general disease dynamics. We find that a key, but often overlooked, determinant of the optimal threshold is the distribution of gathering sizes. Using data on pre-pandemic contact patterns from several sources as well as empirical estimates of transmission parameters for SARS-CoV-2, we apply our model to better understand the relationship between restriction threshold and reduction in cases. We find that, under reasonable transmission parameter ranges, restrictions may have to be set quite low to have any demonstrable effect on cases due to relative frequency of smaller gatherings. We compare our conceptual model with observed changes in reported contacts during lockdown in March of 2020 | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3N4SFTBH9 | ||||||
| Subjects: | 1 | ||||||
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| SDY2141: Household Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 in the United States: Living Density, Viral Load, and Disproportionate Impact on Communities of Color | ||||||||||
| Status: | Updated | |||||||||
| Description: | Background: Households are hot spots for severe acute respiratory syndrome coronavirus 2 transmission. Methods: This prospective study enrolled 100 coronavirus disease 2019 (COVID-19) cases and 208 of their household members in North Carolina though October 2020, including 44% who identified as Hispanic or non-White. Households were enrolled a median of 6 days from symptom onset in the index case. Incident secondary cases within the household were detected using quantitative polymerase chain reaction of weekly nasal swabs (days 7, 14, 21) or by seroconversion at day 28. Results: Excluding 73 household contacts who were PCR-positive at baseline, the secondary attack rate (SAR) among household contacts was 32% (33 of 103; 95% confidence interval [CI], 22%-44%). The majority of cases occurred by day 7, with later cases confirmed as household-acquired by viral sequencing. Infected persons in the same household had similar nasopharyngeal viral loads (intraclass correlation coefficient = 0.45; 95% CI, .23-.62). Households with secondary transmission had index cases with a median viral load that was 1.4 log10 higher than those without transmission (P = .03), as well as higher living density (more than 3 persons occupying fewer than 6 rooms; odds ratio, 3.3; 95% CI, 1.02-10.9). Minority households were more likely to experience high living density and had a higher risk of incident infection than did White households (SAR, 51% vs 19%; P = .01). Conclusions: Household crowding in the context of high-inoculum infections may amplify the spread of COVID-19, potentially contributing to disproportionate impact on communities of color. | |||||||||
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| DOI: | 10.21430/M31ZDULPAH | |||||||||
| Subjects: | 2 | |||||||||
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