DR44 DataRelease
Release Date: 06/22/2022
| SDY1780: B Cell Induction in Pediatric Lung Transplantation (CTOTC-08) | |||||||
| Status: | New | ||||||
| Description: | This is a phase 2, prospective, multi-center, double-blind, randomized, placebo-controlled clinical trial in which 50 primary pediatric lung transplant recipients will be randomized (1:1) to receive either induction therapy with anti- CD20 mAb (375 mg/m2) IV or placebo (IV day 0 and day 12 post-transplant) plus standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids). The study will randomize 50 primary pediatric lung transplant recipients from seven participating centers. Subjects will be screened, consented, and enrolled while on the UNOS waitlist. When the recipient has received the transplant and is deemed hemodynamically stable, randomization will occur. | ||||||
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| DOI: | 10.21430/M35AUJBTW2 | ||||||
| Subjects: | 45 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1803: Neutralizing antibody against SARS-CoV-2 spike in COVID-19 patients, health care workers, and convalescent plasma donors | |||||||||||
| Status: | New | ||||||||||
| Description: | Rapid and specific antibody testing is crucial for improved understanding, control, and treatment of COVID-19 pathogenesis. Herein, we describe and apply a rapid, sensitive, and accurate virus neutralization assay for SARS-CoV-2 antibodies. The assay is based on an HIV-1 lentiviral vector that contains a secreted intron Gaussia luciferase (Gluc) or secreted nano-luciferase reporter cassette, pseudotyped with the SARS-CoV-2 spike (S) glycoprotein, and is validated with a plaque-reduction assay using an authentic, infectious SARS-CoV-2 strain. The assay was used to evaluate SARS-CoV-2 antibodies in serum from individuals with a broad range of COVID-19 symptoms; patients included those in the intensive care unit (ICU), health care workers (HCWs), and convalescent plasma donors. The highest neutralizing antibody titers were observed among ICU patients, followed by general hospitalized patients, HCWs, and convalescent plasma donors. Our study highlights a wide phenotypic variation in human antibody responses against SARS-CoV-2 and demonstrates the efficacy of a potentially novel lentivirus pseudotype assay for high-throughput serological surveys of neutralizing antibody titers in large cohorts. | ||||||||||
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| DOI: | 10.21430/M3BAM4CN94 | ||||||||||
| Subjects: | 5 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY1812: Repeated cross-sectional sero-monitoring of SARS-CoV-2 in New York City | |||||||
| Status: | New | ||||||
| Description: | In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first detected in China and has since caused a pandemic of coronavirus disease 2019 (COVID-19). The first case of COVID-19 in New York City was officially confirmed on 1 March 2020 followed by a severe local epidemic1. Here, to understand seroprevalence dynamics, we conduct a retrospective, repeated cross-sectional analysis of anti-SARS-CoV-2 spike antibodies in weekly intervals from the beginning of February to July 2020 using more than 10,000 plasma samples from patients at Mount Sinai Hospital in New York City. We describe the dynamics of seroprevalence in an 'urgent care' group, which is enriched in cases of COVID-19 during the epidemic, and a 'routine care' group, which more closely represents the general population. Seroprevalence increased at different rates in both groups; seropositive samples were found as early as mid-February, and levelled out at slightly above 20% in both groups after the epidemic wave subsided by the end of May. From May to July, seroprevalence remained stable, suggesting lasting antibody levels in the population. Our data suggest that SARS-CoV-2 was introduced in New York City earlier than previously documented and describe the dynamics of seroconversion over the full course of the first wave of the pandemic in a major metropolitan area. | ||||||
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| DOI: | 10.21430/M3ZV06EAM0 | ||||||
| Subjects: | 6 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1815: Functional characterization of CD4+ T cell receptors crossreactive for SARS-CoV-2 and endemic coronaviruses | |||||||
| Status: | New | ||||||
