DR45 DataRelease
Release Date: 09/03/2022
| SDY1669: Mild and severe COVID-19 | |||||||||||||||
| Status: | New | ||||||||||||||
| Description: | We analyzed immune responses in 76 COVID-19 patients and 69 healthy individuals from Hong Kong and Atlanta, Georgia, United States. | ||||||||||||||
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| DOI: | 10.21430/M3SBPTFZSN | ||||||||||||||
| Subjects: | 201 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
| SDY1752: Quantitative chest CT combined with plasma cytokines predicts outcomes in COVID-19 patients | ||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||
| Description: | 152 patients with a positive PCR for COVID-19, complete plasma cytokine assessment, and a chest-CT upon 5 days from hospital admission were included. Demographics, clinical and laboratory variables, including plasma cytokines (IL-6, IL-8, and TNF-a) were collected. CT qualitative score for each patient, based on the degree of involvement of the five pulmonary lobes (score from 0 to 20), was obtained by two independent radiologists. CT quantitative analysis was performed using a segmentation open-software, supervised by one reader, to calculate the total lung volume (ml), well aerated lung volume (ml), ground-glass opacities (GGO) volume (ml), consolidation volume (ml), and GGO/well aerated lung ratio. The primary endpoints were survival and maximum severity degree according to the WHO scale). A elastic net regression was used to build five models (cytokines, CT qualitative, CT quantitative, combined and optimized models) to predict outcomes after cross-fold validation. Model performance was evaluated using a receiving operating characteristic (ROC) analysis. Interobserver agreement between different CT methods was also calculated using the intraclass correlation coefficient (ICC). | |||||||||||||||||||||
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| DOI: | 10.21430/M3ZK51U9TH | |||||||||||||||||||||
| Subjects: | 152 | |||||||||||||||||||||
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| Assays: | None | |||||||||||||||||||||
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| SDY1903: A Trial of Mepolizumab Adjunctive Therapy for the Prevention of Asthma Exacerbations in Urban Children (ICAC-30) | ||||||||||
| Status: | New | |||||||||
| Description: | Asthma is a growing problem, especially in children. It causes frequent wheezing, shortness of breath, chest tightness, and cough. Asthma attacks, or exacerbations, are problems for children with asthma. The purpose of this study is to see if treatment with a medication called mepolizumab (Nucala?), given along with standard asthma care, makes children less likely to have asthma attacks. Mepolizumab is a new drug that is approved by the Food and Drug Administration (FDA) for use in children with asthma who are aged 12 years and older. Mepolizumab is given by injection. It is being studied by other researchers in children aged 6-11 years. All participants will be prescribed standard asthma medications by a clinician who is trained in asthma care. Medications will include controller medications, a rescue medication, and a medication for severe asthma attacks (prednisone). The amount of medication that participants receive may be increased or decreased during the study based on their symptoms and breathing test results. Study clinicians will treat all participants according to the same guidelines. These treatment guidelines are based on recommendations from a group of national experts in asthma. This study has been designed this way so that all participants will have safe and effective standard asthma care. In order to enroll in this study, participants must be willing to have their asthma managed by the study clinician during the entire study period. Participants must also be willing to bring study medications to all study visits. This study will include up to 20 study visits. Participant involvement in the study will endure for approximately 1 year. During the treatment period, participants will be placed in one of two treatment groups: Mepolizumab injection and guidelines-based asthma care or Placebo injection and guidelines-based asthma care. Participants will not be able to choose which group they are assigned. This assignment is random and by chance, much like flipping a coin. Participants will not know if they are receiving mepolizumab or placebo. Investigators will compare the study results between the participants of each group. | |||||||||
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| DOI: | 10.21430/M3OX86B062 | |||||||||
| Subjects: | 589 | |||||||||
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| SDY1961: Age-related signs of immunosenescence correlate with 3 poor outcome of mRNA COVID-19 vaccination in older 4 adults | |||||||
| Status: | New | ||||||
| Description: | Analysis of the SARS-CoV-2 Spike-specific B and T cell responses in unexposed subjects of various ages, receiving two doses of the BNT162b2 mRNA vaccine and compared with those of age-matched subjects who experienced a mild or asymptomatic 53 SARS-CoV-2 infection. | ||||||
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| DOI: | 10.21430/M3OY06EALQ | ||||||
| Subjects: | 115 | ||||||
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| Publications: | None | ||||||
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| SDY1968: Metabolomic and transcriptomic signatures of influenza vaccine response in healthy young and older adults | ||||||||||
| Status: | New | |||||||||
| Description: | Seasonal epidemics caused by influenza viruses are a major public health concern that result in mild to severe respiratory infections in humans. There is significant morbidity and mortality associated with influenza, particularly among adults aged 65 or older. While three types of effective vaccines (inactivated, live attenuated, and recombinant hemagglutinin antigen (HA) vaccines) have been developed to help improve health outcomes, vaccine response remains poor, particularly in older populations. In this study, we use a combination of transcriptomics and untargeted metabolomics to define signatures of high and low antibody response after vaccination against influenza in a cohort of young and older adults. Through this multi-omics approach, we identify age-related molecular markers associated with influenza vaccine response. Uncovering these molecular profiles will help to identify populations at risk of influenza vaccine failure, as well as to inform design of vaccine development trials to improve vaccine efficacy. | |||||||||
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| DOI: | 10.21430/M320NKDIF3 | |||||||||
| Subjects: | 39 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY1991: Role of Transcriptomics of Acute DENV-Specific CD8+ T Cells in Disease Severity | |||||||||||||
| Status: | New | ||||||||||||
| Description: | To improve the understanding of the relative part of adaptive immunity in disease protection and immunopathology, CD3+CD8+ T-cells were isolated from the peripheral blood of patients hospitalized with either dengue fever (DF) or the more severe dengue hemorrhagic fever (DHF). Samples were taken at the time of admission and discharge and the transcriptomic profiles were determined by RNA sequencing to determine differences correlating with disease severity. | ||||||||||||
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| DOI: | 10.21430/M3ZQI9UOHM | ||||||||||||
| Subjects: | 40 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY1995: Association of CD4+ CD8+ T cells with risk of plasma leakage in Dengue disease | |||||||||||||
| Status: | New | ||||||||||||
| Description: | This study provided novel insight into the host immune response during the acute febrile phase of DENV infection and the role of CD4+CD8+ DP T cells in the pathogenesis of plasma leakage using transcriptome analysis. The frequency of CD4+CD8+ double-positive (DP) T cells was significantly increased in patients at risk of developing plasma leakage. Transcriptomic analysis demonstrated that CD4+CD8+ DP cells co-clustered with CD8+ SP cells, and showed a similar expression profile in patients with and without warning signs of plasma leakage, implying a role of CD4+CD8+ DP cells in plasma leakage through a quantitative increase rather than functional alteration. | ||||||||||||
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| DOI: | 10.21430/M3MK2K78L8 | ||||||||||||
