DR49.1 DataRelease
Release Date: 09/28/2023
New Studies: 22
Updated Studies: 3
New Studies
| SDY2193: MoTrPAC 6-month rat endurance training | |||||||||||||||
| Status: | New | ||||||||||||||
| 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. | ||||||||||||||
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| DOI: | 10.21430/M3XZN09QFF | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
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| SDY2209: CD8 Depletion | |||||||
| Status: | New | ||||||
| Description: | Cell-mediated immunity is critical for control of M. tuberculosis infection. Although the importance of CD4 T cells in control of tuberculosis is well-established, the importance of CD8+ lymphocytes is less clear. Here, we investigated the requirement for all CD8+ lymphocytes (innate and adaptive) or just CD8 alpha/beta adaptive T cells in control of initial and early infection in cynomolgus macaques, using anti-CD8alpha or anti-CD8beta depleting antibodies in vivo. Flow cytometry and single-cell RNA-sequencing analysis of lung granulomas from control (undepleted) macaques at 6 weeks post-infection revealed a rich landscape of cytotoxic CD8+ lymphocytes. Anti-CD8alpha antibody resulted in susbstantial loss of all CD8+ lymphocytes from granulomas, while anti-CD8beta antibody selectively depleted classical CD8alpha beta T cells. In CD8-depleted granulomas, CD4 T cells and gamma delta T cells had increased expression of certain cytotoxic effectors, such as granzymes. However, these cells had reduced expression of perforin, granulysin, and/or CCL5, and thus displayed an incomplete cytotoxic profile. At 6 weeks post-infection, CD8 alpha depleted macaques had increased granuloma numbers, lung inflammation, and total thoracic bacterial burden, while CD8beta-depleted macaques showed increased lymph node bacterial burden. Mtb barcode analysis revealed that depletion of all CD8+ lymphocytes resulted in greater initial establishment of Mtb in the lungs, indicating a loosening of the airway bottleneck for infection, and increased dissemination of Mtb within lungs, to lymph nodes and to extrapulmonary sites. These data suggest that the total CD8+ lymphocyte population is critical for early control of Mtb infection in macaques and support the importance of targeting CD8+ lymphocytes in a vaccine strategy. | ||||||
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| DOI: | 10.21430/M3TEVRE64X | ||||||
| Subjects: | 0 | ||||||
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| SDY2371: Longitudinal analysis of SARS-CoV-2 seroprevalence | ||||||||||
| Status: | New | |||||||||
| Description: | Samples from healthcare workers (HCWs) were collected to perform a longitudinal analysis of the antibody responses using a research-grade RBD and spike-based enzyme-linked immunosorbent assay (ELISA), a commercial RBD and spike-based ELISA, and a commercial NP-based chemiluminescent microparticle immunoassay. | |||||||||
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| DOI: | 10.21430/M3RN7M163W | |||||||||
| Subjects: | 507 | |||||||||
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| SDY2372: Sex and Gender Differences in Testing, Hospital Admission, Clinical Presentation, and Drivers of Severe Outcomes From COVID-19 | ||||||||||
| Status: | New | |||||||||
| Description: | Background: Males experience increased severity of illness and mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared with females, but the mechanisms of male susceptibility are unclear. Methods: We performed a retrospective cohort analysis of SARS-CoV-2 testing and admission data at 5 hospitals in the Maryland/Washington DC area. Using age-stratified logistic regression models, we quantified the impact of male sex on the risk of the composite outcome of severe disease or death (World Health Organization score 5-8) and tested the impact of demographics, comorbidities, health behaviors, and laboratory inflammatory markers on the sex effect. Results: Among 213 175 SARS-CoV-2 tests, despite similar positivity rates, males in age strata between 18 and 74 years were more frequently hospitalized. For the 2626 hospitalized individuals, clinical inflammatory markers (interleukin-6, C-reactive protein, ferritin, absolute lymphocyte count, and neutrophil:lymphocyte ratio) were more favorable for females than males (P < .001). Among 18-49-year-olds, male sex carried a higher risk of severe outcomes, both early (odds ratio [OR], 3.01; 95% CI, 1.75 to 5.18) and at peak illness during hospitalization (OR, 2.58; 95% CI, 1.78 to 3.74). Despite multiple differences in demographics, presentation features, comorbidities, and health behaviors, these variables did not change the association of male sex with severe disease. Only clinical inflammatory marker values modified the sex effect, reducing the OR for severe outcomes in males aged 18-49 years to 1.81 (95% CI, 1.00 to 3.26) early and 1.39 (95% CI, 0.93 to 2.08) at peak illness. Conclusions: Higher inflammatory laboratory test values were associated with increased risk of severe coronavirus disease 2019 for males. A sex-specific inflammatory response to SARS-CoV-2 infection may underlie the sex differences in outcomes. | |||||||||