| Description: | Recent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unexposed donors, possibly due to crossrecognition by T cells specific for common cold coronaviruses (CCCs). True T cell crossreactivity, defined as the recognition by a single TCR of more than one distinct peptide-MHC ligand, has never been shown in the context of SARS-CoV-2.METHODS: We used the viral functional expansion of specific T cells (ViraFEST) platform to identify T cell responses crossreactive for the spike (S) glycoproteins of SARS-CoV-2 and CCCs at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2-unexposed donors. Confirmation of SARS-CoV-2/CCC crossreactivity and assessments of functional avidity were performed using a TCR cloning and transfection system.RESULTS: Memory CD4+ T cell clonotypes that crossrecognized the S proteins of SARS-CoV-2 and at least one other CCC were detected in 65% of CCPs and unexposed donors. Several of these TCRs were shared among multiple donors. Crossreactive T cells demonstrated significantly impaired SARS-CoV-2-specific proliferation in vitro relative to monospecific CD4+ T cells, which was consistent with lower functional avidity of their TCRs for SARS-CoV-2 relative to CCC.CONCLUSIONSOur data confirm, for what we believe is the first time, the existence of unique memory CD4+ T cell clonotypes crossrecognizing SARS-CoV-2 and CCCs. The lower avidity of crossreactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that preexisting CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these crossreactive T cell responses affect clinical outcomes in COVID-19 patients. | ||||||
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| DOI: | 10.21430/M3C1CZ1MF2 | ||||||
| Subjects: | 2 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1816: Vascular Disease and Thrombosis in SARS-CoV-2-Infected Rhesus Macaques | |||||||
| Status: | New | ||||||
| Description: | The COVID-19 pandemic has led to extensive morbidity and mortality throughout the world. Clinical features that drive SARS-CoV-2 pathogenesis in humans include inflammation and thrombosis, but the mechanistic details underlying these processes remain to be determined. In this study, we demonstrate endothelial disruption and vascular thrombosis in histopathologic sections of lungs from both humans and rhesus macaques infected with SARS-CoV-2. To define key molecular pathways associated with SARS-CoV-2 pathogenesis in macaques, we performed transcriptomic analyses of bronchoalveolar lavage and peripheral blood and proteomic analyses of serum. We observed macrophage infiltrates in lung and upregulation of macrophage, complement, platelet activation, thrombosis, and proinflammatory markers, including C-reactive protein, MX1, IL-6, IL-1, IL-8, TNF_, and NF-_B. These results suggest a model in which critical interactions between inflammatory and thrombosis pathways lead to SARS-CoV-2-induced vascular disease. Our findings suggest potential therapeutic targets for COVID-19. | ||||||
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| DOI: | 10.21430/M3ZINJ9X7N | ||||||
| Subjects: | 2 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1818: Correlates of Protection Against SARS-CoV-2 in Rhesus Macaques | |||||||||
| Status: | New | ||||||||
| Description: | Recent studies have reported protective efficacy of both natural immunity and vaccine-induced immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge in rhesus macaques. However, the importance of humoral and cellular immunity for protection against SARS-CoV-2 infection remains to be determined. Here we show that adoptive transfer of purified IgG from convalescent macaques protects naive recipient rhesus macaques against SARS-CoV-2 challenge in a dose dependent fashion. Depletion of CD8+ T cells in convalescent animals partially abrogated the protective efficacy of natural immunity against SARS-CoV-2 re-challenge, suggesting the importance of cellular immunity in the context of waning or subprotective antibody titers. These data demonstrate that relatively low antibody titers are sufficient for protection against SARS-CoV-2 in rhesus macaques, and that cellular immune responses may also contribute to protection if antibody responses are suboptimal. We also show that higher antibody titers are required for therapy of SARS-CoV-2 infection in macaques. These findings have important implications for the development of SARS-CoV-2 vaccines and immune-based therapeutics. | ||||||||
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| DOI: | 10.21430/M3MW65JZHD | ||||||||
| Subjects: | 7 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY1819: Comparison of Subgenomic and Total RNA in SARS-CoV-2 Challenged Rhesus Macaques | |||||||
| Status: | New | ||||||