| Subjects: | 86 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2007: CMV Plasma Proteomics in Kidney Transplant | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Cytomegalovirus (CMV) infection is a frequent infectious complication in an immunocompromised host, as is the case in an organ transplant recipient who faces life-long immunosuppression. CMV infection can occur either from reactivation of recipient or donor CMV or de novo infection in the recipient after transplantation. The clinical spectrum ranges from asymptomatic to systemic infection and end-organ disease with pneumonitis, meningitis, esophagitis, and colitis. Furthermore, CMV infection also results in an increased host susceptibility to secondary infections and increased alloimmunity, leading to acute and chronic allograft rejection. Evaluation of peripheral mRNA changes from clinical and sub-clinical CMV primary infection and reactivation has provided insight into causal factors for allograft dysfunction secondary to CMV, host biological pathways actively altered by the virus, and the dynamic temporal changes of cell cycle, DNA damage molecules8-12 that occur during the evolution of CMV viral replication. Mass spectrometry-based proteomics of human serum and plasma has been used for identifying markers for disease diagnosis, and for the study of viral infections such as influenza, COVID-19, and HIV. Characterizing the host response to CMV infection will allow for an increased understanding biological events associated with CMV infection severity and will also provide insights into the negative impact of CMV infection on the transplanted organ. CMV infection drives alloimmune injury of the engrafted organ through heterologous immunity in an organ transplant recipient and is an important confounder for higher rates of graft failure after kidney transplantation. to address these key questions, we have utilized a highly characterized, propensity-matched cohort of kidney transplant patients with and without post-transplant CMV DNAemia, with serially collected samples at 3 months (pre-CMV infection) and 12 months post-transplant (post-CMV infection), as well as immediate post-CMV time points at 1 week and 1 month post CMV DNAemia and also utilized preexisting transcriptomic data on time-matching PBMCs from the same cohort. | ||||||||||||
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| DOI: | 10.21430/M3B9CZCVUX | ||||||||||||
| Subjects: | 62 | ||||||||||||
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| Publications: | None | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2012: Longitudinal COVID-19-vaccination-induced antibody responses and Omicron neutralization in patients with lung cancer | |||||||||||||
| Status: | New | ||||||||||||
| 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 | ||||||||||||
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| DOI: | 10.21430/M3B4HT6SZU | ||||||||||||
| Subjects: | 5 | ||||||||||||
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| SDY2015: Mass cytometry analysis of PBMCs from peanut-sensitized tolerant and clinically allergic infants | ||||||||||||||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||||||||||||||
| Description: | Not all individuals who produce peanut-specific IgE will react upon consumption of peanut. Infants with detectable peanut sIgE who can eat the food without adverse consequences are referred to as peanut sensitized tolerant (PST). Understanding the immune mechanisms that govern why some individuals go on to develop clinical peanut allergy (PA), whilst others do not, despite the presence of peanut-specific IgE, is central in diagnostic, prevention and early management strategies. This study used mass cytometry-based immune profiling to define the circulating immune cell signatures associated with PST vs. PA vs. non allergic healthy controls (NA) in the first year of life. Resting PBMCs and PBMCs after stimulation with endotoxin-free pure peanut solution or PMA/ionomycin were studied. A sub group of infants from the HealthNuts cohort (total n=5000 children) were used in this study. PA infants (n=12) were defined as having a peanut skin prick test (SPT) wheal diameter of ?2mm or a peanut-specific IgE level of ?0.35 kUA/L, and an unequivocal objective allergic reaction during peanut OFC at age 1 year. PST infants (n=12) had a peanut SPT?2 mm and peanut-specific IgE level of ?0.35 kUA/L and a negative peanut OFC at age 1 year. The NA group infants (n=12) were non-sensitized and non-allergic, with a negative SPT to peanut, egg, sesame, and cow?s milk together with a negative peanut OFC outcome at age 1 year. | |||||||||||||||||||||||||||||||||
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| DOI: | 10.21430/M3VPY49EGU | |||||||||||||||||||||||||||||||||
| Subjects: | 36 | |||||||||||||||||||||||||||||||||
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| SDY2016: The effect of secretor status and the vaginal microbiome on birth outcome | |||||||
| Status: | New | ||||||
| Description: | Mutations in the FUT2 gene that result in a lack of expression of histo-blood group antigens on secreted glycoproteins may shape the vaginal microbiota with consequences for birth outcome. To test this, we analysed the relationship between secretor status, vaginal microbiota and gestational length in an ethnically diverse cohort of 313 pregnant women, including 91 who delivered prematurely. Lactobacillus species were found to co-occur less often with other microbial taxa in non-secretors. Moreover, non-secretors with Lactobacillus spp. depleted vaginal microbiota in early pregnancy had significantly shorter gestational length than Lactobacillus spp. dominated non-secretors (mean of 245.5 (SD=44.5) versus 265.9 (23.6)); p=0.045), but not compared to Lactobacillus spp. dominated (261.8 (27.5)) and depleted (264.3 days (21.2)) secretors. In identifying a relationship between blood-group antigen expression and vaginal microbiota-host interactions, our results point towards stratification by secretor status as an important factor for considering preterm birth risk and prevention. | ||||||
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| DOI: | 10.21430/M3GBS3IQLC | ||||||
| Subjects: | 313 | ||||||
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| Publications: | None | ||||||
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| SDY2024: Durability and Cross-Reactivity of SARS-CoV-2 mRNA Vaccine in Adolescent Children | |||||||||
| Status: | New | ||||||||
| 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. | ||||||||
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| DOI: | 10.21430/M31M7VL89N | ||||||||
| Subjects: | 1 | ||||||||
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| SDY2026: SARS-CoV-2 transmission and impacts of unvaccinated-only screening in populations of mixed vaccination status | ||||||||||
| Status: | New | |||||||||
| Description: | Screening programs that test only the unvaccinated population have been proposed and implemented to mitigate SARS-CoV-2 spread, implicitly assuming that the unvaccinated population drives transmission. To evaluate this premise and quantify the impact of unvaccinated-only screening programs, we introduce a model for SARS-CoV-2 transmission through which we explore a range of transmission rates, vaccine effectiveness scenarios, rates of prior infection, and screening programs. We find that, as vaccination rates increase, the proportion of transmission driven by the unvaccinated population decreases, such that most community spread is driven by vaccine-breakthrough infections once vaccine coverage exceeds 55% (omicron) or 80% (delta), points which shift lower as vaccine effectiveness wanes. Thus, we show that as vaccination rates increase, the transmission reductions associated with unvaccinated-only screening decline, identifying three distinct categories of impact on infections and hospitalizations. More broadly, these results demonstrate that effective unvaccinated-only screening depends on population immunity, vaccination rates, and variant. | |||||||||
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| DOI: | 10.21430/M3T90LW0CA | |||||||||
| Subjects: | 2 | |||||||||
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| SDY2033: Vaccine protection against the SARS-CoV-2 Omicron variant in macaques | |||||||||||||||
| Status: | New | ||||||||||||||