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| DOI: | 10.21430/M3GXSGMPEX | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2373: Neutralization Escape by SARS-CoV-2 Omicron Subvariant BA.4.6 | ||||||||||
| Status: | New | |||||||||
| Description: | The B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has splintered into multiple subvariants with increased transmissibility and immune escape.1 At the time of this report, omicron subvariant BA.5 is the dominant global virus and has shown substantial immune escape as compared with previous omicron subvariants.2-5 BA.4.6 is a sublineage of BA.4 with two additional mutations in the spike protein (R346T and N658S) (Figure 1A) and has recently increased in prevalence in certain regions currently dominated by BA.5, including in the United States. The ability of BA.4.6 to evade neutralizing antibodies that were induced by infection or vaccination remains to be determined. | |||||||||
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| DOI: | 10.21430/M3Y1WRSJZ6 | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2374: Determinants and Mechanisms of the Low Fusogenicity and High Dependence on Endosomal Entry of Omicron Subvariants | |||||||||
| Status: | New | ||||||||
| Description: | The rapid spread and strong immune evasion of the SARS-CoV-2 Omicron subvariants has raised serious concerns for the global COVID-19 pandemic. These new variants exhibit generally reduced fusogenicity and increased endosomal entry pathway utilization compared to the ancestral D614G variant, the underlying mechanisms of which remain elusive. Here, we show that the C-terminal S1 mutations of the BA.1.1 subvariant, H655Y and T547K, critically govern the low fusogenicity of Omicron. Notably, H655Y also dictates the enhanced endosome entry pathway utilization. Mechanistically, T547K and H655Y likely stabilize the spike trimer conformation as suggested by increased molecular interactions in structural modeling and enhanced S1 shedding of their reversion mutants K547T and Y655H in viral producer cells. Importantly, the H655Y mutation also determines the low fusogenicity and enhanced dependence on the endosomal entry pathway of other Omicron subvariants, including BA.2, BA.2.12.1, BA.4/5, and BA.2.75. Together, these results uncover mechanisms governing Omicron subvariant entry and provide insights into altered Omicron tissue tropism and pathogenesis. IMPORTANCE Omicron has been shown to predominantly use the endosomal entry pathway, resulting in reduced lung tropism and reduced disease severity; however, the underlying mechanism is not fully understood. In addition, whether the most recent Omicron subvariants, including BA.5 and BA.2.75, use the same pathway as their ancestor for entry is currently not known. In this study, we show that T547K and H655Y mutations in the C terminus of the S1 subunit critically determine the enhanced dependence on the endosomal entry pathway as well as the reduced cell-cell fusion activity of Omicron BA.1, BA.1.1, and other subvariants. Further experiments and molecular modeling suggest that H655Y and K547T stabilize the spike trimer conformation, likely contributing to the decreased fusogenicity and endosomal entry. Our work uncovers novel mechanisms underlying the distinct entry pathway of Omicron subvariants and advances our understanding of their biological characteristics. | ||||||||
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| DOI: | 10.21430/M3PPVGC75E | ||||||||
| Subjects: | 0 | ||||||||
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| SDY2375: SARS-CoV-2 Delta variant genomic variation associated with breakthrough infection in Northern California: A retrospective cohort study | ||||||||||
| Status: | New | |||||||||
| Description: | Background: The association between SARS-CoV-2 genomic variation and breakthrough infection is not well-defined among persons with Delta variant SARS-CoV-2 infection. Methods: In a retrospective cohort we assessed whether individual non-lineage defining mutations and overall genomic variation (including low frequency alleles) were associated with breakthrough infection defined as SARS-CoV-2 infection after COVID-19 primary vaccine series. We identified all non-synonymous single nucleotide polymorphisms, insertions and deletions in SARS-CoV-2 genomes with ?5% allelic frequency and population frequency of ?5% and ?95%. Using Poisson regression, we assessed the association with breakthrough infection for each individual mutation and a viral genomic risk score. Results: Thirty-six mutations met our inclusion criteria. Among 12,744 persons infected with Delta variant SARS-CoV-2, 5,949 (47%) were vaccinated and 6,795 (53%) were unvaccinated. Viruses with a viral genomic risk score in the highest quintile were 9% more likely to be associated with breakthrough infection than viruses in the lowest quintile, but including the risk score improved overall predictive model performance (measured by c-statistic) by only +0.0006. Conclusions: Genomic variation within SARS-CoV-2 Delta variant was weakly associated with breakthrough infection, however several potential non-lineage defining mutations were identified that might contribute to immune evasion by SARS-CoV-2. | |||||||||