| Description: | Respiratory virus challenge studies involve administration of the challenge virus and sampling to assess for protection in the same anatomical locations. It can therefore be difficult to differentiate actively replicating virus from input challenge virus. For SARS-CoV-2, specific monitoring of actively replicating virus is critical for investigating the protective and therapeutic efficacy of vaccines, monoclonal antibodies, and antiviral drugs. We adapted a SARS-CoV-2 subgenomic RNA (sgRNA) RT-PCR assay to differentiate productive infection from inactivated or neutralized virus. Subgenomic RNAs are generated after cell entry and are poorly incorporated into mature virions, and thus may provide a marker for actively replicating virus. We show envelope (E) sgRNA was degraded by RNase in infected cell lysates, while genomic RNA (gRNA) was protected, presumably due to packaging into virions. To investigate the capacity of the sgRNA assay to distinguish input challenge virus from actively replicating virus in vivo, we compared the E sgRNA assay to a standard nucleoprotein (N) or E total (both gRNA and sgRNA) RNA in convalescent rhesus macaques and in antibody-treated rhesus macaques after experimental SARS-CoV-2 challenge. In both studies, the E sgRNA assay was negative, suggesting protective efficacy, whereas the N and E total RNA assays remained positive. These data suggest the potential utility of sgRNA to monitor actively replicating virus in prophylactic and therapeutic SARS-CoV-2 studies. Importance: Developing therapeutic and prophylactic countermeasures for the SARS-CoV-2 virus is a public health priority. During challenge studies, respiratory viruses are delivered and sampled from the same anatomical location. It is therefore important to distinguish actively replicating virus from input challenge virus. The most common assay for detecting SARS-CoV-2 virus, reverse transcription polymerase chain reaction (RT-PCR) targeting nucleocapsid total RNA, cannot distinguish neutralized input virus from replicating virus. In this study, we assess SARS-CoV-2 subgenomic RNA as a potential measure of replicating virus in rhesus macaques. | ||||||
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| DOI: | 10.21430/M3DM6E1Y0R | ||||||
| Subjects: | 4 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1821: MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells | |||||||||||
| Status: | New | ||||||||||
| Description: | Recent studies have profiled the innate immune signatures in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and suggest that cellular responses to viral challenge may affect disease severity. Yet the molecular events that underlie cellular recognition and response to SARS-CoV-2 infection remain to be elucidated. Here, we find that SARS-CoV-2 replication induces a delayed interferon (IFN) response in lung epithelial cells. By screening 16 putative sensors involved in sensing of RNA virus infection, we found that MDA5 and LGP2 primarily regulate IFN induction in response to SARS-CoV-2 infection. Further analyses revealed that viral intermediates specifically activate the IFN response through MDA5-mediated sensing. Additionally, we find that IRF3, IRF5, and NF-B/p65 are the key transcription factors regulating the IFN response during SARS-CoV-2 infection. In summary, these findings provide critical insights into the molecular basis of the innate immune recognition and signaling response to SARS-CoV-2. | ||||||||||
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| DOI: | 10.21430/M31F88A9QL | ||||||||||
| Subjects: | 3 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY1835: Delayed Rise of Oral Fluid Antibodies, Elevated BMI, and Absence of Early Fever Correlate With Longer Time to SARS-CoV-2 RNA Clearance in a Longitudinally Sampled Cohort of COVID-19 Outpatients | |||||||||
| Status: | New | ||||||||
| Description: | Sustained molecular detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in the upper respiratory tract (URT) in mild to moderate coronavirus disease 2019 (COVID-19) is common. We sought to identify host and immune determinants of prolonged SARS-CoV-2 RNA detection. Methods : Ninety-five symptomatic outpatients self-collected midturbinate nasal, oropharyngeal (OP), and gingival crevicular fluid (oral fluid) samples at home and in a research clinic a median of 6 times over 1-3 months. Samples were tested for viral RNA, virus culture, and SARS-CoV-2 and other human coronavirus antibodies, and associations were estimated using Cox proportional hazards models. Results : Viral RNA clearance, as measured by SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR), in 507 URT samples occurred a median (interquartile range) 33.5 (17-63.5) days post-symptom onset. Sixteen nasal-OP samples collected 2-11 days post-symptom onset were virus culture positive out of 183 RT-PCR-positive samples tested. All participants but 1 with positive virus culture were negative for concomitant oral fluid anti-SARS-CoV-2 antibodies. The mean time to first antibody detection in oral fluid was 8-13 days post-symptom onset. A longer time to first detection of oral fluid anti-SARS-CoV-2 S antibodies (adjusted hazard ratio [aHR], 0.96; 95% CI, 0.92-0.99; P = .020) and body mass index (BMI) >=25 kg/m2 (aHR, 0.37; 95% CI, 0.18-0.78; P = .009) were independently associated with a longer time to SARS-CoV-2 viral RNA clearance. Fever as 1 of first 3 COVID-19 symptoms correlated with shorter time to viral RNA clearance (aHR, 2.06; 95% CI, 1.02-4.18; P = .044). Conclusions : We demonstrate that delayed rise of oral fluid SARS-CoV-2-specific antibodies, elevated BMI, and absence of early fever are independently associated with delayed URT viral RNA clearance. | ||||||||