| Description: | The rapid spread of the SARS-CoV-2 Omicron (B.1.1.529) variant, including in highly vaccinated populations, has raised important questions about the efficacy of current vaccines. In this study, we show that the mRNA-based BNT162b2 vaccine and the adenovirus-vector-based Ad26.COV2.S vaccine provide robust protection against high-dose challenge with the SARS-CoV-2 Omicron variant in cynomolgus macaques. We vaccinated 30 macaques with homologous and heterologous prime-boost regimens with BNT162b2 and Ad26.COV2.S. Following Omicron challenge, vaccinated macaques demonstrated rapid control of virus in bronchoalveolar lavage, and most vaccinated animals also controlled virus in nasal swabs. However, 4 vaccinated animals that had moderate Omicron-neutralizing antibody titers and undetectable Omicron CD8+ T cell responses failed to control virus in the upper respiratory tract. Moreover, virologic control correlated with both antibody and T cell responses. These data suggest that both humoral and cellular immune responses contribute to vaccine protection against a highly mutated SARS-CoV-2 variant. | ||||||||||||||
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| DOI: | 10.21430/M36QZ9VXR6 | ||||||||||||||
| Subjects: | 5 | ||||||||||||||
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| SDY2034: mRNA-1273 and BNT162b2 COVID-19 vaccines elicit antibodies with differences in Fc-mediated effector functions | |||||||||||
| Status: | New | ||||||||||
| 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. | ||||||||||
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| DOI: | 10.21430/M3KWASU913 | ||||||||||
| Subjects: | 3 | ||||||||||
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| SDY2035: SARS-CoV-2 antibodies protect against reinfection for at least 6 months in a multicentre seroepidemiological workplace cohort | |||||||
| Status: | New | ||||||
| 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. | ||||||
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| DOI: | 10.21430/M3AJI51QL1 | ||||||
| Subjects: | 1 | ||||||
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| SDY2036: Durability of Anti-Spike Antibodies in Infants After Maternal COVID-19 Vaccination or Natural Infection | ||||||||||
| Status: | New | |||||||||
| 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. | |||||||||
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| DOI: | 10.21430/M3CK1F3HPK | |||||||||
| Subjects: | 2 | |||||||||
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| SDY2037: Passive transfer of Ad26.COV2.S-elicited IgG from humans attenuates SARS-CoV-2 disease in hamsters | |||||||
| Status: | New | ||||||
| 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. | ||||||
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| DOI: | 10.21430/M3IX6DB4Q8 | ||||||
| Subjects: | 12 | ||||||
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| SDY2038: Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity | |||||||||||||
| Status: | New | ||||||||||||
| 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. | ||||||||||||
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| DOI: | 10.21430/M3V1ZYUVBN | ||||||||||||
| Subjects: | 9 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: |
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| SDY2039: Antibodies elicited by SARS-CoV-2 infection or mRNA vaccines have reduced neutralizing activity against Beta and Omicron pseudoviruses | ||||||||||
| Status: | New | |||||||||
| 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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| Clinical Assessments: |
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| SDY2040: Durable Humoral and Cellular Immune Responses 8 Months after Ad26.COV2.S Vaccination | |||||||||
| Status: | New | ||||||||
| 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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| SDY2041: Immunogenicity of Ad26.COV2.S vaccine against SARS-CoV-2 variants in humans | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | The Ad26.COV2.S vaccine1-3 has demonstrated clinical efficacy against symptomatic COVID-19, including against the B.1.351 variant that is partially resistant to neutralizing antibodies1. However, the immunogenicity of this vaccine in humans against SARS-CoV-2 variants of concern remains unclear. Here we report humoral and cellular immune responses from 20 Ad26.COV2.S vaccinated individuals from the COV1001 phase I-IIa clinical trial2 against the original SARS-CoV-2 strain WA1/2020 as well as against the B.1.1.7, CAL.20C, P.1 and B.1.351 variants of concern. Ad26.COV2.S induced median pseudovirus neutralizing antibody titres that were 5.0-fold and 3.3-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020 on day 71 after vaccination. Median binding antibody titres were 2.9-fold and 2.7-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020. Antibody-dependent cellular phagocytosis, complement deposition and natural killer cell activation responses were largely preserved against the B.1.351 variant. CD8 and CD4 T cell responses, including central and effector memory responses, were comparable among the WA1/2020, B.1.1.7, B.1.351, P.1 and CAL.20C variants. These data show that neutralizing antibody responses induced by Ad26.COV2.S were reduced against the B.1.351 and P.1 variants, but functional non-neutralizing antibody responses and T cell responses were largely preserved against SARS-CoV-2 variants. These findings have implications for vaccine protection against SARS-CoV-2 variants of concern. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3RLFPEUYM | ||||||||||||||||||
| Subjects: | 5 | ||||||||||||||||||
| Study PI, contact: |
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| SDY2042: Omicron variant Spike-specific antibody binding and Fc activity are preserved in recipients of mRNA or inactivated COVID-19 vaccines | ||||||||||
| Status: | New | |||||||||
| 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 | |||||||||
| Study PI, contact: |
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| Publications: |
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| Clinical Assessments: |
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| SDY2043: One-Stop Serum Assay Identifies COVID-19 Disease Severity and Vaccination Responses | |||||||
| Status: | New | ||||||
| Description: | We developed a multiplex immunoassay from serum/plasma of acutely infected and convalescent COVID-19 patients and prepandemic and postpandemic healthy adults. We measured IgA, IgG, and/or IgM against SARS-CoV-2 nucleocapsid (N), spike domain 1 (S1), S1-receptor binding domain (RBD) and S1-N-terminal domain. For diagnosis, the combined [IgA + IgG + IgM] or IgG levels measured for N, S1, and S1-RBD yielded area under the curve values ?0.90. Virus-specific Ig levels were higher in patients with severe/critical compared with mild/moderate infections. A strong prozone effect was observed in sera from severe/critical patients-a possible source of underestimated Ab concentrations in previous studies. Mild/moderate patients displayed a slower rise and lower peak in anti-N and anti-S1 IgG levels compared with severe/critical patients, but anti-RBD IgG and neutralization responses reached similar levels at 2-4 mo after symptom onset. Measurement of the Ab responses in sera from 18 COVID-19-vaccinated patients revealed specific responses for the S1-RBD Ag and none against the N protein. This highly sensitive, SARS-CoV-2-specific, multiplex immunoassay measures the magnitude, complexity, and kinetics of the Ab response and can distinguish serum Ab responses from natural SARS-CoV-2 infections (mild or severe) and mRNA COVID-19 vaccines. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3FRD03J1F | ||||||
| Subjects: | 5 | ||||||
| Study PI, contact: |
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| Publications: |
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| Clinical Assessments: |
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| 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: | New | |||||||||
| 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 | |||||||||
| Study PI, contact: |
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| Publications: |
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| Clinical Assessments: |
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| SDY2045: Maternal immune response and placental antibody transfer after COVID-19 vaccination across trimester and platforms | |||||||||||
| Status: | New | ||||||||||
