DR51.2 DataRelease
Release Date: May 2024
New Studies: 36
Updated Studies: 14
New Studies
| SDY2277: T cell signatures of bacterial clearance among M. tuberculosis ‘resisters’ | |||||||
| Status: | New | ||||||
| Description: | A subset of individuals with a high probability of exposure to M. tuberculosis (M.tb) appears to ‘resist’ established M.tb infection, as demonstrated by serially negative tuberculin skin test (TST) or IFN-γ release assay (IGRA) results. While these ‘resisters’ (RSTR) display IFN-γ-independent T cell responses to the M.tb-specific antigens ESAT-6 and CFP-10, it is currently unknown whether unique T cell functional programs are associated with this clinical outcome. We used multi-modal single-cell RNA, TCR sequencing, multi-parameter flow cytometry, and cytokine analysis in a discovery and validation format to compare the phenotypes and functions of M.tb-specific T cells between RSTRs and matched controls with ‘latent’ M.tb infection (LTBI). M.tb-specific T cells were clonally expanded in both RSTRs and LTBIs, confirming the priming of adaptive immune responses after M.tb exposure. However, M.tb-specific T cells derived from RSTRs showed enrichment of T regulatory as well as Th17-like functional programs compared to LTBIs, which were characterized by Th1*-like effector programs. Th17-like functional programs were also associated with a lack of progression to active TB among South African adolescents with LTBI, as well as bacterial control in published non-human primate studies. Together, these data suggest that ‘resisters’ may successfully control M.tb after exposure and immune priming and establish a set of T cell biomarkers to facilitate further study of this important clinical phenotype. | ||||||
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| DOI: | 10.21430/M3EEUCJII9 | ||||||
| Subjects: | 0 | ||||||
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| Publications: | None | ||||||
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| SDY2583: Blood Immunotypes | ||||||||||
| Status: | New | |||||||||
| Description: | We developed an immunoprofiling platform that uses multiparameter flow cytometry to characterize immune cell heterogeneity in the peripheral blood of healthy donors and patients with advanced cancers. Using unsupervised clustering, we identified five immunotypes with unique distributions of different cell types, and gene expression profiles. | |||||||||
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| DOI: | 10.21430/M3A0B9RD5T | |||||||||
| Subjects: | 850 | |||||||||
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| Publications: | None | |||||||||
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| SDY2621: MR1-restricted clonotypes are associated with resistance to M. Tuberculosis infection | |||||||
| Status: | New | ||||||
| Description: | The aim of this study was to determine whether the frequencies of donor-unrestricted T-cells (DURTs) in peripheral blood were associated with resistance to M. Tuberculosis infection. Peripheral blood samples were collected from donors designated as resistant (RSTRs) or latently infected with M. Tuberculosis (LTBI). Subsets of DURTs were defined by tetramer staining and enumerated by flow cytometry. | ||||||
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| DOI: | 10.21430/M3FQI1C4HJ | ||||||
| Subjects: | 46 | ||||||
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| SDY2629: Health Canada/Columbia University Micronucleus Intercomparison | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | Following a mass-casualty nuclear or radiological event, there will be an important need for rapid and accurate estimation of absorbed dose for biological triage. The cytokinesis-block micronucleus (CBMN) assay is an established and validated cytogenetic biomarker used to assess DNA damage in irradiated peripheral blood lymphocytes. Here, we describe an intercomparison experiment between two biodosimetry laboratories, located at Columbia University (CU) and Health Canada (HC) that performed different variants of the human blood CBMN assay to reconstruct dose in human blood, with CU performing the assay on isolated lymphocytes and using semi-automated scoring whereas HC used the more conventional whole blood assay. Although the micronucleus yields varied significantly between the two assays, the predicted doses closely matched up to 4 Gy - the range from which the HC calibration curve was previously established. These results highlight the importance of a robust calibration curve(s) across a wide age range of donors that match the exposure scenario as closely as possible and that will account for differences in methodology between laboratories. We have seen that at low doses, variability in the results may be attributed to variation in the processing whilst at higher doses the variation is dominated by inter-individual variation in cell proliferation. This inter-laboratory collaboration further highlights the usefulness of the CBMN endpoint to accurately reconstruct absorbed dose in human blood after ionizing radiation exposure. | |||||||||||||||
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| DOI: | 10.21430/M31ID136IF | |||||||||||||||
| Subjects: | 16 | |||||||||||||||
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| Assays: | None | |||||||||||||||
| Clinical Assessments: | None | |||||||||||||||
| SDY2631: Chimeric spike mRNA vaccines protect against Sarbecovirus challenge in mice | |||||||||||||
| Status: | New | ||||||||||||
| Description: | The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and SARS-CoV-2 in 2019 highlights the need to develop universal vaccination strategies against the broader Sarbecovirus subgenus. Using chimeric spike designs, we demonstrate protection against challenge from SARS-CoV, SARS-CoV-2, SARS-CoV-2 B.1.351, bat CoV (Bt-CoV) RsSHC014, and a heterologous Bt-CoV WIV-1 in vulnerable aged mice. Chimeric spike messenger RNAs (mRNAs) induced high levels of broadly protective neutralizing antibodies against high-risk Sarbecoviruses. By contrast, SARS-CoV-2 mRNA vaccination not only showed a marked reduction in neutralizing titers against heterologous Sarbecoviruses, but SARS-CoV and WIV-1 challenge in mice resulted in breakthrough infections. Chimeric spike mRNA vaccines efficiently neutralized D614G, mink cluster five, and the UK B.1.1.7 and South African B.1.351 variants of concern. Thus, multiplexed-chimeric spikes can prevent SARS-like zoonotic coronavirus infections with pandemic potential. | ||||||||||||
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| DOI: | 10.21430/M3KG3AGBNR | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2632: Neutralization of the SARS-CoV-2 Omicron BA.1 and BA.2 Variants | |||||||
| Status: | New | ||||||
| Description: | Neutralizing antibody responses were evaluated against the parental WA1/2020 strain of the virus, as well as against the omicron BA.1 and BA.2 variants, in 24 persons who had been vaccinated and boosted with the BNT162b2 mRNA vaccine (Pfizer–BioNTech)5 and had not had infection with SARS-CoV-2 and in 8 persons with a history of SARS-CoV-2 infection, irrespective of vaccination status. | ||||||
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| DOI: | 10.21430/M3M0X8T0EB | ||||||
| Subjects: | 0 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2633: Three doses of COVID-19 mRNA vaccine induce class-switched antibody responses in inflammatory arthritis patients on immunomodulatory therapies | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | Patients with inflammatory arthritis (IA) are at increased risk of severe COVID-19 due to medication-induced immunosuppression that impairs host defenses. The aim of this study was to assess antibody and B cell responses to COVID-19 mRNA vaccination in IA patients receiving immunomodulatory therapies. Adults with IA were enrolled through the Johns Hopkins Arthritis Center and compared with healthy controls (HC). Paired plasma and peripheral blood mononuclear cell (PBMC) samples were collected prior to and 30 days or 6 months following the first two doses of mRNA vaccines (D2; HC=77 and IA=31 patients), or 30 days following a third dose of mRNA vaccines (D3; HC=11 and IA=96 patients). Neutralizing antibody titers, total binding antibody titers, and B cell responses to vaccine and Omicron variants were analyzed. Anti-Spike (S) IgG and S-specific B cells developed appropriately in most IA patients following D3, with reduced responses to Omicron variants, and negligible effects of medication type or drug withholding. Neutralizing antibody responses were lower compared to healthy controls after both D2 and D3, with a small number of individuals demonstrating persistently undetectable neutralizing antibody levels. Most IA patients respond as well to mRNA COVID-19 vaccines as immunocompetent individuals by the third dose, with no evidence of improved responses following medication withholding. These data suggest that IA-associated immune impairment may not hinder immunity to COVID-19 mRNA vaccines in most individuals. | |||||||||||||||
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| DOI: | 10.21430/M3MRUIWTXB | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||