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| DOI: | 10.21430/M3NG59FFQ5 | ||||||||
| Subjects: | 3 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY1840: Tissue-based SARS-CoV-2 detection in fatal COVID-19 infections: Sustained direct viral-induced damage is not necessary to drive disease progression | |||||||||||
| Status: | New | ||||||||||
| Description: | Coronavirus disease 2019 (COVID-19) is an ongoing pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although viral infection is known to trigger inflammatory processes contributing to tissue injury and organ failure, it is unclear whether direct viral damage is needed to sustain cellular injury. An understanding of pathogenic mechanisms has been handicapped by the absence of optimized methods to visualize the presence and distribution of SARS-CoV-2 in damaged tissues. We first developed a positive control cell line (Vero E6) to validate SARS-CoV-2 detection assays. We then evaluated multiple organs (lungs, kidneys, heart, liver, brain, intestines, lymph nodes, and spleen) from fourteen COVID-19 autopsy cases using immunohistochemistry (IHC) for the spike and the nucleoprotein proteins, and RNA in situ hybridization (RNA ISH) for the spike protein mRNA. Tissue detection assays were compared with quantitative polymerase chain reaction (qPCR)-based detection. SARS-CoV-2 was histologically detected in the Vero E6 positive cell line control, 1 of 14 (7%) lungs, and none (0%) of the other 59 organs. There was perfect concordance between the IHC and RNA ISH results. qPCR confirmed high viral load in the SARS-CoV-2 ISH-positive lung tissue, and absent or low viral load in all ISH-negative tissues. In patients who die of COVID-19-related organ failure, SARS-CoV-2 is largely not detectable using tissue-based assays. Even in lungs showing widespread injury, SARS-CoV-2 viral RNA or proteins were detected in only a small minority of cases. This observation supports the concept that viral infection is primarily a trigger for multiple-organ pathogenic proinflammatory responses. Direct viral tissue damage is a transient phenomenon that is generally not sustained throughout disease progression. | ||||||||||
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| DOI: | 10.21430/M3IDUI9TUU | ||||||||||
| Subjects: | 2 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY1849: Estimating SARS-CoV-2 seroprevalence and epidemiological parameters with uncertainty from serological surveys | |||||||
| Status: | New | ||||||
| Description: | Establishing how many people have been infected by SARS-CoV-2 remains an urgent priority for controlling the COVID-19 pandemic. Serological tests that identify past infection can be used to estimate cumulative incidence, but the relative accuracy and robustness of various sampling strategies have been unclear. We developed a flexible framework that integrates uncertainty from test characteristics, sample size, and heterogeneity in seroprevalence across subpopulations to compare estimates from sampling schemes. Using the same framework and making the assumption that seropositivity indicates immune protection, we propagated estimates and uncertainty through dynamical models to assess uncertainty in the epidemiological parameters needed to evaluate public health interventions and found that sampling schemes informed by demographics and contact networks outperform uniform sampling. The framework can be adapted to optimize serosurvey design given test characteristics and capacity, population demography, sampling strategy, and modeling approach, and can be tailored to support decision-making around introducing or removing interventions. | ||||||
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| DOI: | 10.21430/M3M73PFN8O | ||||||
| Subjects: | 1 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1850: Model-informed COVID-19 vaccine prioritization strategies by age and serostatus | |||||||
| Status: | New | ||||||