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| DOI: | 10.21430/M3CTYNVL3V | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2376: Coronavirus Disease 2019 Messenger RNA Vaccine Immunogenicity in Immunosuppressed Individuals | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | Individuals on immunosuppressive (IS) therapy have increased mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and delayed viral clearance may lead to new viral variants. IS therapy reduces antibody responses following coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccination; however, a comprehensive assessment of vaccine immunogenicity is lacking. Here we show that IS therapy reduced neutralizing, binding, and nonneutralizing antibody functions in addition to CD4 and CD8 T-cell interferon-? responses following COVID-19 mRNA vaccination compared to immunocompetent individuals. Moreover, IS therapy reduced cross-reactivity against SARS-CoV-2 variants. These data suggest that the standard COVID-19 mRNA vaccine regimens will likely not provide optimal protection in immunocompromised individuals. | ||||||||||||||||||
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| DOI: | 10.21430/M3XAUTDG0K | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2377: Immunogenicity of COVID-19 mRNA Vaccines in Pregnant and Lactating Women | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | Importance: Pregnant women are at increased risk of morbidity and mortality from COVID-19 but have been excluded from the phase 3 COVID-19 vaccine trials. Data on vaccine safety and immunogenicity in these populations are therefore limited. Objective: To evaluate the immunogenicity of COVID-19 messenger RNA (mRNA) vaccines in pregnant and lactating women, including against emerging SARS-CoV-2 variants of concern. Design, setting, and participants: An exploratory, descriptive, prospective cohort study enrolled 103 women who received a COVID-19 vaccine from December 2020 through March 2021 and 28 women who had confirmed SARS-CoV-2 infection from April 2020 through March 2021 (the last follow-up date was March 26, 2021). This study enrolled 30 pregnant, 16 lactating, and 57 neither pregnant nor lactating women who received either the mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) COVID-19 vaccines and 22 pregnant and 6 nonpregnant unvaccinated women with SARS-CoV-2 infection. Main outcomes and measures: SARS-CoV-2 receptor binding domain binding, neutralizing, and functional nonneutralizing antibody responses from pregnant, lactating, and nonpregnant women were assessed following vaccination. Spike-specific T-cell responses were evaluated using IFN-? enzyme-linked immunospot and multiparameter intracellular cytokine-staining assays. Humoral and cellular immune responses were determined against the original SARS-CoV-2 USA-WA1/2020 strain as well as against the B.1.1.7 and B.1.351 variants. Results: This study enrolled 103 women aged 18 to 45 years (66% non-Hispanic White) who received a COVID-19 mRNA vaccine. After the second vaccine dose, fever was reported in 4 pregnant women (14%; SD, 6%), 7 lactating women (44%; SD, 12%), and 27 nonpregnant women (52%; SD, 7%). Binding, neutralizing, and functional nonneutralizing antibody responses as well as CD4 and CD8 T-cell responses were present in pregnant, lactating, and nonpregnant women following vaccination. Binding and neutralizing antibodies were also observed in infant cord blood and breast milk. Binding and neutralizing antibody titers against the SARS-CoV-2 B.1.1.7 and B.1.351 variants of concern were reduced, but T-cell responses were preserved against viral variants. Conclusion and relevance: In this exploratory analysis of a convenience sample, receipt of a COVID-19 mRNA vaccine was immunogenic in pregnant women, and vaccine-elicited antibodies were transported to infant cord blood and breast milk. Pregnant and nonpregnant women who were vaccinated developed cross-reactive antibody responses and T-cell responses against SARS-CoV-2 variants of concern. | |||||||||||||||
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| DOI: | 10.21430/M39GU9W1LH | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
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| SDY2378: Characterization of immune responses in fully vaccinated individuals after breakthrough infection with the SARS-CoV-2 delta variant | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have been reported frequently in vaccinated individuals with waning immunity. In particular, a cluster of over 1000 infections with the SARS-CoV-2 delta variant was identified in a predominantly fully vaccinated population in Provincetown, Massachusetts in July 2021. In this study, vaccinated individuals who tested positive for SARS-CoV-2 (n = 16) demonstrated substantially higher serum antibody responses than vaccinated individuals who tested negative for SARS-CoV-2 (n = 23), including 32-fold higher binding antibody titers and 31-fold higher neutralizing antibody titers against the SARS-CoV-2 delta variant. Vaccinated individuals who tested positive also showed higher mucosal antibody responses in nasal secretions and higher spike protein-specific CD8+ T cell responses in peripheral blood than did vaccinated individuals who tested negative. These data demonstrate that fully vaccinated individuals developed robust anamnestic antibody and T cell responses after infection with the SARS-CoV-2 delta variant. Moreover, these findings suggest that population immunity will likely increase over time by a combination of widespread vaccination and breakthrough infections. | ||||||||||||