| SDY2634: Immunity elicited by natural infection or Ad26.COV2.S vaccination protects hamsters against SARS-CoV-2 variants of concern | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern have emerged and may pose a threat to both the efficacy of vaccines based on the original WA1/2020 strain and the natural immunity induced by infection with earlier SARS-CoV-2 variants. We investigated how mutations in the spike protein of circulating SARS-CoV-2 variants, which have been shown to partially evade neutralizing antibodies, affect natural and vaccine-induced immunity. We adapted a Syrian hamster model of moderate to severe clinical disease for two variant strains of SARS-CoV-2: B.1.1.7 (alpha variant) and B.1.351 (beta variant). We then assessed the protective efficacy conferred by either natural immunity from WA1/2020 infection or by vaccination with a single dose of the adenovirus serotype 26 vaccine, Ad26.COV2.S. Primary infection with the WA1/2020 strain provided potent protection against weight loss and viral replication in lungs after rechallenge with WA1/2020, B.1.1.7, or B.1.351. Ad26.COV2.S induced cross-reactive binding and neutralizing antibodies that were reduced against the B.1.351 strain compared with WA1/2020 but nevertheless still provided robust protection against B.1.351 challenge, as measured by weight loss and pathology scoring in the lungs. Together, these data support hamsters as a preclinical model to study protection against emerging variants of SARS-CoV-2 conferred by prior infection or vaccination. | ||||||||||||
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| DOI: | 10.21430/M32TFJSND8 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2635: Pharmacokinetics of convalescent plasma therapy in a COVID-19 patient with X-linked Agammaglobulinemia | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Convalescent plasma (CP) has been the first line of defense against numerous infectious diseases throughout history. The COVID-19 pandemic created a need for a quick, easily accessible, and effective treatment for severe disease and CP was able to meet that immediate need. The utility of CP warrants a better understanding of the pharmacokinetics of CP treatment. Here we present the case of a COVID-19 patient with a genetic deficiency in antibody production who received CP as a part of the treatment regimen. In depth serological analysis revealed a surprising lack of SARS-CoV-2 specific antibodies and reduced serum IgG following CP infusion. Our study highlights plasma dilution and accelerated antibody clearance as potential mechanisms for the variable efficacy of CP therapy. | ||||||||||||
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| DOI: | 10.21430/M323RV7XOK | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2636: A broadly cross-reactive antibody neutralizes and protects against sarbecovirus challenge in mice | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | Severe acute respiratory syndrome coronaviruses 1 (SARS-CoV) and 2 (SARS-CoV-2), including SARS-CoV-2 variants of concern, can cause deadly infections. The mortality associated with sarbecovirus infection underscores the importance of developing broadly effective countermeasures against them, which could be key in the prevention and mitigation of current and future zoonotic events. Here, we demonstrate the neutralization of SARS-CoV; bat coronaviruses WIV-1 and RsSHC014; and SARS-CoV-2 variants D614G, B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, B.1.617.1, and B.1.617.2 by a receptor binding domain (RBD)–specific human antibody, DH1047. Prophylactic and therapeutic treatment with DH1047 was protective against SARS-CoV, WIV-1, RsSHC014, and SARS-CoV-2 B.1.351 infection in mice. Binding and structural analysis showed high affinity binding of DH1047 to an epitope that is highly conserved among sarbecoviruses. Thus, DH1047 is a broadly protective antibody that can prevent infection and mitigate outbreaks caused by SARS-related strains and SARS-CoV-2 variants. Our results also suggest that the conserved RBD epitope bound by DH1047 is a rational target for a universal sarbecovirus vaccine. | ||||||||||||||||||
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| DOI: | 10.21430/M36GGGAZ0O | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2637: Evaluation of SARS-CoV-2-Specific T-Cell Activation with a Rapid On-Chip IGRA | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Interferon-gamma release assays (IGRAs) that measure pathogen-specific T-cell response rates can provide a more reliable estimate of protection than specific antibody levels but have limited potential for widespread use due to their workflow, personnel, and instrumentation demands. The major vaccines for SARS-CoV-2 have demonstrated substantial efficacy against all of its current variants, but approaches are needed to determine how these vaccines will perform against future variants, as they arise, to inform vaccine and public health policies. Here we describe a rapid, sensitive, nanolayer polylysine-integrated microfluidic chip IGRA read by a fluorescent microscope that has a 5 h sample-to-answer time and uses ∼25 μL of a fingerstick whole blood sample. Results from this assay correlated with those of a comparable clinical IGRA when used to evaluate the T-cell response to SARS-CoV-2 peptides in a population of vaccinated and/or infected individuals. Notably, this streamlined and inexpensive assay is suitable for high-throughput analyses in resource-limited settings for other infectious diseases. | ||||||||||||
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| DOI: | 10.21430/M35FH8NSOD | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2638: Loss of Pfizer (BNT162b2) Vaccine-Induced Antibody Responses against the SARS-CoV-2 Omicron Variant in Adolescents and Adults | |||||||||||||
| Status: | New | ||||||||||||
| Description: | We compared the magnitude and breadth of humoral immune responses in adolescents and adults 1 month after the two-dose Pfizer (BNT162b2) vaccination. We found that adolescents (aged 11 to 16) demonstrated more robust binding antibody and neutralization responses against the wild-type SARS-CoV-2 virus spike protein contained in the vaccine compared to adults (aged 27 to 55). The quality of the antibody responses against VOCs in adolescents were very similar to adults, with modest changes in binding and neutralization of Beta, Gamma, and Delta variants. In comparison, a significant reduction of binding titers and a striking lack of neutralization was observed against the newly emerging Omicron variant for both adolescents and adults. Overall, our data show that a two-dose BNT162b2 vaccine series may be insufficient to protect against the Omicron variant. IMPORTANCE While plasma binding and neutralizing antibody responses have been reported for cohorts of infected and vaccinated adults, much less is known about the vaccine-induced antibody responses to variants including Omicron in children. This illustrates the need to characterize vaccine efficacy in key vulnerable populations. | ||||||||||||
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| DOI: | 10.21430/M3RB8PC5NW | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2639: Substantial Neutralization Escape by SARS-CoV-2 Omicron Variants BQ.1.1 and XBB.1 | ||||||||||
| Status: | New | |||||||||
| Description: | The omicron BA.5 subvariant was the dominant variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1 from July to November 2022 and showed substantial neutralization escape as compared with previous variants.2,3 Additional omicron variants have recently emerged, including the BA.4 sublineage BA.4.6, the BA.5 sublineages BF.7 and BQ.1.1, the BA.2 sublineage BA.2.75.2, and the BA.2 lineage recombinant XBB.1 (Figure 1A, and Figs. S1 through S5 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). All these variants have the R346T mutation in the spike protein. BQ.1.1 and XBB.1 have rapidly increased in frequency and have replaced BA.5 as dominant variants worldwide. However, the ability of these variants to evade neutralizing antibodies induced by vaccination and infection is unclear. | |||||||||
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| DOI: | 10.21430/M35KFIBVLJ | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2640: SARS-CoV-2 Nucleocapsid Plasma Antigen for Diagnosis and Monitoring of COVID-19 | ||||||||||
| Status: | New | |||||||||
| Description: | Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid antigen in blood has been described, but the diagnostic and prognostic role of antigenemia is not well understood. This study aimed to determine the frequency, duration, and concentration of nucleocapsid antigen in plasma and its association with coronavirus disease 2019 (COVID-19) severity. We utilized an ultrasensitive electrochemiluminescence immunoassay targeting SARS-CoV-2 nucleocapsid antigen to evaluate 777 plasma samples from 104 individuals with COVID-19. We compared plasma antigen to respiratory nucleic acid amplification testing (NAAT) in 74 individuals with COVID-19 from samples collected ±1 day of diagnostic respiratory NAAT and in 52 SARS-CoV-2-negative individuals. We used Kruskal-Wallis tests, multivariable logistic regression, and mixed-effects modeling to evaluate whether plasma antigen concentration was associated with disease severity. Plasma antigen had 91.9% (95% CI 83.2%-97.0%) clinical sensitivity and 94.2% (84.1%-98.8%) clinical specificity. Antigen-negative plasma samples belonged to patients with later respiratory cycle thresholds (Ct) when compared with antigen-positive plasma samples. Median plasma antigen concentration (log10 fg/mL) was 5.4 (interquartile range 3.9-6.0) in outpatients, 6.0 (5.4-6.5) in inpatients, and 6.6 (6.1-7.2) in intensive care unit (ICU) patients. In models adjusted for age, sex, diabetes, and hypertension, plasma antigen concentration at diagnosis was associated with ICU admission [odds ratio 2.8 (95% CI 1.2-6.2), P=.01] but not with non-ICU hospitalization. Rate of antigen decrease was not associated with disease severity. SARS-CoV-2 plasma nucleocapsid antigen exhibited comparable diagnostic performance to upper respiratory NAAT, especially among those with late respiratory Ct. In addition to currently available tools, antigenemia may facilitate patient triage to optimize intensive care utilization. | |||||||||