| Description: | Here, we characterize the antibody profile after Ad26.COV2.S, mRNA-1273 or BNT162b2 vaccination in 158 pregnant individuals and evaluate transplacental antibody transfer by profiling maternal and umbilical cord blood in 175 maternal-neonatal dyads. These analyses reveal lower vaccine-induced functions and Fc receptor-binding after Ad26.COV2.S compared to mRNA vaccination and subtle advantages in titer and function with mRNA-1273 versus BN162b2. mRNA vaccines have higher titers and functions against SARS-CoV-2 variants of concern. First and third trimester vaccination results in enhanced maternal antibody-dependent NK-cell activation, cellular and neutrophil phagocytosis, and complement deposition relative to second trimester. Higher transplacental transfer ratios following first and second trimester vaccination may reflect placental compensation for waning maternal titers. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3JP0UEVB0 | ||||||||||
| Subjects: | 5 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Clinical Assessments: |
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| SDY2047: Protective efficacy of rhesus adenovirus COVID-19 vaccines against mouse-adapted SARS-CoV-2 | |||||||||||||
| Status: | New | ||||||||||||
| 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 | ||||||||||||
| 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 | ||||||||||||
| SDY2052: Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19 | |||||||||||
| Status: | New | ||||||||||
| 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 | ||||||||||
| 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 | ||||||||||
| SDY2053: Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination | |||||||||||||
| Status: | New | ||||||||||||
| 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 | ||||||||||||
| Study PI, contact: |
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| Publications: |
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| SDY67: Bioinformatics Approach to 2010-2011 TIV Influenza A/H1N1 Vaccine Immune Profiling | |||||||||||||||||||||||||
| Status: | Updated | ||||||||||||||||||||||||
| Description: | Aim 1: Characterize Immune Profiles Over Time, Aim 2: Correlate Immune Profiles with Vaccine Immunogenicity,Aim 3: Replication of Immune Profiles and Verification of Models | ||||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3OYWCJHO1 | ||||||||||||||||||||||||
| Subjects: | 159 | ||||||||||||||||||||||||
| 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 | ||||||||||||||||||||||||
| SDY1644: Urban Environmental Factors and Childhood Asthma (URECA) (ICAC-07) | |||||||||||||||||||||||
| Status: | Updated | ||||||||||||||||||||||
| Description: | The purpose of this study is to determine the way environmental factors (like the components of inner-city household dust) affect immune system development and symptoms of asthma in inner city children. The study is divided into three periods, as the subjects age from birth to 10 years old. Each age bracket will explore different objectives and endpoints. Study Objectives/Hypotheses: Subjects age 0 to 3 years old: Environmental factors in the inner city adversely influence the development of the immune system to promote cytokine dysregulation, allergy, and recurrent wheezing by age 3. Children who have had a viral lower respiratory infection and have developed cytokine dysregulation by age 3 are at increased risk for the development of asthma by age 6. Subjects age 4 to 7 years old: There is a unique pattern of immune development that is driven by specific urban exposures in early life, and this pattern of immune development is characterized by: 1) impairment of antiviral responses and 2) accentuation of Th2-like responses (e.g. cockroach-specific Interleukin-13(IL-13)). The clinical effects of these changes in immune development are frequent virus-induced wheezing and allergic sensitization by 3-4 years of age, and these characteristics synergistically increase the risk of asthma at age 7 years. Subjects age 7 to 10 years old: There are unique combinations of environmental exposures (cockroach allergens, indoor pollutants [Environmental Tobacco Smoke (ETS) and Nitrogen Dioxide (NO2)], lack of microbial exposure), and family characteristics (stress, genetic factors related to innate immunity) that synergistically promote asthma onset, persistence, and morbidity in urban neighborhoods. These exposures and characteristics influence immune expression and lung development during critical periods of growth, resulting in specific asthma phenotypes. Subjects age 10 to 16 years old: To determine the wheezing, asthma and atopy phenotypes in minority children growing up in poor urban neighborhoods as they develop from birth through adolescence. | ||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3H1YHLR5Z | ||||||||||||||||||||||
| Subjects: | 1218 | ||||||||||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: | None | ||||||||||||||||||||||
| Clinical Assessments: |
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| SDY1769: Maternal and Infant Immune Repertoire Sequencing in PPROM study | ||||||||||
| Status: | Updated | |||||||||
| Description: | To identify distinct features of immunoglobulin and T-cell receptor development in Preterm labor, the study analyzed T-cell receptor beta chain (TCR-?) and immunoglobulin heavy chain (IgH) diversity, CDR3 lengths, clonal sharing, and preferential usage of variable (V), diversity (D), and joining (J) gene segments. Additionally, the rates of somatic hypermutation (SHM) in IgH were studied. Overall, the cord blood IgH repertoires had significantly (padj < 0.05) lower rates of SHM and both TCR-? and IgH repertoires had shorter CDR3s compared to maternal blood. From the comparative analysis of term vs PPROM cord blood samples, RESULTs 1) CDR3 lengths correlated with gestational age, with the shorter CDR3s in preterm neonates suggesting a `less developed? repertoire. 2) Preterm cord blood displayed preferential usage of a number of V genes and J genes. 3) the term maternal repertoires displayed significant preferential usage of TRBV7-8 compared to preterm maternal repertoires. 4) Significantly higher prevalence of convergent clones between mother/baby pairs in preterm pregnancies. Together, these results suggest the repertoire of preterm infants displays a combination of immature features yet preferential use of particular genes and convergence with maternal TCR-? clones. While the higher TCR-? diversity might reflect less clonal expansion, the higher clonal convergence between mothers and infants in PTL could represent mother and fetus both responding to a shared stimulus like an infection. These data provide a detailed analysis of the maternal-fetal immune repertoire in term and preterm patients, and contribute to a better understanding of neonate immune repertoire development and potential changes associated with preterm labor | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3GUQMUDWL | |||||||||
| Subjects: | 48 | |||||||||
| Study PI, contact: |
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| SDY1781: Proinflammatory IgG Fc structures in patients with severe COVID-19 | ||||||||||
| Status: | Updated | |||||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 infections can cause coronavirus disease 2019 (COVID-19), which manifests with a range of severities from mild illness to life-threatening pneumonia and multi-organ failure. Severe COVID-19 is characterized by an inflammatory signature, including high levels of inflammatory cytokines, alveolar inflammatory infiltrates and vascular microthrombi. Here we show that patients with severe COVID-19 produced a unique serologic signature, including an increased likelihood of IgG1 with afucosylated Fc glycans. This Fc modification on severe acute respiratory syndrome coronavirus 2 IgGs enhanced interactions with the activating Fc-Gamma receptor Fc-Gamma RIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including interleukin-6 and tumor necrosis factor. These results show that disease severity in COVID-19 correlates with the presence of proinflammatory IgG Fc structures, including afucosylated IgG1. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M33D4Y9RTM | |||||||||
| Subjects: | 4 | |||||||||
| Study PI, contact: |
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| Clinical Assessments: |
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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. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3NPEVXJWP | ||||||