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| DOI: | 10.21430/M3EK86TJV6 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2379: Neutralization escape of Omicron XBB, BR.2, and BA.2.3.20 subvariants | ||||||||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||||||||
| Description: | New Omicron subvariants continue to emerge throughout the world. In particular, the XBB subvariant, which is a recombinant virus between BA.2.10.1.1 and BA.2.75.3.1.1.1, as well as the BA.2.3.20 and BR.2 subvariants that contain mutations distinct from BA.2 and BA.2.75, are currently increasing in proportion of variants sequenced. Here we show that antibodies induced by 3-dose mRNA booster vaccination as well as BA.1- and BA.4/5-wave infection effectively neutralize BA.2, BR.2, and BA.2.3.20 but have significantly reduced efficiency against XBB. In addition, the BA.2.3.20 subvariant exhibits enhanced infectivity in the lung-derived CaLu-3 cells and in 293T-ACE2 cells. Overall, our results demonstrate that the XBB subvariant is highly neutralization resistant, which highlights the need for continued monitoring of the immune escape and tissue tropism of emerging Omicron subvariants. | |||||||||||||||||||||||||||
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| DOI: | 10.21430/M36HJYNY0B | |||||||||||||||||||||||||||
| Subjects: | 0 | |||||||||||||||||||||||||||
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| SDY2380: Differential Kinetics of Immune Responses Elicited by Covid-19 Vaccines | |||||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||||
| Description: | As shown in previous studies,the BNT162b2 and mRNA-1273 vaccines were characterized by high peak antibody responses that declined sharply by 6 months; these responses declined further by 8 months. Antibody titers in recipients of the mRNA-1273 vaccine were generally higher than those in recipients of the BNT162b2 vaccine. The Ad26.COV2.S vaccine induced lower initial antibody responses, but these responses were relatively stable over the 8-month follow-up period, with minimal-to-no evidence of decline. | ||||||||||||||||||||||||
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| DOI: | 10.21430/M3DT6LU7EW | ||||||||||||||||||||||||
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| SDY2381: Right Ventricular Abnormality in Patients Hospitalized With COVID-19 Infection During Omicron Variant Surge. | |||||||||||||
| Status: | New | ||||||||||||
| Description: | We aimed at studying the association of in-hospital mortality with echocardiographic measures of RV performance during the COVID-19 infection surge in New York City attributed to the spread of the Omicron variant. | ||||||||||||
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| DOI: | 10.21430/M3YP5OULP0 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2382: Coronavirus disease 2019 vaccine response in pregnant and lactating women: a cohort study | ||||||||||
| Status: | New | |||||||||
| Description: | Background: Pregnant and lactating women were excluded from initial coronavirus disease 2019 vaccine trials; thus, data to guide vaccine decision making are lacking. Objective: This study aimed to evaluate the immunogenicity and reactogenicity of coronavirus disease 2019 messenger RNA vaccination in pregnant and lactating women compared with: (1) nonpregnant controls and (2) natural coronavirus disease 2019 infection in pregnancy. Study Design: A total of 131 reproductive-age vaccine recipients (84 pregnant, 31 lactating, and 16 nonpregnant women) were enrolled in a prospective cohort study at 2 academic medical centers. Titers of severe acute respiratory syndrome coronavirus 2 spike and receptor-binding domain immunoglobulin G, immunoglobulin A, and immunoglobulin M were quantified in participant sera (n=131) and breastmilk (n=31) at baseline, at the second vaccine dose, at 2 to 6 weeks after the second vaccine, and at delivery by Luminex. Umbilical cord sera (n=10) titers were assessed at delivery. Titers were compared with those of pregnant women 4 to 12 weeks from the natural infection (n=37) by enzyme-linked immunosorbent assay. A pseudovirus neutralization assay was used to quantify neutralizing antibody titers for the subset of women who delivered during the study period. Postvaccination symptoms were assessed via questionnaire. Kruskal-Wallis tests and a mixed-effects model, with correction for multiple comparisons, were used to assess differences among groups. | |||||||||
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| DOI: | 10.21430/M3E2GTI9WO | |||||||||