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| DOI: | 10.21430/M3XM1VOWHO | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2641: Selective functional antibody transfer into the breastmilk after SARS-CoV-2 infection | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Antibody transfer via breastmilk represents an evolutionary strategy to boost immunity in early life. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies have been observed in the breastmilk, the functional quality of these antibodies remains unclear. Here, we apply systems serology to characterize SARS-CoV-2-specific antibodies in maternal serum and breastmilk to compare the functional characteristics of antibodies in these fluids. Distinct SARS-CoV-2-specific antibody responses are observed in the serum and breastmilk of lactating individuals previously infected with SARS-CoV-2, with a more dominant transfer of immunoglobulin A (IgA) and IgM into breastmilk. Although IgGs are present in breastmilk, they are functionally attenuated. We observe preferential transfer of antibodies capable of eliciting neutrophil phagocytosis and neutralization compared to other functions, pointing to selective transfer of certain functional antibodies to breastmilk. These data highlight the preferential transfer of SARS-CoV-2-specific IgA and IgM to breastmilk, accompanied by select IgG subpopulations, positioned to create a non-pathologic but protective barrier against coronavirus disease 2019 (COVID-19). | ||||||||||||
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| DOI: | 10.21430/M3Z904NDDC | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2642: Immune responses and therapeutic challenges in paediatric patients with new‐onset acute myeloid leukaemia and concomitant COVID‐19 | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Acute myeloid leukaemia (AML) is a medical emergency often presenting with hyperleucocytosis, coagulopathy and pulmonary infiltration necessitating emergent initiation of therapy. AML with concomitant severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection presents a unique challenge given the lack of evidence‐based guidelines or historical experience. While cohort studies have shown early serological responses to SARS‐CoV‐2 in healthy adults, 1 , 2 little is known about the serological responses to infection in patients with AML and the impact of chemotherapy on this response. In the present study, we detail the clinical presentations, treatments, serological and virological responses, and outcomes of two adolescents who presented with AML and concurrent coronavirus disease 2019 (COVID‐19). | ||||||||||||
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| DOI: | 10.21430/M3WGKBAENU | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2643: SARS-CoV-2 seroprevalence rates of children seeking medical care in Louisiana during the state stay at home order | ||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||
| Description: | Children with acute coronavirus disease 2019 (COVID-19) typically have milder symptoms than adults, thus it is likely that more children are infected than tested [1]. SARS-CoV-2 virus shed by asymptomatic, pre-symptomatic, or mildly symptomatic subjects has likely contributed to the spread of the virus [2]. High level shedding has been demonstrated in infected children, even those who are asymptomatic; therefore, children may be efficient vectors of transmission [3–5]. There is a critical and urgent need to understand the levels of past and current infection in children, and their roles in viral transmission. Serological studies have largely been limited to adults. Our objective was to define SARS-CoV-2 seroprevalence in children seeking medical care during the first Stay at Home Order in New Orleans, Louisiana, from March through May 2020. | |||||||||||||||||||||
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| DOI: | 10.21430/M3STSP1YG8 | |||||||||||||||||||||
| Subjects: | 0 | |||||||||||||||||||||
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| SDY2644: Sensitive tracking of circulating viral RNA through all stages of SARS-CoV-2 infection | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | BACKGROUND. Circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA may represent a more reliable indicator of infection than nasal RNA, but quantitative reverse transcription PCR (RT-qPCR) lacks diagnostic sensitivity for blood samples. METHODS. A CRISPR-augmented RT-PCR assay that sensitively detects SARS-CoV-2 RNA was employed to analyze viral RNA kinetics in longitudinal plasma samples from nonhuman primates (NHPs) after virus exposure; to evaluate the utility of blood SARS-CoV-2 RNA detection for coronavirus disease 2019 (COVID-19) diagnosis in adults cases confirmed by nasal/nasopharyngeal swab RT-PCR results; and to identify suspected COVID-19 cases in pediatric and at-risk adult populations with negative nasal swab RT-qPCR results. All blood samples were analyzed by RT-qPCR to allow direct comparisons. RESULTS. CRISPR-augmented RT-PCR consistently detected SARS-CoV-2 RNA in the plasma of experimentally infected NHPs from 1 to 28 days after infection, and these increases preceded and correlated with rectal swab viral RNA increases. In a patient cohort (n = 159), this blood-based assay demonstrated 91.2% diagnostic sensitivity and 99.2% diagnostic specificity versus a comparator RT-qPCR nasal/nasopharyngeal test, whereas RT-qPCR exhibited 44.1% diagnostic sensitivity and 100% specificity for the same blood samples. This CRISPR-augmented RT-PCR assay also accurately identified patients with COVID-19 using one or more negative nasal swab RT-qPCR results. CONCLUSION. Results of this study indicate that sensitive detection of SARS-CoV-2 RNA in blood by CRISPR-augmented RT-PCR permits accurate COVID-19 diagnosis, and can detect COVID-19 cases with transient or negative nasal swab RT-qPCR results, suggesting that this approach could improve COVID-19 diagnosis and the evaluation of SARS-CoV-2 infection clearance, and predict the severity of infection. | ||||||||||||||||||
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| DOI: | 10.21430/M31W1UTGAH | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| SDY2645: ACE2-IgG1 fusions with improved in vitro and in vivo activity against SARS-CoV-2 | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | SARS-CoV-2, the etiologic agent of COVID-19, uses ACE2 as a cell entry receptor. Soluble ACE2 has been shown to have neutralizing antiviral activity but has a short half-life and no active transport mechanism from the circulation into the alveolar spaces of the lung. To overcome this, we constructed an ACE2-human IgG1 fusion protein with mutations in the catalytic domain of ACE2. A mutation in the catalytic domain of ACE2, MDR504, significantly increased binding to SARS-CoV-2 spike protein, as well as to a spike variant, in vitro with more potent viral neutralization in plaque assays. Parental administration of the protein showed stable serum concentrations with excellent bioavailability in the epithelial lining fluid of the lung, and ameliorated lung SARS-CoV-2 infection in vivo. These data support that the MDR504 hACE2-Fc is an excellent candidate for treatment or prophylaxis of COVID-19 and potentially emerging variants. | ||||||||||||||||||
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| DOI: | 10.21430/M3VFSW4ZDV | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2646: SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8+ T cells | ||||||||||
| Status: | New | |||||||||
| Description: | Although mRNA vaccine efficacy against severe coronavirus disease 2019 remains high, variant emergence has prompted booster immunizations. However, the effects of repeated exposures to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens on memory T cells are poorly understood. Here, we utilize major histocompatibility complex multimers with single-cell RNA sequencing to profile SARS-CoV-2-responsive T cells ex vivo from humans with one, two or three antigen exposures, including vaccination, primary infection and breakthrough infection. Exposure order determined the distribution between spike-specific and non-spike-specific responses, with vaccination after infection leading to expansion of spike-specific T cells and differentiation to CCR7 CD45RA+ effectors. In contrast, individuals after breakthrough infection mount vigorous non-spike-specific responses. Analysis of over 4,000 epitope-specific T cell antigen receptor (TCR) sequences demonstrates that all exposures elicit diverse repertoires characterized by shared TCR motifs, confirmed by monoclonal TCR characterization, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and current vaccination protocols continue to expand and differentiate spike-specific memory. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M376J9D2NT | |||||||||