| Description: | Limited initial supply of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine raises the question of how to prioritize available doses. We used a mathematical model to compare five age-stratified prioritization strategies. A highly effective transmission-blocking vaccine prioritized to adults ages 20 to 49 years minimized cumulative incidence, but mortality and years of life lost were minimized in most scenarios when the vaccine was prioritized to adults greater than 60 years old. Use of individual-level serological tests to redirect doses to seronegative individuals improved the marginal impact of each dose while potentially reducing existing inequities in COVID-19 impact. Although maximum impact prioritization strategies were broadly consistent across countries, transmission rates, vaccination rollout speeds, and estimates of naturally acquired immunity, this framework can be used to compare impacts of prioritization strategies across contexts. | ||||||
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| DOI: | 10.21430/M3NEXZIAC5 | ||||||
| Subjects: | 1 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1851: Interpreting vaccine efficacy trial results for infection and transmission | |||||||
| Status: | New | ||||||
| Description: | Randomized controlled trials (RCTs) have shown high efficacy of multiple vaccines against SARS-CoV-2 disease (COVID-19), and recent studies have shown the vaccines are also effective against infection. Evidence for the effect of each of these vaccines on ability to transmit the virus is also beginning to emerge. We describe an approach to estimate these vaccines' effects on viral positivity, a prevalence measure which under the reasonable assumption that vaccinated individuals who become infected are no more infectious than unvaccinated individuals forms a lower bound on efficacy against transmission. Specifically, we recommend separate analysis of positive tests triggered by symptoms (usually the primary RCT outcome) and cross-sectional prevalence of positive tests obtained regardless of symptoms. The odds ratio of carriage for vaccine vs. placebo provides an unbiased estimate of vaccine effectiveness against viral positivity, under certain assumptions, and we show through simulations that likely departures from these assumptions will only modestly bias this estimate. Applying this approach to published data from the RCT of the Moderna vaccine, we estimate that one dose of vaccine reduces the potential for transmission by at least 61%, possibly considerably more. We describe how these approaches can be translated into observational studies of vaccine effectiveness. | ||||||
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| DOI: | 10.21430/M3S4GR1BIO | ||||||
| Subjects: | 2 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1852: Modeling the impact of racial and ethnic disparities on COVID-19 epidemic dynamics | |||||||
| Status: | New | ||||||
| Description: | Background: The impact of variable infection risk by race and ethnicity on the dynamics of SARS-CoV-2 spread is largely unknown. Methods: Here, we fit structured compartmental models to seroprevalence data from New York State and analyze how herd immunity thresholds (HITs), final sizes, and epidemic risk change across groups. Results: A simple model where interactions occur proportionally to contact rates reduced the HIT, but more realistic models of preferential mixing within groups increased the threshold toward the value observed in homogeneous populations. Across all models, the burden of infection fell disproportionately on minority populations: in a model fit to Long Island serosurvey and census data, 81% of Hispanics or Latinos were infected when the HIT was reached compared to 34% of non-Hispanic whites. Conclusions: Our findings, which are meant to be illustrative and not best estimates, demonstrate how racial and ethnic disparities can impact epidemic trajectories and result in unequal distributions of SARS-CoV-2 infection. Funding: K.C.M. was supported by National Science Foundation GRFP grant DGE1745303. Y.H.G. and M.L. were funded by the Morris-Singer Foundation. M.L. was supported by SeroNet cooperative agreement U01 CA261277 | ||||||
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| DOI: | 10.21430/M33DAWUEID | ||||||
| Subjects: | 2 | ||||||
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| SDY1889: Regimen Optimization Trial of PfSPZ Vaccine in Equatorial Guinea (EGSPZV3) | |||||||
| Status: | New | ||||||