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| SDY2383: Methodological approaches to optimize multiplex oral fluid SARS-CoV-2 IgG assay performance and correlation with serologic and neutralizing antibody responses | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Background: Oral fluid (hereafter, saliva) is a non-invasive and attractive alternative to blood for SARS-CoV-2 IgG testing; however, the heterogeneity of saliva as a matrix poses challenges for immunoassay performance. Objectives: To optimize performance of a magnetic microparticle-based multiplex immunoassay (MIA) for SARS-CoV-2 IgG measurement in saliva, with consideration of: i) threshold setting and validation across different MIA bead batches; ii) sample qualification based on salivary total IgG concentration; iii) calibration to U.S. SARS-CoV-2 serological standard binding antibody units (BAU); and iv) correlations with blood-based SARS-CoV-2 serological and neutralizing antibody (nAb) assays. Methods: The salivary SARS-CoV-2 IgG MIA included 2 nucleocapsid (N), 3 receptor-binding domain (RBD), and 2 spike protein (S) antigens. Gingival crevicular fluid (GCF) swab saliva samples were collected before December 2019 (n = 555) and after molecular test-confirmed SARS-CoV-2 infection from 113 individuals (providing up to 5 repeated-measures; n = 398) and used to optimize and validate MIA performance (total n = 953). Combinations of IgG responses to N, RBD and S and total salivary IgG concentration (?g/mL) as a qualifier of nonreactive samples were optimized and validated, calibrated to the U.S. SARS-CoV-2 serological standard, and correlated with blood-based SARS-CoV-2 IgG ELISA and nAb assays. Results: The sum of signal to cutoff (S/Co) to all seven MIA SARS-CoV-2 antigens and disqualification of nonreactive saliva samples with ?15 ?g/mL total IgG led to correct classification of 62/62 positives (sensitivity [Se] = 100.0%; 95% confidence interval [CI] = 94.8%, 100.0%) and 108/109 negatives (specificity [Sp] = 99.1%; 95% CI = 97.3%, 100.0%) at 8-million beads coupling scale and 80/81 positives (Se = 98.8%; 95% CI = 93.3%, 100.0%] and 127/127 negatives (Sp = 100%; 95% CI = 97.1%, 100.0%) at 20-million beads coupling scale. Salivary SARS-CoV-2 IgG crossed the MIA cutoff of 0.1 BAU/mL on average 9 days post-COVID-19 symptom onset and peaked around day 30. Among n = 30 matched saliva and plasma samples, salivary SARS-CoV-2 MIA IgG levels correlated with corresponding-antigen plasma ELISA IgG (N: ? = 0.76, RBD: ? = 0.83, S: ? = 0.82; all p < 0.001). Correlations of plasma SARS-CoV-2 nAb assay area under the curve (AUC) with salivary MIA IgG (N: ? = 0.68, RBD: ? = 0.78, S: ? = 0.79; all p < 0.001) and with plasma ELISA IgG (N: ? = 0.76, RBD: ? = 0.79, S: ? = 0.76; p < 0.001) were similar. Conclusions: A salivary SARS-CoV-2 IgG MIA produced consistently high Se (> 98.8%) and Sp (> 99.1%) across two bead coupling scales and correlations with nAb responses that were similar to blood-based SARS-CoV-2 IgG ELISA data. This non-invasive salivary SARS-CoV-2 IgG MIA could increase engagement of vulnerable populations and improve broad understanding of humoral immunity (kinetics and gaps) within the evolving context of booster vaccination, viral variants and waning immunity. | ||||||||||||
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| DOI: | 10.21430/M369ETTADW | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2384: Dissecting strategies to tune the therapeutic potential of SARS-CoV-2?specific monoclonal antibody CR3022 | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coupled with a lack of therapeutics, has paralyzed the globe. Although significant effort has been invested in identifying antibodies that block infection, the ability of antibodies to target infected cells through Fc interactions may be vital to eliminate the virus. To explore the role of Fc activity in SARS-CoV-2 immunity, the functional potential of a cross?SARS-reactive antibody, CR3022, was assessed. CR3022 was able to broadly drive antibody effector functions, providing critical immune clearance at entry and upon egress. Using selectively engineered Fc variants, no protection was observed after administration of WT IgG1 in mice or hamsters. Conversely, the functionally enhanced Fc variant resulted in increased pathology in both the mouse and hamster models, causing weight loss in mice and enhanced viral replication and weight loss in the more susceptible hamster model, highlighting the pathological functions of Fc-enhancing mutations. These data point to the critical need for strategic Fc engineering for the treatment of SARS-CoV-2 infection. | |||||||||||||||
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| DOI: | 10.21430/M3NWOS0BYJ | |||||||||||||||
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| SDY2385: Significant Reduction in Vaccine Induced Antibody Levels and Neutralization Activity Among Healthcare Workers and Nursing Home Residents 6 Months Following Coronavirus Disease 2019 BNT162b2 mRNA Vaccination | |||||||
| Status: | New | ||||||
| Description: | Antibody decline occurred from 2 weeks to 6 months post-BNT162b2 mRNA vaccination in nursing home (NH) residents and healthcare workers. Antispike, receptor-binding domain, and neutralization levels dropped >81% irrespective of prior infection. Notably, 69% of infection-naive NH residents had neutralizing antibodies at or below the assay?s limit of detection. | ||||||