| Subjects: | 0 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2647: Relationship between hemagglutinin stability and influenza virus persistence after exposure to low pH or supraphysiological heating | |||||||
| Status: | New | ||||||
| Description: | The hemagglutinin (HA) surface glycoprotein is triggered by endosomal low pH to cause membrane fusion during influenza A virus (IAV) entry yet must remain sufficiently stable to avoid premature activation during virion transit between cells and hosts. HA activation pH and/or virion inactivation pH values less than pH 5.6 are thought to be required for IAV airborne transmissibility and human pandemic potential. To enable higher-throughput screening of emerging IAV strains for ""humanized"" stability, we developed a luciferase reporter assay that measures the threshold pH at which IAVs are inactivated. The reporter assay yielded results similar to TCID50 assay yet required one-fourth the time and one-tenth the virus. For four A/TN/09 (H1N1) HA mutants and 73 IAVs of varying subtype, virion inactivation pH was compared to HA activation pH and the rate of inactivation during 55 degree C heating. HA stability values correlated highly with virion acid and thermal stability values for isogenic viruses containing HA point mutations. HA stability also correlated with virion acid stability for human isolates but did not correlate with thermal stability at 55 degree C, raising doubt in the use of supraphysiological heating assays. Some animal isolates had virion inactivation pH values lower than HA activation pH, suggesting factors beyond HA stability can modulate virion stability. The coupling of HA activation pH and virion inactivation pH, and at a value below 5.6, was associated with human adaptation. This suggests that both virologic properties should be considered in risk assessment algorithms for pandemic potential. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3D15GQKGE | ||||||
| Subjects: | 2 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2648: Association of Frailty, Age, and Biological Sex With Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Vaccine-Induced Immunity in Older Adults | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | Male sex and old age are risk factors for severe coronavirus disease 2019, but the intersection of sex and aging on antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has not been characterized. Plasma samples were collected from older adults (aged 75-98 years) before and after 3 doses of SARS-CoV-2 mRNA vaccination, and from younger adults (aged 18-74 years) post-dose 2, for comparison. Antibody binding to SARS-CoV-2 antigens (spike protein [S], S receptor-binding domain, and nucleocapsid), functional activity against S, and live-virus neutralization were measured against the vaccine virus and the Alpha, Delta, and Omicron variants of concern (VOCs). Vaccination induced greater antibody titers in older females than in older males, with both age and frailty associated with reduced antibody responses in males but not females. Responses declined significantly in the 6 months after the second dose. The third dose restored functional antibody responses and eliminated disparities caused by sex, age, and frailty in older adults. Responses to the VOCs, particularly the Omicron variant, were significantly reduced relative to the vaccine virus, with older males having lower titers to the VOCs than older females. Older adults had lower responses to the vaccine and VOC viruses than younger adults, with greater disparities in males than in females. Older and frail males may be more vulnerable to breakthrough infections owing to low antibody responses before receipt of a third vaccine dose. Promoting third dose coverage in older adults, especially males, is crucial to protecting this vulnerable population. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3HY5YGXT6 | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2649: Immunogenicity testing of a recombinant N1 vaccine candidate in vivo | ||||||||||
| Status: | New | |||||||||
| Description: | Female 6-8 week old BALB/c mice were vaccinated in a prime/boost regimen with 3ug of recombinant N1-MPP protein. The protein was administered intramuscularly either alone or in combination with different adjuvants to enhance the immune response. Furthermore, N1-MPP was used to supplement different seasonal available QIVs and was then either administered in a mixture containing both N1 and QIV or administered in different legs, QIV in the left leg and N1 at the same time in the right leg. Afterward, the mice were challenged with 25x LD50 of A/Singapore/GP1908/2015 (H1N1) virus, and weight loss and survival were monitored over 2 weeks. Afterward, serological analysis of the serum obtained after 1st and 2nd vaccination was conducted. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M32JMCQP66 | |||||||||
| Subjects: | 205 | |||||||||
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| SDY2650: SARS-CoV-2 seroprevalence and risk factors among meat packing, produce processing, and farm workers | ||||||||||
| Status: | New | |||||||||
| Description: | Meat packing, produce processing, and farm workers are known to have an elevated risk of COVID-19, but occupational risk factors in this population are unclear. We performed an observational cohort study of meat packing, produce processing, and farm workers in North Carolina in fall 2020. Blood, saliva, and nasal turbinate samples were collected to assess for SARS-CoV-2 seropositivity. Risk factors for SARS-CoV-2 seropositivity were investigated using chi-square tests, two-sample t-tests, and adjusted risk ratio analyses. Among 118 enrolled workers, the baseline SARS-CoV-2 seroprevalence was 50.0%. Meat packing plant workers had the highest SARS-CoV-2 seroprevalence (64.6%), followed by farm workers (45.0%) and produce processing workers (10.0%), despite similar sociodemographic characteristics. Compared to SARS-CoV-2 seronegative workers, seropositive workers were more likely to work in loud environments that necessitated yelling to communicate (RR: 1.83, 95% CI: 1.25-2.69), work in cold environments (RR: 1.58, 95% CI: 1.12-2.24), or continue working despite developing symptoms at work (RR: 1.63, 95% CI: 1.14-2.32). After adjusting for age and working despite symptoms, high occupational noise levels were associated with a 1.72 times higher risk of SARS-CoV-2 seropositivity (95% CI: 1.16-2.55). Half of food processing workers showed evidence of past SARS-CoV-2 infection, a prevalence five times higher than most of the United States population at the time of the study. Work environments with loud ambient noise may pose elevated risks for SARS-CoV-2 transmission. Our findings also highlight the disproportionate burden of COVID-19 among underserved and economically disadvantaged Latinx communities in the United States. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3JQ2EU16S | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2651: Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes | |||||||||||||||
| Status: | New | ||||||||||||||
| Description: | The molecular composition and binding epitopes of the immunoglobulin G (IgG) antibodies that circulate in blood plasma after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are unknown. Proteomic deconvolution of the IgG repertoire to the spike glycoprotein in convalescent subjects revealed that the response is directed predominantly (>80%) against epitopes residing outside the receptor binding domain (RBD). In one subject, just four IgG lineages accounted for 93.5% of the response, including an amino (N)-terminal domain (NTD)-directed antibody that was protective against lethal viral challenge. Genetic, structural, and functional characterization of a multidonor class of ""public"" antibodies revealed an NTD epitope that is recurrently mutated among emerging SARS-CoV-2 variants of concern. These data show that ""public"" NTD-directed and other non-RBD plasma antibodies are prevalent and have implications for SARS-CoV-2 protection and antibody escape | ||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M36CGG8MU7 | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
| SDY2652: UV 222 disinfection of SARS-CoV-2 in solution | |||||||||
| Status: | New | ||||||||
| Description: | There is an urgent need for evidence-based engineering controls to reduce transmission of SARS-CoV-2, which causes COVID-19. Although ultraviolet (UV) light is known to inactivate coronaviruses, conventional UV lamps contain toxic mercury and emit wavelengths (254 nm) that are more hazardous to humans than krypton chlorine excimer lamps emitting 222 nm (UV222). Here we used culture and molecular assays to provide the first dose response for SARS-CoV-2 solution exposed to UV222. Culture assays (plaque infectivity to Vero host) demonstrated more than 99.99% disinfection of SARS-CoV-2 after a UV222 dose of 8 mJ/cm2 (pseudo-first order rate constant = 0.64 cm2/mJ). Immediately after UV222 treatment, RT-qPCR assays targeting the nucleocapsid (N) gene demonstrated ~ 10% contribution of N gene damage to disinfection kinetics, and an ELISA assay targeting the N protein demonstrated no contribution of N protein damage to disinfection kinetics. Molecular results suggest other gene and protein damage contributed more to disinfection. After 3 days incubation with host cells, RT-qPCR and ELISA kinetics of UV222 treated SARS-CoV-2 were similar to culture kinetics, suggesting validity of using molecular assays to measure UV disinfection without culture. These data provide quantitative disinfection kinetics which can inform implementation of UV222 for preventing transmission of COVID-19. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3KI3KV40A | ||||||||