| Description: | This randomized, double-blind, placebo-controlled regimen optimization trial will evaluate the safety, tolerability, immunogenicity and protective efficacy in healthy Equatoguinean men and women age 18-45 years of an attenuated whole Pf sporozoite (SPZ) malaria vaccine (Sanaria? PfSPZ Vaccine) administered by direct venous inoculation (DVI). PfSPZ Vaccine, which is composed of aseptic, purified, live (metabolically active), radiation-attenuated, cryopreserved PfSPZ, will be administered according to 4 different regimens, focusing on condensed regimens 4 weeks or less in duration. Should these condensed regimens prove to be as safe and efficacious as a gold standard 16-week regimen when evaluated in this trial, they will be adopted preferentially for further development based on improved feasibility for any purpose: immunizing children and adults in endemic areas, immunizing prior to travel, immunizing whole populations in mass vaccination programs (MVPs), or immunizing women to protect against pregnancy malaria. In each of these circumstances, rapid immunization regimens would offer a distinct advantage. The first of the 4 regimens to be tested is a standard 16-week regimen that consists of a 4-dose priming series (injections on Days 1, 3, 5, 7) and a 16 -week boost. This regimen is identical to a highly protective regimen studied in a prior trial performed in malaria-naive adults (Warfighter 2 trial), except that the number of PfSPZ injected per dose (4.5x105 PfSPZ in Warfighter 2) has been increased to 9.0x105 PfSPZ for the current trial in Equatorial Guinea. A dose of 9.0x105 PfSPZ has been selected because this dose was highly protective in the BSPZV2 trial conducted in Tanzania. It is also selected because of the presence of naturally acquired immunity (NAI) in the Equatoguinean study population. As shown in prior studies in Africa, prior exposure to malaria in Africans is associated with reduced PfSPZ Vaccine immunogenicity, and to compensate, a somewhat higher dose of PfSPZ is likely required, compared to what may be optimal in malaria naive individuals. This 16-week regimen was the most protective among four different 16-week regimens evaluated in the Warfighter 2 trial. It is thought that the multiple dose prime is the main reason for improved efficacy. In the current study, this gold standard regimen will be compared to three condensed regimens: one with the same 4-dose prime as the 16-week regimen, but with a 28 day (as opposed to 16 week) interval prior to boost; one with the same 4-dose prime and no boost; and one where only two immunizations are used as the prime (Days 1, 7) followed by a 28 day interval boost. The efficacy of each regimen will be evaluated against controlled human malaria infection (CHMI) performed at 8 weeks after immunization. CHMI will be done by injecting a second whole PfSPZ product manufactured by Sanaria: PfSPZ Challenge. PfSPZ Challenge is identical to PfSPZ Vaccine, except the PfSPZ have not been attenuated by irradiation, and therefore are fully infectious. Both PfSPZ Challenge and PfSPZ Vaccine are derived from the NF54 strain of Pf; therefore the CHMIs to be performed in this study will be considered homologous. The overall objective of the trial is to collect data on safety, tolerability, immunogenicity and protection that indicate the best regimen(s) for further development. While the trial is not powered for a formal statistical comparison between the 4 regimens, it will provide important guidance for down-selection. The 4 regimens are: 1. 9.0x105 PfSPZ administered four times on Days 1, 3, 5 and 7 (0, +2, +4, +6 days) as a prime, followed by a boost of 9.0x105 PfSPZ on Day 113 (+16 weeks) (as described above, this is similar to a standard, protective regimen from the Warfighter 2 trial, and will serve as a comparator) 2. 9.0x105 PfSPZ administered four times on Days 1, 3, 5 and 7 (0, +2, +4, +6 days) as a prime, without a boost (to evaluate whether a boost is needed) 3. 9.0x105 PfSPZ administered four times on Days 1, 3, 5 and 7 (0, +2, +4, +6 days) as a prime, followed by a boost of 9.0x105 PfSPZ on Day 29 (+4 weeks) (same as 1, but the interval to the boost is significantly shortened) 4. 9.0x105 PfSPZ administered two times on Days 1 and 8 (0, +7 days) as a prime, followed by a boost of 9.0x105 PfSPZ on Day 29 (+4 weeks) (same as 3, but assesses whether 2 priming immunizations are enough; previously studied in the MAVACHE trial in Germany) The safety and tolerability of each regimen will be measured by recording (1) solicited and unsolicited adverse events, (2) immunogenicity by assessing humoral and cellular immune responses pre- and post-vaccination, and (3) vaccine efficacy (VE) by measuring protection against homologous CHMI administered by DVI of PfSPZ Challenge (NF54) at 8 weeks post-final vaccination. | ||||||
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| DOI: | 10.21430/M3DN79ZRCP | ||||||
| Subjects: | 104 | ||||||
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| SDY1936: Targeted Microbiome Transplant in Atopic Dermatitis (ADRN-08) | |||||||