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| DOI: | 10.21430/M3ET0ZGOYY | ||||||
| Subjects: | 0 | ||||||
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| SDY2386: A Machine Learning Algorithm Predicts Duration of hospitalization in COVID-19 patients. | ||||||||||
| Status: | New | |||||||||
| Description: | The COVID-19 pandemic has placed unprecedented strain on the healthcare system, particularly hospital bed capacity in the setting of large variations in patient length of stay (LOS). Using electronic health record data from 966 COVID-19 patients at a large academic medical center, we developed three machine learning algorithms to predict the likelihood of prolonged LOS, defined as >8 days. The models included 353 variables and were trained on 80% of the cohort, with 20% used for model validation. The three models were created on hospital days 1, 2 and 3, each including information available at or before that point in time. The models' predictive capabilities improved sequentially over time, reaching an accuracy of 0.765, with an AUC of 0.819 by day 3. These models, developed using readily available data, may help hospital systems prepare for bed capacity needs, and help clinicians counsel patients on their likelihood of prolonged hospitalization. | |||||||||
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| DOI: | 10.21430/M36U7RSKAO | |||||||||
| Subjects: | 0 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2387: Progression and Resolution of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Golden Syrian Hamsters | |||||||||||
| Status: | New | ||||||||||
| Description: | To catalyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research, including development of novel interventive and preventive strategies, the progression of disease was characterized in a robust coronavirus disease 2019 (COVID-19) animal model. In this model, male and female golden Syrian hamsters were inoculated intranasally with SARS-CoV-2 USA-WA1/2020. Groups of inoculated and mock-inoculated uninfected control animals were euthanized at 2, 4, 7, 14, and 28 days after inoculation to track multiple clinical, pathology, virology, and immunology outcomes. SARS-CoV-2-inoculated animals consistently lost body weight during the first week of infection, had higher lung weights at terminal time points, and developed lung consolidation per histopathology and quantitative image analysis measurements. High levels of infectious virus and viral RNA were reliably present in the respiratory tract at days 2 and 4 after inoculation, corresponding with widespread necrosis and inflammation. At day 7, when the presence of infectious virus was rare, interstitial and alveolar macrophage infiltrates and marked reparative epithelial responses (type II hyperplasia) dominated in the lung. These lesions resolved over time, with only residual epithelial repair evident by day 28 after inoculation. The use of quantitative approaches to measure cellular and morphologic alterations in the lung provides valuable outcome measures for developing therapeutic and preventive interventions for COVID-19 using the hamster COVID-19 model. | ||||||||||
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| DOI: | 10.21430/M3P39UDC8C | ||||||||||
| Subjects: | 0 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2388: 124I-Iodo-DPA-713 Positron Emission Tomography in a Hamster Model of SARS-CoV-2 Infection | |||||||||||
| Status: | New | ||||||||||
| Description: | Purpose: Molecular imaging has provided unparalleled opportunities to monitor disease processes, although tools for evaluating infection remain limited. Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by lung injury that we sought to model. Activated macrophages/phagocytes have an important role in lung injury, which is responsible for subsequent respiratory failure and death. We performed pulmonary PET/CT with 124I-iodo-DPA-713, a low-molecular-weight pyrazolopyrimidine ligand selectively trapped by activated macrophages cells, to evaluate the local immune response in a hamster model of SARS-CoV-2 infection. Procedures: Pulmonary 124I-iodo-DPA-713 PET/CT was performed in SARS-CoV-2-infected golden Syrian hamsters. CT images were quantified using a custom-built lung segmentation tool. Studies with DPA-713-IRDye680LT and a fluorescent analog of DPA-713 as well as histopathology and flow cytometry were performed on post-mortem tissues. Results: Infected hamsters were imaged at the peak of inflammatory lung disease (7 days post-infection). Quantitative CT analysis was successful for all scans and demonstrated worse pulmonary disease in male versus female animals (P < 0.01). Increased 124I-iodo-DPA-713 PET activity co-localized with the pneumonic lesions. Additionally, higher pulmonary 124I-iodo-DPA-713 PET activity was noted in male versus female hamsters (P = 0.02). DPA-713-IRDye680LT also localized to the pneumonic lesions. Flow cytometry demonstrated a higher percentage of myeloid and CD11b + cells (macrophages, phagocytes) in male versus female lung tissues (P = 0.02). Conclusion: 124I-Iodo-DPA-713 accumulates within pneumonic lesions in a hamster model of SARS-CoV-2 infection. As a novel molecular imaging tool, 124I-Iodo-DPA-713 PET could serve as a noninvasive, clinically translatable approach to monitor SARS-CoV-2-associated pulmonary inflammation and expedite the development of novel therapeutics for COVID-19. | ||||||||||