| Subjects: | 0 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY2653: Study of efficacy and longevity of immune response to third and fourth doses of COVID-19 vaccines in patients with cancer: A single arm clinical trial | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Background: Cancer patients show increased morbidity with COVID-19 and need effective immunization strategies. Many healthcare regulatory agencies recommend administering 'booster' doses of COVID-19 vaccines beyond the standard two-dose series, for this group of patients. Therefore, studying the efficacy of these additional vaccine doses against SARS-CoV-2 and variants of concern is of utmost importance in this immunocompromised patient population. Methods: We conducted a prospective single arm clinical trial enrolling patients with cancer that had received two doses of mRNA or one dose of AD26.CoV2.S vaccine and administered a third dose of mRNA vaccine. We further enrolled patients that had no or low responses to three mRNA COVID vaccines and assessed the efficacy of a fourth dose of mRNA vaccine. Efficacy was assessed by changes in anti-spike antibody, T-cell activity, and neutralization activity, which were again assessed at baseline and 4 weeks. Results: We demonstrate that a third dose of COVID-19 vaccine leads to seroconversion in 57% of patients that were seronegative after primary vaccination series. The immune response is durable as assessed by anti-SARS-CoV-2 (anti-S) antibody titers, T-cell activity, and neutralization activity against wild-type (WT) SARS-CoV2 and BA1.1.529 at 6 months of follow-up. A subset of severely immunocompromised hematologic malignancy patients that were unable to mount an adequate immune response (titer <1000 AU/mL) after the third dose and were treated with a fourth dose in a prospective clinical trial which led to adequate immune boost in 67% of patients. Low baseline IgM levels and CD19 counts were associated with inadequate seroconversion. Booster doses induced limited neutralization activity against the Omicron variant. Conclusions: These results indicate that third dose of COVID vaccine induces durable immunity in cancer patients and an additional dose can further stimulate immunity in a subset of patients with inadequate response. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3X4DFJ39H | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2654: Intravenous BCG vaccination reduces SARS-CoV-2 severity and promotes extensive reprogramming of lung immune cells | |||||||||||||||||
| Status: | New | ||||||||||||||||
| Description: | Bacillus Calmette-Guérin (BCG) confers heterologous immune protection against viral infections and has been proposed as vaccine against SARS-CoV-2 (SCV2). Here, we tested intravenous BCG vaccination against COVID-19 using the golden Syrian hamster model. BCG vaccination conferred a modest reduction on lung SCV2 viral load, bronchopneumonia scores, and weight loss, accompanied by a reversal of SCV2-mediated T cell lymphopenia, and reduced lung granulocytes. BCG uniquely recruited immunoglobulin-producing plasma cells to the lung suggesting accelerated local antibody production. BCG vaccination also recruited elevated levels of Th1, Th17, Treg, CTLs, and Tmem cells, with a transcriptional shift away from exhaustion markers and toward antigen presentation and repair. Similarly, BCG enhanced recruitment of alveolar macrophages and reduced key interstitial macrophage subsets, that show reduced IFN-associated gene expression. Our observations indicate that BCG vaccination protects against SCV2 immunopathology by promoting early lung immunoglobulin production and immunotolerizing transcriptional patterns among key myeloid and lymphoid populations. | ||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M37N1W8UXX | ||||||||||||||||
| Subjects: | 0 | ||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||
| SDY2655: Broadly neutralizing anti-S2 antibodies protect against all three human betacoronaviruses that cause deadly disease | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against novel pandemic coronaviruses and to more effectively respond to SARS-CoV-2 variants. The emergence of Omicron and subvariants of SARS-CoV-2 illustrates the limitations of solely targeting the receptor-binding domain (RBD) of the spike (S) protein. Here, we isolated a large panel of broadly neutralizing antibodies (bnAbs) from SARS-CoV-2 recovered-vaccinated donors, which targets a conserved S2 region in the betacoronavirus spike fusion machinery. Select bnAbs showed broad in vivo protection against all three deadly betacoronaviruses, SARS-CoV-1, SARS-CoV-2, and MERS-CoV, which have spilled over into humans in the past two decades. Structural studies of these bnAbs delineated the molecular basis for their broad reactivity and revealed common antibody features targetable by broad vaccination strategies. These bnAbs provide new insights and opportunities for antibody-based interventions and for developing pan-betacoronavirus vaccines. | ||||||||||||||||||
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| DOI: | 10.21430/M3QG1JQWI5 | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2656: SeroNet Reference Study | ||||||||||||||||||||||||||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||||||||||||||||||||||||||
| Description: | The National Cancer Institute’s Serological Sciences Network (SeroNet) is the nation’s largest coordinated effort to study the immune response to COVID-19 and increase the nation’s antibody testing capacity. SeroNet is a collaboration across 26 biomedical research institutions to enhance understanding of the immune response to the novel coronavirus, SARS-CoV-2. The COVID-19 Serology Laboratory coordinates much of the SeroNet research and is leading COVID-19 serology standardization efforts for the network. The SeroNet Coordinating Center, headquartered at and managed by the Vaccine, Immunity, and Cancer Directorate at the Frederick National Laboratory, provides program logistical support. SeroNet launched in October 2020, less than a year into the COVID-19 pandemic. It aims to answer critical questions regarding serology and the pandemic. SeroNet is a major component of the National Cancer Institute’s response to COVID-19. In April 2020, the National Cancer Institute received an emergency appropriation of $306 million from Congress to develop, validate, and implement serological testing and associated technologies. More than half of the funding is devoted to SeroNet. Data and studies generated by SeroNet are available on the ImmPort system, which provides a sustainable, publicly accessible archive of data generated by investigators at the National Institute of Allergy and Infectious Diseases. In early 2021, the Frederick National Laboratory supported the development and production of the Human SARS-CoV-2 Serology Standard for calibration in COVID-19 studies conducted around the U.S. and world. Lab scientists have worked with the National Cancer Institute, U.S. Food and Drug Administration, Centers for Disease Control and Prevention, other government agencies, and universities to develop sample evaluation panels to evaluate the performance (sensitivity and specificity) of antibody tests developed by external organizations before they are made available to the public. | |||||||||||||||||||||||||||||||||||||||||||||
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| DOI: | 10.21430/M3AUTZYP4Q | |||||||||||||||||||||||||||||||||||||||||||||
| Subjects: | 909 | |||||||||||||||||||||||||||||||||||||||||||||
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| Publications: | None | |||||||||||||||||||||||||||||||||||||||||||||
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| SDY2657: Seroepidemiology and risk factors for SARS-CoV-2 infection among household members of food processing and farm workers in North Carolina | ||||||||||
| Status: | New | |||||||||
| Description: | Background: Racial and ethnic minorities have borne a disproportionate burden from coronavirus disease 2019 (COVID-19). Certain essential occupations, including food processing and farm work, employ large numbers of Hispanic migrant workers and have been shown to carry an especially high risk of infection. Methods: This observational cohort study measured the seroprevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and assessed the risk factors for seropositivity among food processing and farm workers, and members of their households, in North Carolina, USA. Participants completed questionnaires, blood samples were collected, and an enzyme-linked immunosorbent assay was used to assess SARS-CoV-2 seropositivity. Univariate and multi-variate analyses were undertaken to identify risk factors associated with seropositivity, using generalized estimating equations to account for household clustering. Findings: Among the 218 participants, 94.5% were Hispanic, and SARS-CoV-2 seropositivity was 50.0%. Most seropositive individuals did not report a history of illness compatible with COVID-19. Attending church, having a prior history of COVID-19, having a seropositive household member, and speaking Spanish as one's primary language were associated with SARS-CoV-2 seropositivity, while preventive behaviours were not. Interpretation: These findings underscore the substantial burden of COVID-19 among a population of mostly Hispanic essential workers and their households in rural North Carolina. This study contributes to a large body of evidence showing that Hispanic Americans have suffered a disproportionate burden of COVID-19. This study also highlights the epidemiologic importance of viral transmission within the household. | |||||||||