| Status: | New | ||||||
| Description: | This study will enroll adult participants, 18-60 years of age, with moderate-to-severe atopic dermatitis (AD) and a positive Staphylococcus aureus (S. aureus) colonized lesion (at least 15 cm^2 in size) on the upper extremities. Participants who are eligible based on their positive Staph culture results will be randomized to one of two treatments: Targeted Microbiome Transplant Lotion (TMT) or Placebo (2:1 randomization). One lesional site measuring at least 15 cm^2 and one non-lesional site of equal size will be identified on the participant's ventral upper extremities as the target swabbing areas. These sites will be photographed and marked for swabbing for reference at the participant's future visits. Participants will be instructed to apply investigational product with gloved hands to their ventral upper extremities bilaterally from the wrist to the upper humerus, which will include the identified lesional and non-lesional swabbing sites twice a day for 1 week starting on Day 0. Participants will return to clinic on Day 4 for the assessment of adverse events, the collection of skin swabs from the identified target sites, and to obtain additional investigational product and gloves. Participants will complete an additional clinic visit on Day 7 to correspond with the end of their 1 week treatment. During this visit, participants will be assessed for AEs and provide skin swab samples. All unused product and empty packets will be returned during the Day 4 and Day 7 visits. Three additional clinic visits on Days 8, 9, and 11 will be scheduled for additional skin swabs to assess the safety and the stability of the microbiome transplant and time to recurrence of Staph colonization. Participants will be followed through Day 38 to assess for safety and disease status. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3COUZOPK1 | ||||||
| Subjects: | 79 | ||||||
| Study PI, contact: |
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1937: The Non-pregnant and Pregnant Human Cervix: a Systematic Proteomic Analysis | |||||||
| Status: | New | ||||||
| Description: | Appropriate timing of cervical remodeling (CR) is key to normal term parturition. To date, mechanisms behind normal and abnormal (premature or delayed) CR remain unclear. Recent studies show regional differences exist in human cervical tissue structure. While the entire cervix contains extracellular matrix (ECM), the internal os is highly cellular containing 50a??60% cervical smooth muscle (CSM). The external os contains 10a??20% CSM. Previously, we reported ECM rigidity and different ECM proteins influence CSM cell function, highlighting the importance of understanding not only how cervical cells orchestrate cervical ECM remodeling in pregnancy, but also how changes in specific ECM proteins can influence resident cellular function. To understand this dynamic process, we utilized a systematic proteomic approach to understand which soluble ECM and cellular proteins exist in the different regions of the human cervix and how the proteomic profiles change from the non-pregnant (NP) to the pregnant (PG) state. We found the human cervix proteome contains at least 4548 proteins and establish the types and relative abundance of cellular and soluble matrisome proteins found in the NP and PG human cervix. Further, we report the relative abundance of proteins involved with elastic fiber formation and ECM organization/degradation were significantly increased while proteins involved in RNA polymerase I/promoter opening, DNA methylation, senescence, immune system, and compliment activation were decreased in the PG compared to NP cervix. These findings establish an initial platform from which we can further comprehend how changes in the human cervix proteome results in normal and abnormal CR. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3UI1HK603 | ||||||
| Subjects: | 20 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY1944: Flow cytometer data for investigation into an integrated microfluidic system for basophil isolation from whole blood | |||||||
| Status: | New | ||||||
| Description: | Purity and recovery of basophils isolated from 100 uL of whole blood are measured for the integrated system and subcomponents of the system; artificial activation of basophils by the integrated system is quantified, and basophils are shown to be functional in downstream activation experiments. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3K94PIVEY | ||||||
| Subjects: | 8 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY1945: A humanized mouse model of chronic COVID-19 | |||||||
| Status: | New | ||||||