| Subjects: | 2 | ||||||
| Study PI, contact: |
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| Publications: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY1800: Durable SARS-CoV-2 B cell immunity after mild or severe disease | ||||||||||
| Status: | Updated | |||||||||
| Description: | Multiple studies have shown loss of severe acute respiratory syndrome coronavirus 2-specific (SARS-CoV-2-specific) antibodies over time after infection, raising concern that humoral immunity against the virus is not durable. If immunity wanes quickly, millions of people may be at risk for reinfection after recovery from coronavirus disease 2019 (COVID-19). However, memory B cells (MBCs) could provide durable humoral immunity even if serum neutralizing antibody titers decline. We performed multidimensional flow cytometric analysis of S protein receptor binding domain-specific (S-RBD-specific) MBCs in cohorts of ambulatory patients with COVID-19 with mild disease (n = 7), and hospitalized patients with moderate to severe disease (n = 7), at a median of 54 days (range, 39-104 days) after symptom onset. We detected S-RBD-specific class-switched MBCs in 13 of 14 participants, failing only in the individual with the lowest plasma levels of anti-S-RBD IgG and neutralizing antibodies. Resting MBCs (rMBCs) made up the largest proportion of S-RBD-specific MBCs in both cohorts. FCRL5, a marker of functional memory on rMBCs, was more dramatically upregulated on S-RBD-specific rMBCs after mild infection than after severe infection. These data indicate that most SARS-CoV-2-infected individuals develop S-RBD-specific, class-switched rMBCs that resemble germinal center-derived B cells induced by effective vaccination against other pathogens, providing evidence for durable B cell-mediated immunity against SARS-CoV-2 after mild or severe disease. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3YQ1SXVS6 | |||||||||
| Subjects: | 3 | |||||||||
| Study PI, contact: |
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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. | ||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3BAM4CN94 | ||||||||||||||
| Subjects: | 5 | ||||||||||||||
| Study PI, contact: |
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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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| SDY1810: Pseudo-safety in a cohort of patients with COVID-19 discharged home from the emergency department | ||||||||||
| Status: | Updated | |||||||||
| Description: | Introduction: Emergency Departments (ED) are often the first line of contact with individuals infected with COVID-19 and play a key role in triage. However, there is currently little specific guidance for deciding when patients with COVID-19 require hospitalisation and when they may be safely observed as an outpatient. Methods: In this retrospective study, we characterised all patients with COVID-19 discharged home from EDs in our US multisite healthcare system from March 2020 to August 2020, focusing on individuals who returned within 2 weeks and required hospital admission. We restricted analyses to first-encounter data that do not depend on laboratory or imaging diagnostics in order to inform point-of-care assessments in resource-limited environments. Vitals and comorbidities were extracted from the electronic health record. We performed ordinal logistic regression analyses to identify predictors of inpatient admission, intensive care and intubation. Results: Of n=923 patients who were COVID-19 positive discharged from the ED, n=107 (11.6%) returned within 2 weeks and were admitted. In a multivariable-adjusted model including n=788 patients with complete risk factor information, history of hypertension increased odds of hospitalisation and severe illness by 1.92-fold (95% CI 1.07 to 3.41), diabetes by 2.20-fold (1.18 to 4.02), chronic lung disease by 2.21-fold (1.22 to 3.92) and fever by 2.89-fold (1.71 to 4.82). Having at least two of these risk factors increased the odds of future hospitalisation by 6.68-fold (3.54 to 12.70). Patients with hypertension, diabetes, chronic lung disease or fever had significantly longer hospital stays (median 5.92 days, 3.08-10.95 vs 3.21, 1.10-5.75, p<0.01) with numerically higher but not significantly different rates of intensive care unit admission (27.02% vs 14.30%, p=0.27) and intubation (12.16% vs 7.14%, p=0.71). Discussion: Patients infected with COVID-19 may appear clinically safe for home convalescence. However, those with hypertension, diabetes, chronic lung disease and fever may in fact be only 'pseudo-safe' and are most at risk for subsequent hospitalisation with more severe illness and longer hospital stays. | |||||||||
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| DOI: | 10.21430/M3OOUUIKO5 | |||||||||
| Subjects: | 1 | |||||||||
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| SDY1812: Repeated cross-sectional sero-monitoring of SARS-CoV-2 in New York City | |||||||
| Status: | Updated | ||||||
| Description: | In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first detected in China and has since caused a pandemic of coronavirus disease 2019 (COVID-19). The first case of COVID-19 in New York City was officially confirmed on 1 March 2020 followed by a severe local epidemic1. Here, to understand seroprevalence dynamics, we conduct a retrospective, repeated cross-sectional analysis of anti-SARS-CoV-2 spike antibodies in weekly intervals from the beginning of February to July 2020 using more than 10,000 plasma samples from patients at Mount Sinai Hospital in New York City. We describe the dynamics of seroprevalence in an 'urgent care' group, which is enriched in cases of COVID-19 during the epidemic, and a 'routine care' group, which more closely represents the general population. Seroprevalence increased at different rates in both groups; seropositive samples were found as early as mid-February, and levelled out at slightly above 20% in both groups after the epidemic wave subsided by the end of May. From May to July, seroprevalence remained stable, suggesting lasting antibody levels in the population. Our data suggest that SARS-CoV-2 was introduced in New York City earlier than previously documented and describe the dynamics of seroconversion over the full course of the first wave of the pandemic in a major metropolitan area. | ||||||
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| DOI: | 10.21430/M3ZV06EAM0 | ||||||
| Subjects: | 6 | ||||||
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| SDY1813: Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | T cells are involved in control of SARS-CoV-2 infection. To establish the patterns of immunodominance of different SARS-CoV-2 antigens and precisely measure virus-specific CD4+ and CD8+ T cells, we study epitope-specific T cell responses of 99 convalescent coronavirus disease 2019 (COVID-19) cases. The SARS-CoV-2 proteome is probed using 1,925 peptides spanning the entire genome, ensuring an unbiased coverage of human leukocyte antigen (HLA) alleles for class II responses. For HLA class I, we study an additional 5,600 predicted binding epitopes for 28 prominent HLA class I alleles, accounting for wide global coverage. We identify several hundred HLA-restricted SARS-CoV-2-derived epitopes. Distinct patterns of immunodominance are observed, which differ for CD4+ T cells, CD8+ T cells, and antibodies. The class I and class II epitopes are combined into epitope megapools to facilitate identification and quantification of SARS-CoV-2-specific CD4+ and CD8+ T cells. | ||||||||||||
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| DOI: | 10.21430/M3F1F8OJDN | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY1815: Functional characterization of CD4+ T cell receptors crossreactive for SARS-CoV-2 and endemic coronaviruses | |||||||
| Status: | Updated | ||||||