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| DOI: | 10.21430/M3X3PEYOKR | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2658: Dysregulated naive B cells and de novo autoreactivity in severe COVID-19 | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | Severe SARS-CoV-2 infection1 has been associated with highly inflammatory immune activation since the earliest days of the COVID-19 pandemic2–5. More recently, these responses have been associated with the emergence of self-reactive antibodies with pathologic potential6–10, although their origins and resolution have remained unclear11. Previously, we and others have identified extrafollicular B cell activation, a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity12,13, as a dominant feature of severe and critical COVID-19. Here, using single-cell B cell repertoire analysis of patients with mild and severe disease, we identify the expansion of a naive-derived, low-mutation IgG1 population of antibody-secreting cells (ASCs) reflecting features of low selective pressure. These features correlate with progressive, broad, clinically relevant autoreactivity, particularly directed against nuclear antigens and carbamylated proteins, emerging 10–15 days after the onset of symptoms. Detailed analysis of the low-selection compartment shows a high frequency of clonotypes specific for both SARS-CoV-2 and autoantigens, including pathogenic autoantibodies against the glomerular basement membrane. We further identify the contraction of this pathway on recovery, re-establishment of tolerance standards and concomitant loss of acute-derived ASCs irrespective of antigen specificity. However, serological autoreactivity persists in a subset of patients with postacute sequelae, raising important questions as to the contribution of emerging autoreactivity to continuing symptomology on recovery. In summary, this study demonstrates the origins, breadth and resolution of autoreactivity in severe COVID-19, with implications for early intervention and the treatment of patients with post-COVID sequelae. | ||||||||||||||||||
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| DOI: | 10.21430/M3BG5XDB1N | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2659: NK T cells SARS-CoV-2 | |||||||
| Status: | New | ||||||
| Description: | Immune responses in pregnant women | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3TFVC6NAQ | ||||||
| Subjects: | 128 | ||||||
| Study PI, contact: |
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| Assays: | None | ||||||
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| SDY2660: Pre-existing humoral immunity to human common cold coronaviruses negatively impacts the protective SARS-CoV-2 antibody response | ||||||||||
| Status: | New | |||||||||
| Description: | SARS-CoV-2 infection causes diverse outcomes ranging from asymptomatic infection to respiratory distress and death. A major unresolved question is whether prior immunity to endemic, human common cold coronaviruses (hCCCoVs) impacts susceptibility to SARS-CoV-2 infection or immunity following infection and vaccination. Therefore, we analyzed samples from the same individuals before and after SARS-CoV-2 infection or vaccination. We found hCCCoV antibody levels increase after SARS-CoV-2 exposure, demonstrating cross-reactivity. However, a case-control study indicates that baseline hCCCoV antibody levels are not associated with protection against SARS-CoV-2 infection. Rather, higher magnitudes of pre-existing betacoronavirus antibodies correlate with more SARS-CoV-2 antibodies following infection, an indicator of greater disease severity. Additionally, immunization with hCCCoV spike proteins before SARS-CoV-2 immunization impedes the generation of SARS-CoV-2-neutralizing antibodies in mice. Together, these data suggest that pre-existing hCCCoV antibodies hinder SARS-CoV-2 antibody-based immunity following infection and provide insight on how pre-existing coronavirus immunity impacts SARS-CoV-2 infection, which is critical considering emerging variants. | |||||||||
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| DOI: | 10.21430/M3QUAIWU0U | |||||||||
| Subjects: | 0 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2661: Broadly Reactive H2 Hemagglutinin Vaccines Elicit Cross-Reactive Antibodies in Ferrets Preimmune to Seasonal Influenza A Viruses | |||||||
| Status: | New | ||||||
| Description: | In this study, previously described H2 computationally optimized broadly reactive antigen (COBRA) hemagglutinin vaccines (Z1 and Z5) were tested in influenza virus | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3CWE7D59L | ||||||
| Subjects: | 120 | ||||||
| Study PI, contact: |
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2662: Broadly protective bispecific antibodies that simultaneously target influenza hemagglutinin and neuraminidase | |||||||
| Status: | New | ||||||
| Description: | Here, the investigators engineered bispecific antibodies (bsAbs) combining the variable domains of CR9114 and 1G01, and evaluated their properties in vitro and in vivo. | ||||||
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| DOI: | 10.21430/M3QVEFRG2S | ||||||
| Subjects: | 521 | ||||||
| Study PI, contact: |
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| Publications: | None | ||||||
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| Assays: | None | ||||||
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Updated Studies
| SDY1484: Role of CD4+ Memory Phenotype, Memory, and Effector T Cells in Vaccination and Infection (SLVP030) | |||||||||||
| Status: | Updated | ||||||||||
| Description: | This is a Phase IV study of up to 100 healthy children, ages 6 months to 10 years of age, who will receive either Flumist live, attenuated influenza virus vaccine, quadrivalent (LAIV4) or the current Fluzone inactivated influenza vaccine, quadrivalent (IIV4). The volunteers will be enrolled into one of 3 Groups (A, B, C). Volunteers will return each year until 2018-2019 for annual flu immunizations and study visits. Questionnaires will be administered annually to record demographic characteristics, vaccination history, exposure to animals, day care and medically attended illness. There are no exclusions for gender, ethnicity or race. Volunteers in Group C will also receive the measles, mumps, rubella and varicella (MMRV) vaccine at approximately 12-15 months of age (to be administered by the volunteers' personal pediatrician, not as a study vaccine). They will then come for a study visit to collect blood 60 days later. Each twin is counted as a single participant. All reporting numbers reflect the number of participants, not the number of twin pairs. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3VRIZVVE5 | ||||||||||
| Subjects: | 81 | ||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||
| SDY1644: Urban Environmental Factors and Childhood Asthma (URECA) (ICAC-07) | ||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||
| Description: | The purpose of this study is to determine the way environmental factors (like the components of inner-city household dust) affect immune system development and symptoms of asthma in inner city children. The study is divided into three periods, as the subjects age from birth to 10 years old. Each age bracket will explore different objectives and endpoints. Study Objectives/Hypotheses: Subjects age 0 to 3 years old: Environmental factors in the inner city adversely influence the development of the immune system to promote cytokine dysregulation, allergy, and recurrent wheezing by age 3. Children who have had a viral lower respiratory infection and have developed cytokine dysregulation by age 3 are at increased risk for the development of asthma by age 6. Subjects age 4 to 7 years old: There is a unique pattern of immune development that is driven by specific urban exposures in early life, and this pattern of immune development is characterized by: 1) impairment of antiviral responses and 2) accentuation of Th2-like responses (e.g. cockroach-specific Interleukin-13(IL-13)). The clinical effects of these changes in immune development are frequent virus-induced wheezing and allergic sensitization by 3-4 years of age, and these characteristics synergistically increase the risk of asthma at age 7 years. Subjects age 7 to 10 years old: There are unique combinations of environmental exposures (cockroach allergens, indoor pollutants [Environmental Tobacco Smoke (ETS) and Nitrogen Dioxide (NO2)], lack of microbial exposure), and family characteristics (stress, genetic factors related to innate immunity) that synergistically promote asthma onset, persistence, and morbidity in urban neighborhoods. These exposures and characteristics influence immune expression and lung development during critical periods of growth, resulting in specific asthma phenotypes. Subjects age 10 to 16 years old: To determine the wheezing, asthma and atopy phenotypes in minority children growing up in poor urban neighborhoods as they develop from birth through adolescence. | |||||||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3H1YHLR5Z | |||||||||||||||||||||||||||