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| DOI: | 10.21430/M3GXF3V8PA | ||||||||||
| Subjects: | 0 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2389: Exposure of progressive immune dysfunction by SARS-CoV-2 mRNA vaccination in patients with chronic lymphocytic leukemia: A prospective cohort study | |||||||||||
| Status: | New | ||||||||||
| Description: | Patients with chronic lymphocytic leukemia (CLL) have reduced seroconversion rates and lower binding antibody (Ab) and neutralizing antibody (NAb) titers than healthy individuals following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccination. Here, we dissected vaccine-mediated humoral and cellular responses to understand the mechanisms underlying CLL-induced immune dysfunction. We performed a prospective observational study in SARS-CoV-2 infection-naive CLL patients (n = 95) and healthy controls (n = 30) who were vaccinated between December 2020 and June 2021. Sixty-one CLL patients and 27 healthy controls received 2 doses of the Pfizer-BioNTech BNT162b2 vaccine, while 34 CLL patients and 3 healthy controls received 2 doses of the Moderna mRNA-1273 vaccine. The median time to analysis was 38 days (IQR, 27 to 83) for CLL patients and 36 days (IQR, 28 to 57) for healthy controls. Testing plasma samples for SARS-CoV-2 anti-spike and receptor-binding domain Abs by enzyme-linked immunosorbent assay (ELISA), we found that all healthy controls seroconverted to both antigens, while CLL patients had lower response rates (68% and 54%) as well as lower median titers (23-fold and 30-fold; both p < 0.001). Similarly, NAb responses against the then prevalent D614G and Delta SARS-CoV-2 variants were detected in 97% and 93% of controls, respectively, but in only 42% and 38% of CLL patients, who also exhibited >23-fold and >17-fold lower median NAb titers (both p < 0.001). Interestingly, 26% of CLL patients failed to develop NAbs but had high-titer binding Abs that preferentially reacted with the S2 subunit of the SARS-CoV-2 spike. Since these patients were also seropositive for endemic human coronaviruses (HCoVs), these responses likely reflect cross-reactive HCoV Abs rather than vaccine-induced de novo responses. CLL disease status, advanced Rai stage (III-IV), elevated serum beta-2 microglobulin levels (?2m >2.4 mg/L), prior therapy, anti-CD20 immunotherapy (<12 months), and intravenous immunoglobulin (IVIg) prophylaxis were all predictive of an inability to mount SARS-CoV-2 NAbs (all p ? 0.03). T cell response rates determined for a subset of participants were 2.8-fold lower for CLL patients compared to healthy controls (0.05, 95% CI 0.01 to 0.27, p < 0.001), with reduced intracellular IFN? staining (p = 0.03) and effector polyfunctionality (p < 0.001) observed in CD4+ but not in CD8+ T cells. Surprisingly, in treatment-naive CLL patients, BNT162b2 vaccination was identified as an independent negative risk factor for NAb generation (5.8, 95% CI 1.6 to 27, p = 0.006). CLL patients who received mRNA-1273 had 12-fold higher (p < 0.001) NAb titers and 1.7-fold higher (6.5, 95% CI 1.3 to 32, p = 0.02) response rates than BNT162b2 vaccinees despite similar disease characteristics. The absence of detectable NAbs in CLL patients was associated with reduced naive CD4+ T cells (p = 0.03) and increased CD8+ effector memory T cells (p = 0.006). Limitations of the study were that not all participants were subjected to the same immune analyses and that pre-vaccination samples were not available. CLL pathogenesis is characterized by a progressive loss of adaptive immune functions, including in most treatment-naive patients, with preexisting memory being preserved longer than the capacity to mount responses to new antigens. In addition, higher NAb titers and response rates identify mRNA-1273 as a superior vaccine for CLL patients. | ||||||||||
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| DOI: | 10.21430/M3PV8VPKP0 | ||||||||||
| Subjects: | 0 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2390: Conflict in the EMS Workforce: An Analysis of an Open-Ended Survey Question Reveals a Complex Assemblage of Stress, Burnout, and Pandemic-Related Factors Influencing Well-Being | ||||||||||
| Status: | New | |||||||||