| Description: | Recent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unexposed donors, possibly due to crossrecognition by T cells specific for common cold coronaviruses (CCCs). True T cell crossreactivity, defined as the recognition by a single TCR of more than one distinct peptide-MHC ligand, has never been shown in the context of SARS-CoV-2.METHODS: We used the viral functional expansion of specific T cells (ViraFEST) platform to identify T cell responses crossreactive for the spike (S) glycoproteins of SARS-CoV-2 and CCCs at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2-unexposed donors. Confirmation of SARS-CoV-2/CCC crossreactivity and assessments of functional avidity were performed using a TCR cloning and transfection system.RESULTS: Memory CD4+ T cell clonotypes that crossrecognized the S proteins of SARS-CoV-2 and at least one other CCC were detected in 65% of CCPs and unexposed donors. Several of these TCRs were shared among multiple donors. Crossreactive T cells demonstrated significantly impaired SARS-CoV-2-specific proliferation in vitro relative to monospecific CD4+ T cells, which was consistent with lower functional avidity of their TCRs for SARS-CoV-2 relative to CCC.CONCLUSIONSOur data confirm, for what we believe is the first time, the existence of unique memory CD4+ T cell clonotypes crossrecognizing SARS-CoV-2 and CCCs. The lower avidity of crossreactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that preexisting CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these crossreactive T cell responses affect clinical outcomes in COVID-19 patients. | ||||||
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| DOI: | 10.21430/M3C1CZ1MF2 | ||||||
| Subjects: | 2 | ||||||
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| SDY1816: Vascular Disease and Thrombosis in SARS-CoV-2-Infected Rhesus Macaques | |||||||||
| Status: | Updated | ||||||||
| Description: | The COVID-19 pandemic has led to extensive morbidity and mortality throughout the world. Clinical features that drive SARS-CoV-2 pathogenesis in humans include inflammation and thrombosis, but the mechanistic details underlying these processes remain to be determined. In this study, we demonstrate endothelial disruption and vascular thrombosis in histopathologic sections of lungs from both humans and rhesus macaques infected with SARS-CoV-2. To define key molecular pathways associated with SARS-CoV-2 pathogenesis in macaques, we performed transcriptomic analyses of bronchoalveolar lavage and peripheral blood and proteomic analyses of serum. We observed macrophage infiltrates in lung and upregulation of macrophage, complement, platelet activation, thrombosis, and proinflammatory markers, including C-reactive protein, MX1, IL-6, IL-1, IL-8, TNF-Alpha, and NF-KappaB. These results suggest a model in which critical interactions between inflammatory and thrombosis pathways lead to SARS-CoV-2-induced vascular disease. Our findings suggest potential therapeutic targets for COVID-19. | ||||||||
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| DOI: | 10.21430/M3ZINJ9X7N | ||||||||
| Subjects: | 2 | ||||||||
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| SDY1818: Correlates of Protection Against SARS-CoV-2 in Rhesus Macaques | |||||||||
| Status: | Updated | ||||||||
| Description: | Recent studies have reported protective efficacy of both natural immunity and vaccine-induced immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge in rhesus macaques. However, the importance of humoral and cellular immunity for protection against SARS-CoV-2 infection remains to be determined. Here we show that adoptive transfer of purified IgG from convalescent macaques protects naive recipient rhesus macaques against SARS-CoV-2 challenge in a dose dependent fashion. Depletion of CD8+ T cells in convalescent animals partially abrogated the protective efficacy of natural immunity against SARS-CoV-2 re-challenge, suggesting the importance of cellular immunity in the context of waning or subprotective antibody titers. These data demonstrate that relatively low antibody titers are sufficient for protection against SARS-CoV-2 in rhesus macaques, and that cellular immune responses may also contribute to protection if antibody responses are suboptimal. We also show that higher antibody titers are required for therapy of SARS-CoV-2 infection in macaques. These findings have important implications for the development of SARS-CoV-2 vaccines and immune-based therapeutics. | ||||||||
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| DOI: | 10.21430/M3MW65JZHD | ||||||||
| Subjects: | 7 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY1819: Comparison of Subgenomic and Total RNA in SARS-CoV-2 Challenged Rhesus Macaques | |||||||
| Status: | Updated | ||||||
| Description: | Respiratory virus challenge studies involve administration of the challenge virus and sampling to assess for protection in the same anatomical locations. It can therefore be difficult to differentiate actively replicating virus from input challenge virus. For SARS-CoV-2, specific monitoring of actively replicating virus is critical for investigating the protective and therapeutic efficacy of vaccines, monoclonal antibodies, and antiviral drugs. We adapted a SARS-CoV-2 subgenomic RNA (sgRNA) RT-PCR assay to differentiate productive infection from inactivated or neutralized virus. Subgenomic RNAs are generated after cell entry and are poorly incorporated into mature virions, and thus may provide a marker for actively replicating virus. We show envelope (E) sgRNA was degraded by RNase in infected cell lysates, while genomic RNA (gRNA) was protected, presumably due to packaging into virions. To investigate the capacity of the sgRNA assay to distinguish input challenge virus from actively replicating virus in vivo, we compared the E sgRNA assay to a standard nucleoprotein (N) or E total (both gRNA and sgRNA) RNA in convalescent rhesus macaques and in antibody-treated rhesus macaques after experimental SARS-CoV-2 challenge. In both studies, the E sgRNA assay was negative, suggesting protective efficacy, whereas the N and E total RNA assays remained positive. These data suggest the potential utility of sgRNA to monitor actively replicating virus in prophylactic and therapeutic SARS-CoV-2 studies. Importance: Developing therapeutic and prophylactic countermeasures for the SARS-CoV-2 virus is a public health priority. During challenge studies, respiratory viruses are delivered and sampled from the same anatomical location. It is therefore important to distinguish actively replicating virus from input challenge virus. The most common assay for detecting SARS-CoV-2 virus, reverse transcription polymerase chain reaction (RT-PCR) targeting nucleocapsid total RNA, cannot distinguish neutralized input virus from replicating virus. In this study, we assess SARS-CoV-2 subgenomic RNA as a potential measure of replicating virus in rhesus macaques. | ||||||
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| DOI: | 10.21430/M3DM6E1Y0R | ||||||
| Subjects: | 4 | ||||||
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| SDY1821: MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Recent studies have profiled the innate immune signatures in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and suggest that cellular responses to viral challenge may affect disease severity. Yet the molecular events that underlie cellular recognition and response to SARS-CoV-2 infection remain to be elucidated. Here, we find that SARS-CoV-2 replication induces a delayed interferon (IFN) response in lung epithelial cells. By screening 16 putative sensors involved in sensing of RNA virus infection, we found that MDA5 and LGP2 primarily regulate IFN induction in response to SARS-CoV-2 infection. Further analyses revealed that viral intermediates specifically activate the IFN response through MDA5-mediated sensing. Additionally, we find that IRF3, IRF5, and NF-B/p65 are the key transcription factors regulating the IFN response during SARS-CoV-2 infection. In summary, these findings provide critical insights into the molecular basis of the innate immune recognition and signaling response to SARS-CoV-2. | ||||||||||||
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| DOI: | 10.21430/M31F88A9QL | ||||||||||||
| Subjects: | 3 | ||||||||||||