| Subjects: | 1218 | |||||||||||||||||||||||||||
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| SDY2079: Sex and Dose Rate Effects in High Throughput Cytogenetics | |||||||
| Status: | Updated | ||||||
| Description: | Blood from adult and pediatric donors was collected into sodium heparin vacutainer tubes. Blood from each donor was diluted (1:4) in RPMI and exposed to 0, 3 or8 Gy f radiation at various dose rates with the irradiation taking between 5 usec and 48h. Samples were then assayed for micronucleus formation and for dicentric chromosomes using a high throughput assay in 96-well plates. We have seen essentially no effect of Sex on the dicentric or micronucleus yields. High dose rates resulted in decrease in both micronucleus and dicentric yields, primarily at high doses. Age data has not yet been analyzed. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M33REGWY6X | ||||||
| Subjects: | 591 | ||||||
| Study PI, contact: |
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| Publications: | None | ||||||
| Resources: |
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2193: MoTrPAC 6-month rat endurance training | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | The MoTrPAC program is supported by the NIH Common Fund and is managed by a trans-agency working group representing multiple NIH institutes and centers, led by the NIH Office of Strategic Coordination, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, and National Institute of Biomedical Imaging and Bioengineering. | ||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3XZN09QFF | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
| Study PI, contact: |
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| Resources: |
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| Assays: | None | ||||||||||||||
| Clinical Assessments: | None | ||||||||||||||
| SDY2234: Optimizing prevalence estimates for a novel pathogen by reducing uncertainty in test characteristics | |||||||
| Status: | Updated | ||||||
| Description: | Emergence of a novel pathogen drives the urgent need for diagnostic tests that can aid in defining disease prevalence. The limitations associated with rapid development and deployment of these tests result in a dilemma: In efforts to optimize prevalence estimates, would tests be better used in the lab to reduce uncertainty in test characteristics or to increase sample size in field studies? Here, we provide a framework to address this question through a joint Bayesian model that simultaneously analyzes lab validation and field survey data, and we define the impact of test allocation on inferences of sensitivity, specificity, and prevalence. In many scenarios, prevalence estimates can be most improved by apportioning additional effort towards validation rather than to the field. The joint model provides superior estimation of prevalence, sensitivity, and specificity, compared with typical analyses that model lab and field data separately, and it can be used to inform sample allocation when testing is limited. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3O5E1Q8JY | ||||||
| Subjects: | 0 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2328: The Kinetics of SARS-CoV-2 Antibody Development Is Associated with Clearance of RNAemia | ||||||||||
| Status: | Updated | |||||||||
| Description: | Persistent SARS-CoV-2 replication and systemic dissemination are linked to increased COVID-19 disease severity and mortality. However, the precise immune profiles that track with enhanced viral clearance, particularly from systemic RNAemia, remain incompletely defined. To define whether antibody characteristics, specificities, or functions that emerge during natural infection are linked to accelerated containment of viral replication, we examined the relationship of SARS-CoV-2-specific humoral immune evolution in the setting of SARS-CoV-2 plasma To define whether antibody characteristics, specificities, or functions that emerge during natural infection are linked to accelerated containment of viral replication, we examined the relationship of SARS-CoV-2-specific humoral immune evolution in the setting of SARS-CoV-2 plasma RNAemia, which is tightly associated with disease severity and death. On presentation to the emergency department, S-specific IgG3, IgA1, and Fc-γ-receptor (Fcγ R) binding antibodies were all inversely associated with higher baseline plasma RNAemia. Importantly, the rapid development of spike (S) and its subunit (S1/S2/receptor binding domain)-specific IgG, especially FcγR binding activity, were associated with clearance of RNAemia. These results point to a potentially critical and direct role for SARS-CoV-2-specific humoral immune clearance on viral dissemination, persistence, and disease outcome, providing novel insights for the development of more effective therapeutics to resolve COVID-19. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M31UN2QQ3Z | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2343: Fab and Fc contribute to maximal protection against SARS-CoV-2 following NVX-CoV2373 subunit vaccine with Matrix-M vaccination | |||||||||||||||||
| Status: | Updated | ||||||||||||||||
| Description: | Recently approved vaccines have shown remarkable efficacy in limiting SARS-CoV-2-associated disease. However, with the variety of vaccines, immunization strategies, and waning antibody titers, defining the correlates of immunity across a spectrum of antibody titers is urgently required. Thus, we profiled the humoral immune response in a cohort of non-human primates immunized with a recombinant SARS-CoV-2 spike glycoprotein (NVX-CoV2373) at two doses, administered as a single- or two-dose regimen. Both antigen dose and boosting significantly altered neutralization titers and Fc-effector profiles, driving unique vaccine-induced antibody fingerprints. Combined differences in antibody effector functions and neutralization were associated with distinct levels of protection in the upper and lower respiratory tract. Moreover, NVX-CoV2373 elicited antibodies that functionally targeted emerging SARS-CoV-2 variants. Collectively, the data presented here suggest that a single dose may prevent disease via combined Fc/Fab functions but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants. | ||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3U21VQOCM | ||||||||||||||||
| Subjects: | 0 | ||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||
| SDY2347: COVID-19 booster dose induces robust antibody response in pregnant, lactating, and nonpregnant women | ||||||||||
| Status: | Updated | |||||||||
| Description: | Background: Although emerging data during the SARS-CoV-2 pandemic have demonstrated robust messenger RNA vaccine-induced immunogenicity across populations, including pregnant and lactating individuals, the rapid waning of vaccine-induced immunity and the emergence of variants of concern motivated the use of messenger RNA vaccine booster doses. Whether all populations, including pregnant and lactating individuals, will mount a comparable response to a booster dose is not known. Objective: This study aimed to profile the humoral immune response to a COVID-19 messenger RNA booster dose in a cohort of pregnant, lactating, and nonpregnant age-matched women. Study design: This study characterized the antibody response against ancestral Spike and Omicron in a cohort of 31 pregnant, 12 lactating, and 20 nonpregnant age-matched controls who received a BNT162b2 or messenger RNA-1273 booster dose after primary COVID-19 vaccination. In addition, this study examined the vaccine-induced antibody profiles of 15 maternal-to-cord dyads at delivery. Results: Receiving a booster dose during pregnancy resulted in increased immunoglobulin G1 levels against Omicron Spike (postprimary vaccination vs postbooster dose; P=.03). Pregnant and lactating individuals exhibited equivalent Spike-specific total immunoglobulin G1, immunoglobulin M, and immunoglobulin A levels and neutralizing titers against Omicron compared with nonpregnant women. Subtle differences in Fc receptor binding and antibody subclass profiles were observed in the immune response to a booster dose in pregnant vs nonpregnant individuals. The analysis of maternal and cord antibody profiles at delivery demonstrated equivalent total Spike-specific immunoglobulin G1 in maternal and cord blood, yet higher Spike-specific FcγR3a-binding antibodies in the cord relative to maternal blood (P=.002), consistent with the preferential transfer of highly functional immunoglobulin. Spike-specific immunoglobulin G1 levels in the cord were positively correlated with the time elapsed since receiving the booster dose (Spearman R, .574; P=.035). Conclusion: Study data suggested that receiving a booster dose during pregnancy induces a robust Spike-specific humoral immune response, including against Omicron. If boosting occurs in the third trimester of pregnancy, higher Spike-specific cord immunoglobulin G1 levels are achieved with greater time elapsed between receiving the booster and delivery. Receiving a booster dose has the potential to augment maternal and neonatal immunity. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3ZR1DTL20 | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2434: Comparative performance of between-population vaccine allocation strategies with applications for emerging pandemics | |||||||