| Description: | Emergency Medical Services (EMS) clinicians provide patient care within a high-stakes, unpredictable, and complex work environment in which conflict is inevitable. Our objective was to explore the extent to which added stressors of the pandemic exacerbated EMS workplace conflict. We administered our survey to a sample of U.S. nationally certified EMS clinicians during the COVID-19 pandemic in April 2022. Out of 1881 respondents, 46% (n = 857) experienced conflict and 79% (n = 674) provided free-text descriptions of their experience. The responses were analyzed for themes using qualitative content analysis, and they were then sorted into codes using word unit sets. Code counts, frequencies, and rankings were tabulated, enabling quantitative comparisons of the codes. Of the fifteen codes to emerge, stress (a precursor of burnout) and burnout-related fatigue were the key factors contributing to EMS workplace conflict. We mapped our codes to a conceptual model guided by the National Academies of Sciences, Engineering, and Medicine (NASEM) report on using a systems approach to address clinician burnout and professional well-being to explore implications for addressing conflict within that framework. Factors attributed to conflict mapped to all levels of the NASEM model, lending empirical legitimacy to a broad systems approach to fostering worker well-being. Our findings lead us to propose that active surveillance (enhanced management information and feedback systems) of frontline clinicians' experiences during public health emergencies could increase the effectiveness of regulations and policies across the healthcare system. Ideally, the contributions of the occupational health discipline would become a mainstay of a sustained response to promote ongoing worker well-being. The maintenance of a robust EMS workforce, and by extension the health professionals in its operational sphere, is unquestionably essential to our preparedness for the likelihood that pandemic threats may become more commonplace. | |||||||||
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| DOI: | 10.21430/M3E361589T | |||||||||
| Subjects: | 0 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
Updated Studies
| SDY472: Plasmablast response to inactivated and live attenuated influenza vaccines (TIV3/TIV3 ID) in SLVP021 2013 | |||||||||||
| Status: | Updated | ||||||||||
| Description: | The aim of this study is to compare the response to different formulations of licensed influenza vaccines. The type of seasonal influenza vaccination(s) received independently by volunteers in the year(s) since their last study visit will not impact eligibility. Volunteers will be assigned into one of three vaccine groups (intramuscular trivalent inactivated influenza vaccine (TIV); live attenuated influenza vaccine (LAIV- given year 1 only) or intradermal TIV, based on the type of study vaccine they received in 2010, 2011, 2012, or 2013. All participants will receive a single dose of their assigned seasonal influenza vaccine. Volunteers will complete 3 study visits at Day 0, Day 6-8 and Day 24-32. | ||||||||||
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| DOI: | 10.21430/M3KHTSSSN7 | ||||||||||
| Subjects: | 25 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2279: CD8+ T cells protect against CVB3 infection in females. | ||||||||||
| Status: | Updated | |||||||||
| Description: | Sex is a significant contributor to the outcome of human infections. Males are frequently more susceptible to viral, bacterial, and fungal infections, often attributed to weaker immune responses. In contrast, a heightened immune response in females enables better pathogen elimination but leaves females more predisposed to autoimmune diseases. Unfortunately, the underlying basis for sex-specific immune responses remains poorly understood. Here, we show a sex difference in the CD8+ T cell response to an enteric virus, Coxsackievirus B3 (CVB3). We found that CVB3 induced expansion of CD8+ T cells in female mice but not in male mice. CVB3 also increased the proportion and number of CD11ahiCD62Llo CD8+ T cells in female mice, indicative of activation. This response was independent of the inoculation route and type I interferon. Using a recombinant CVB3 virus expressing a model CD8+ T cell epitope, we found that the expansion of CD8+ T cells in females is viral-specific and not due to bystander activation. Finally, the depletion of CD8+ T cells, prior to infection, led to enhanced mortality, indicating that CD8+ T cells are protective against CVB3 in female mice. These data demonstrate that CVB3 induces a CD8+ T cell response in female mice and highlight the importance of sex-specific immune responses to viral pathogens. | |||||||||
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| DOI: | 10.21430/M3NKQRGD8N | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2351: Variable cellular responses to SARS-CoV-2 in fully vaccinated patients with multiple myeloma | ||||||||||
| Status: | Updated | |||||||||
| Description: | In immunocompromised patients without hematologic malignancies, SARS-CoV-2 vaccines elicit T cell responses even in patients without anti-S IgG antibodies. The production of SARS-CoV-2 T cell immunity is, however, much lower in patients with hematologic malignancies that require steroid use. We wanted to determine whether MM patients without detectable anti-S IgG antibodies to SARS-CoV-2 immunization (seronegative) had detectable SARS-CoV-2 B and T cell responses after SARS-CoV-2 vaccination, which would possibly provide some protection against severe disease even in the absence of anti-S antibodies. | |||||||||
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| DOI: | 10.21430/M3G2TAS469 | |||||||||
| Subjects: | 56 | |||||||||
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| Publications: | None | |||||||||
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