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| SDY1829: Severely ill COVID-19 patients display impaired exhaustion features in SARS-CoV-2-reactive CD8+ T cells | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | The molecular properties of CD8+ T cells that respond to SARS-CoV-2 infection are not fully known. Here, we report on the single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells, obtained using a modified Antigen-Reactive T cell Enrichment (ARTE) assay, from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patients segregated into two groups based on whether the dominant CD8+ T cell response to SARS-CoV-2 was 'exhausted' or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed lesser cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the dominant non-exhausted subset from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival NF-KappaB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8+ T cell memory responses in patients with severe COVID-19 illness. CD8+ T cells reactive to influenza and respiratory syncytial virus from healthy subjects displayed polyfunctional features and enhanced glycolysis. Cells with such features were largely absent in SARS-CoV-2-reactive cells from both COVID-19 patients and healthy controls non-exposed to SARS-CoV-2. Overall, our single-cell analysis revealed substantial diversity in the nature of CD8+ T cells responding to SARS-CoV-2. | ||||||||||||
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| DOI: | 10.21430/M3A57H738Q | ||||||||||||
| Subjects: | 4 | ||||||||||||
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| SDY1831: Serological analysis reveals an imbalanced IgG subclass composition associated with COVID-19 disease severity | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | Coronavirus disease 2019 (COVID-19) is associated with a wide spectrum of disease presentation, ranging from asymptomatic infection to acute respiratory distress syndrome (ARDS). Paradoxically, a direct relationship has been suggested between COVID-19 disease severity and the levels of circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies, including virus-neutralizing titers. A serological analysis of 536 convalescent healthcare workers reveals that SARS-CoV-2-specific and virus-neutralizing antibody levels are elevated in individuals that experience severe disease. The severity-associated increase in SARS-CoV-2-specific antibody is dominated by immunoglobulin G (IgG), with an IgG subclass ratio skewed toward elevated receptor binding domain (RBD)- and S1-specific IgG3. In addition, individuals that experience severe disease show elevated SARS-CoV-2-specific antibody binding to the inflammatory receptor Fc?RIIIa. Based on these correlational studies, we propose that spike-specific IgG subclass utilization may contribute to COVID-19 disease severity through potent Fc-mediated effector functions. These results may have significant implications for SARS-CoV-2 vaccine design and convalescent plasma therapy. | |||||||||||||||
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| DOI: | 10.21430/M3B6163WG1 | |||||||||||||||
| Subjects: | 5 | |||||||||||||||
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| SDY1832: Immunological imprinting of the antibody response in COVID-19 patients | ||||||||||
| Status: | Updated | |||||||||
| Description: | In addition to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), humans are also susceptible to six other coronaviruses, for which consecutive exposures to antigenically related and divergent seasonal coronaviruses are frequent. Despite the prevalence of COVID-19 pandemic and ongoing research, the nature of the antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here we longitudinally profile the early humoral immune response against SARS-CoV-2 in hospitalized coronavirus disease 2019 (COVID-19) patients and quantify levels of pre-existing immunity to OC43, HKU1 and 229E seasonal coronaviruses, and find a strong back-boosting effect to conserved but not variable regions of OC43 and HKU1 betacoronaviruses spike protein. However, such antibody memory boost to human coronaviruses negatively correlates with the induction of IgG and IgM against SARS-CoV-2 spike and nucleocapsid protein. Our findings thus provide evidence of immunological imprinting by previous seasonal coronavirus infections that can potentially modulate the antibody profile to SARS-CoV-2 infection. | |||||||||
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| DOI: | 10.21430/M3EMGZH7G6 | |||||||||
| Subjects: | 3 | |||||||||
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| SDY1835: Delayed Rise of Oral Fluid Antibodies, Elevated BMI, and Absence of Early Fever Correlate With Longer Time to SARS-CoV-2 RNA Clearance in a Longitudinally Sampled Cohort of COVID-19 Outpatients | ||||||||||
| Status: | Updated | |||||||||
| Description: | Sustained molecular detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in the upper respiratory tract (URT) in mild to moderate coronavirus disease 2019 (COVID-19) is common. We sought to identify host and immune determinants of prolonged SARS-CoV-2 RNA detection. Methods : Ninety-five symptomatic outpatients self-collected midturbinate nasal, oropharyngeal (OP), and gingival crevicular fluid (oral fluid) samples at home and in a research clinic a median of 6 times over 1-3 months. Samples were tested for viral RNA, virus culture, and SARS-CoV-2 and other human coronavirus antibodies, and associations were estimated using Cox proportional hazards models. Results : Viral RNA clearance, as measured by SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR), in 507 URT samples occurred a median (interquartile range) 33.5 (17-63.5) days post-symptom onset. Sixteen nasal-OP samples collected 2-11 days post-symptom onset were virus culture positive out of 183 RT-PCR-positive samples tested. All participants but 1 with positive virus culture were negative for concomitant oral fluid anti-SARS-CoV-2 antibodies. The mean time to first antibody detection in oral fluid was 8-13 days post-symptom onset. A longer time to first detection of oral fluid anti-SARS-CoV-2 S antibodies (adjusted hazard ratio [aHR], 0.96; 95% CI, 0.92-0.99; P = .020) and body mass index (BMI) >=25 kg/m2 (aHR, 0.37; 95% CI, 0.18-0.78; P = .009) were independently associated with a longer time to SARS-CoV-2 viral RNA clearance. Fever as 1 of first 3 COVID-19 symptoms correlated with shorter time to viral RNA clearance (aHR, 2.06; 95% CI, 1.02-4.18; P = .044). Conclusions : We demonstrate that delayed rise of oral fluid SARS-CoV-2-specific antibodies, elevated BMI, and absence of early fever are independently associated with delayed URT viral RNA clearance. | |||||||||
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| DOI: | 10.21430/M3NG59FFQ5 | |||||||||
| Subjects: | 3 | |||||||||
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| SDY1840: Tissue-based SARS-CoV-2 detection in fatal COVID-19 infections: Sustained direct viral-induced damage is not necessary to drive disease progression | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Coronavirus disease 2019 (COVID-19) is an ongoing pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although viral infection is known to trigger inflammatory processes contributing to tissue injury and organ failure, it is unclear whether direct viral damage is needed to sustain cellular injury. An understanding of pathogenic mechanisms has been handicapped by the absence of optimized methods to visualize the presence and distribution of SARS-CoV-2 in damaged tissues. We first developed a positive control cell line (Vero E6) to validate SARS-CoV-2 detection assays. We then evaluated multiple organs (lungs, kidneys, heart, liver, brain, intestines, lymph nodes, and spleen) from fourteen COVID-19 autopsy cases using immunohistochemistry (IHC) for the spike and the nucleoprotein proteins, and RNA in situ hybridization (RNA ISH) for the spike protein mRNA. Tissue detection assays were compared with quantitative polymerase chain reaction (qPCR)-based detection. SARS-CoV-2 was histologically detected in the Vero E6 positive cell line control, 1 of 14 (7%) lungs, and none (0%) of the other 59 organs. There was perfect concordance between the IHC and RNA ISH results. qPCR confirmed high viral load in the SARS-CoV-2 ISH-positive lung tissue, and absent or low viral load in all ISH-negative tissues. In patients who die of COVID-19-related organ failure, SARS-CoV-2 is largely not detectable using tissue-based assays. Even in lungs showing widespread injury, SARS-CoV-2 viral RNA or proteins were detected in only a small minority of cases. This observation supports the concept that viral infection is primarily a trigger for multiple-organ pathogenic proinflammatory responses. Direct viral tissue damage is a transient phenomenon that is generally not sustained throughout disease progression. | ||||||||||
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| DOI: | 10.21430/M3IDUI9TUU | ||||||||||
| Subjects: | 2 | ||||||||||
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| SDY1849: Estimating SARS-CoV-2 seroprevalence and epidemiological parameters with uncertainty from serological surveys | ||||||||||