| Status: | Updated | ||||||
| Description: | Vaccine allocation decisions during emerging pandemics have proven to be challenging due to competing ethical, practical, and political considerations. Complicating decision making, policy makers need to consider vaccine allocation strategies that balance needs both within and between populations. When vaccine stockpiles are limited, doses should be allocated in locations to maximize their impact. Using a susceptible-exposed-infectious-recovered (SEIR) model we examine optimal vaccine allocation decisions across two populations considering the impact of characteristics of the population (e.g., size, underlying immunity, heterogeneous risk structure, interaction), vaccine (e.g., vaccine efficacy), pathogen (e.g., transmissibility), and delivery (e.g., varying speed and timing of rollout). Across a wide range of characteristics considered, we find that vaccine allocation proportional to population size (i.e., pro-rata allocation) performs either better or comparably to nonproportional allocation strategies in minimizing the cumulative number of infections. These results may argue in favor of sharing of vaccines between locations in the context of an epidemic caused by an emerging pathogen, where many epidemiologic characteristics may not be known. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M34IWWJ4HH | ||||||
| Subjects: | 0 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2446: Fc-mediated pan-sarbecovirus protection after alphavirus vector vaccination | |||||||||||||||||
| Status: | Updated | ||||||||||||||||
| Description: | Group 2B β-coronaviruses (sarbecoviruses) have caused regional and global epidemics in modern history. Here, we evaluate the mechanisms of cross-sarbecovirus protective immunity, currently less clear yet important for pan-sarbecovirus vaccine development, using a panel of alphavirus-vectored vaccines covering bat to human strains. While vaccination does not prevent virus replication, it protects against lethal heterologous disease outcomes in both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clade 2 bat sarbecovirus challenge models. The spike vaccines tested primarily elicit a highly S1-specific homologous neutralizing antibody response with no detectable cross-virus neutralization. Rather, non-neutralizing antibody functions, mechanistically linked to FcgR4 and spike S2, mediate cross-protection in wild-type mice. Protection is lost in FcR knockout mice, further supporting a model for non-neutralizing, protective antibodies. These data highlight the importance of FcR-mediated cross-protective immune responses in universal pan-sarbecovirus vaccine designs. | ||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3EDQ0ZAF9 | ||||||||||||||||
| Subjects: | 0 | ||||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||||||
| SDY2509: A chimeric haemagglutinin-based universal influenza virus vaccine boosts human cellular immune responses directed towards the conserved haemagglutinin stalk domain and the viral nucleoprotein. | |||||||
| Status: | Updated | ||||||
| Description: | The authors sought to determine whether the vaccines utilized in the observer-blind, randomized placebo-controlled phase I trial (NCT03300050) could, in addition to elicit durable HA stalk specific antibodies, boost T-cell responses against HA stalk, and nucleoprotein (NP). | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M35DPFGEQJ | ||||||
| Subjects: | 40 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY2533: The TLR2/TLR6 ligand FSL-1 mitigates radiation-induced hematopoietic injury in mice and nonhuman primates | ||||||||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||||||||
| Description: | Thrombocytopenia, hemorrhage, anemia, and infection are life-threatening issues following accidental or intentional radiation exposure. Since few therapeutics are available, safe and efficacious small molecules to mitigate radiation-induced injury need to be developed. Our previous study showed the synthetic TLR2/TLR6 ligand fibroblast stimulating lipopeptide (FSL-1) prolonged survival and provided MyD88-dependent mitigation of hematopoietic acute radiation syndrome (H-ARS) in mice. Although mice and humans differ in TLR number, expression, and function, nonhuman primate (NHP) TLRs are like those of humans; therefore, studying both animal models is critical for drug development. The objectives of this study were to determine the efficacy of FSL-1 on hematopoietic recovery in small and large animal models subjected to sublethal total body irradiation and investigate its mechanism of action. In mice, we demonstrate a lack of adverse effects, an easy route of delivery (subcutaneous) and efficacy in promoting hematopoietic progenitor cell proliferation by FSL-1. NHP given radiation, followed a day later with a single subcutaneous administration of FSL-1, displayed no adversity but showed elevated hematopoietic cells. Our analyses revealed that FSL-1 promoted red blood cell development and induced soluble effectors following radiation exposure. Cytologic analysis of bone marrow aspirates revealed a striking enhancement of mononuclear progenitor cells in FSL-1-treated NHP. Combining the efficacy of FSL-1 in promoting hematopoietic cell recovery with the lack of adverse effects induced by a single administration supports the application of FSL-1 as a viable countermeasure against H-ARS. | |||||||||||||||||||||||||||||||||
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| DOI: | 10.21430/M3WMW4268C | |||||||||||||||||||||||||||||||||
| Subjects: | 0 | |||||||||||||||||||||||||||||||||
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| Assays: | None | |||||||||||||||||||||||||||||||||
| Clinical Assessments: | None | |||||||||||||||||||||||||||||||||
| SDY2594: A phase II randomized trial with autologous polyclonal expanded regulatory T cells in children with new onset type 1 diabetes | |||||||
| Status: | Updated | ||||||
| Description: | CD4+CD25hiCD127lo/-FOXP3+ regulatory T cells (Tregs) play a key role in preventing autoimmunity. In autoimmune type 1 diabetes (T1D), adoptive transfer of autologous polyclonal Tregs has been shown to be safe in adults in Phase I clinical trials. We explored factors contributing to efficacy of autologous polyclonal expanded Tregs (expTregs) in a randomized Phase II multi-center, double-blind, clinical trial in 110 treated children and adolescents with new-onset T1D (Sanford/Lisata Therapeutics T-Rex Phase II trial) randomized 1:1:1 to high- (24*10^6 cells/kg) or low- (1*10^6 cells/kg) dose treatments or to matching placebo. Cytometry, bulk and single-cell RNA-sequencing were performed on selected expTregs and peripheral blood samples from participants. The single doses of expTregs were safe but did not prevent the decline in residual beta cell function over one year compared to placebo (P = 0.94 low dose, P = 0.21 high dose), regardless of age or baseline C-peptide. ExpTregs were highly activated and suppressive in vitro. A transient increase of activated memory Tregs was detectable one week after infusion in the high dose cohort suggesting effective transfer of expTregs. However, in vitro fold expansion of expTregs varied across participants even when accounting for age and lower fold expansion and its associated gene signature were linked with better C-peptide preservation regardless of Treg dose. These results suggest that a single dose of polyclonal expTregs does not alter progression in T1D; instead, Treg quality may be an important factor. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3O7O5SQZT | ||||||
| Subjects: | 73 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY2612: ChAdOx1 nCoV-19 (AZD1222) vaccine-induced Fc receptor binding tracks with differential susceptibility to COVID-19 | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | Despite the success of COVID-19 vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern have emerged that can cause breakthrough infections. Although protection against severe disease has been largely preserved, the immunological mediators of protection in humans remain undefined. We performed a substudy on the ChAdOx1 nCoV-19 (AZD1222) vaccinees enrolled in a South African clinical trial. At peak immunogenicity, before infection, no differences were observed in immunoglobulin (Ig)G1-binding antibody titers; however, the vaccine induced different Fc-receptor-binding antibodies across groups. Vaccinees who resisted COVID-19 exclusively mounted FcγR3B-binding antibodies. In contrast, enhanced IgA and IgG3, linked to enriched FcγR2B binding, was observed in individuals who experienced breakthrough. Antibodies unable to bind to FcγR3B led to immune complex clearance and resulted in inflammatory cascades. Differential antibody binding to FcγR3B was linked to Fc-glycosylation differences in SARS-CoV-2-specific antibodies. These data potentially point to specific FcγR3B-mediated antibody functional profiles as critical markers of immunity against COVID-19. | ||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3U2ME6QLL | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||