| Status: | Updated | |||||||||
| Description: | Establishing how many people have been infected by SARS-CoV-2 remains an urgent priority for controlling the COVID-19 pandemic. Serological tests that identify past infection can be used to estimate cumulative incidence, but the relative accuracy and robustness of various sampling strategies have been unclear. We developed a flexible framework that integrates uncertainty from test characteristics, sample size, and heterogeneity in seroprevalence across subpopulations to compare estimates from sampling schemes. Using the same framework and making the assumption that seropositivity indicates immune protection, we propagated estimates and uncertainty through dynamical models to assess uncertainty in the epidemiological parameters needed to evaluate public health interventions and found that sampling schemes informed by demographics and contact networks outperform uniform sampling. The framework can be adapted to optimize serosurvey design given test characteristics and capacity, population demography, sampling strategy, and modeling approach, and can be tailored to support decision-making around introducing or removing interventions. | |||||||||
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| DOI: | 10.21430/M3M73PFN8O | |||||||||
| Subjects: | 1 | |||||||||
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| 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. | ||||||
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| DOI: | 10.21430/M3NEXZIAC5 | ||||||
| Subjects: | 1 | ||||||
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| 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. | ||||||
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| DOI: | 10.21430/M3S4GR1BIO | ||||||
| Subjects: | 2 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1852: Modeling the impact of racial and ethnic disparities on COVID-19 epidemic dynamics | ||||||||||
| Status: | Updated | |||||||||
| Description: | Background: The impact of variable infection risk by race and ethnicity on the dynamics of SARS-CoV-2 spread is largely unknown. Methods: Here, we fit structured compartmental models to seroprevalence data from New York State and analyze how herd immunity thresholds (HITs), final sizes, and epidemic risk change across groups. Results: A simple model where interactions occur proportionally to contact rates reduced the HIT, but more realistic models of preferential mixing within groups increased the threshold toward the value observed in homogeneous populations. Across all models, the burden of infection fell disproportionately on minority populations: in a model fit to Long Island serosurvey and census data, 81% of Hispanics or Latinos were infected when the HIT was reached compared to 34% of non-Hispanic whites. Conclusions: Our findings, which are meant to be illustrative and not best estimates, demonstrate how racial and ethnic disparities can impact epidemic trajectories and result in unequal distributions of SARS-CoV-2 infection. Funding: K.C.M. was supported by National Science Foundation GRFP grant DGE1745303. Y.H.G. and M.L. were funded by the Morris-Singer Foundation. M.L. was supported by SeroNet cooperative agreement U01 CA261277 | |||||||||
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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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| 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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| 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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| 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 | ||||||||||||
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| 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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| 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 | ||||||||||
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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 | ||||||
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| 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 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
| SDY1964: Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine | |||||||||||
| Status: | Updated | ||||||||||
| Description: | The CVnCoV (CureVac) mRNA vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was recently evaluated in a phase 2b/3 efficacy trial in humans1. CV2CoV is a second-generation mRNA vaccine containing non-modified nucleosides but with optimized non-coding regions and enhanced antigen expression. Here we report the results of a head-to-head comparison of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in non-human primates. We immunized 18 cynomolgus macaques with two doses of 12??g lipid nanoparticle-formulated CVnCoV or CV2CoV or with sham (n?=?6 per group). Compared with CVnCoV, CV2CoV induced substantially higher titres of binding and neutralizing antibodies, memory B cell responses and T cell responses as well as more potent neutralizing antibody responses against SARS-CoV-2 variants, including the Delta variant. Moreover, CV2CoV was found to be comparably immunogenic to the BNT162b2 (Pfizer) vaccine in macaques. Although CVnCoV provided partial protection against SARS-CoV-2 challenge, CV2CoV afforded more robust protection with markedly lower viral loads in the upper and lower respiratory tracts. Binding and neutralizing antibody titres were correlated with protective efficacy. These data demonstrate that optimization of non-coding regions can greatly improve the immunogenicity and protective efficacy of a non-modified mRNA SARS-CoV-2 vaccine in non-human primates. | ||||||||||
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| DOI: | 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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| 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 | ||||||||
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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. | |||||||||
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| DOI: | 10.21430/M3BGVPR3CN | |||||||||
| Subjects: | 3 | |||||||||
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| 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. | |||||||||||||||
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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. | |||||||||
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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 | |||||||||
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| 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. | ||||||||||
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| DOI: | 10.21430/M3W5SK65XI | ||||||||||
| Subjects: | 6 | ||||||||||
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| 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 | |||||||||
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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. | |||||||||
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| DOI: | 10.21430/M3TGZSFQZZ | |||||||||
| Subjects: | 4 | |||||||||
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| 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 | |||||||||
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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. | ||||||
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| DOI: | 10.21430/M381LM05UM | ||||||
| Subjects: | 7 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1990: Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection | |||||||||||
| Status: | Updated | ||||||||||
| Description: | SARS-CoV-2-specific antibodies, CD4+ T cells, and CD8+ T cells are made in response to SARS-CoV-2 infection. Understanding the kinetics and durability of immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines and assessing the likely future course of the COVID-19 pandemic. We assessed the immune memory of all three branches of adaptive immunity (CD4+ T cell, CD8+ T cell, and humoral immunity) in a predominantly cross-sectional study, including a longitudinal subset, extending for up to eight months post-infection. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M31TX0GFHU | ||||||||||
| Subjects: | 1 | ||||||||||
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| Clinical Assessments: | None | ||||||||||