| Description: | Coronavirus disease 2019 (COVID-19) is an infectious disease that can present as an uncontrolled, hyperactive immune response, causing severe immunological injury. Existing rodent models do not recapitulate the sustained immunopathology of patients with severe disease. Here we describe a humanized mouse model of COVID-19 that uses adeno-associated virus to deliver human ACE2 to the lungs of humanized MISTRG6 mice. This model recapitulates innate and adaptive human immune responses to severe acute respiratory syndrome coronavirus 2 infection up to 28 days after infection, with key features of chronic COVID-19, including weight loss, persistent viral RNA, lung pathology with fibrosis, a human inflammatory macrophage response, a persistent interferon-stimulated gene signature and T cell lymphopenia. We used this model to study two therapeutics on immunopathology, patient-derived antibodies and steroids and found that the same inflammatory macrophages crucial to containing early infection later drove immunopathology. This model will enable evaluation of COVID-19 disease mechanisms and treatments. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3S6CCM01K | ||||||
| Subjects: | 2 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY1947: Function Is More Reliable Than Quantity to Follow Up the Humoral Response to the Receptor-Binding Domain of SARS-CoV-2-Spike Protein after Natural Infection or COVID-19 Vaccination | |||||||
| Status: | New | ||||||
| Description: | Both the SARS-CoV-2 pandemic and emergence of variants of concern have highlighted the need for functional antibody assays to monitor the humoral response over time. Antibodies directed against the spike (S) protein of SARS-CoV-2 are an important component of the neutralizing antibody response. In this work, we report that in a subset of patients -despite a decline in total S-specific antibodies- neutralizing antibody titers remain at a similar level for an average of 98 days in longitudinal sampling of a cohort of 59 Hispanic/Latino patients exposed to SARS-CoV-2. Our data suggest that 100% of seroconverting patients make detectable neutralizing antibody responses which can be quantified by a surrogate viral neutralization test. Examination of sera from ten out of the 59 subjects which received mRNA-based vaccination revealed that both IgG titers and neutralizing activity of sera were higher after vaccination compared to a cohort of 21 SARS-CoV-2 naive subjects. One dose was sufficient for the induction of a neutralizing antibody, but two doses were necessary to reach 100% surrogate virus neutralization in subjects irrespective of previous SARS-CoV-2 natural infection status. Like the pattern observed after natural infection, the total anti-S antibodies titers declined after the second vaccine dose; however, neutralizing activity remained relatively constant for more than 80 days after the first vaccine dose. Furthermore, our data indicates that -compared with mRNA vaccination- natural infection induces a more robust humoral immune response in unexposed subjects. This work is an important contribution to understanding the natural immune response to the novel coronavirus in a population severely impacted by SARS-CoV-2. Furthermore, by comparing the dynamics of the immune response after the natural infection vs. the vaccination, these findings suggest that functional neutralizing antibody tests are more relevant indicators than the presence or absence of binding antibodies. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M337OBG0UC | ||||||
| Subjects: | 3 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY1960: Gestational Dating by Urine Metabolic Profile at High Resolution Weekly Sampling Timepoints | |||||||
| Status: | New | ||||||
| Description: | Background: Pregnancy triggers longitudinal metabolic alterations in women to allow precisely-programmed fetal growth. Comprehensive characterization of such a ?metabolic clock? of pregnancy may provide a molecular reference in relation to studies of adverse pregnancy outcomes. However, a high-resolution temporal profile of metabolites along a healthy pregnancy remains to be defined. Methods: Two independent, normal pregnancy cohorts with high-density weekly urine sampling (discovery: 478 samples from 19 subjects at California; validation: 171 samples from 10 subjects at Alabama) were studied. Urine samples were profiled by liquid chromatography-mass spectrometry (LC-MS) for untargeted metabolomics, which was applied for gestational age dating and prediction of time to delivery. Results: 5,473 urinary metabolic features were identified. Partial least-squares discriminant analysis on features with robust signals (n = 1,716) revealed that the samples were distributed on the basis of the first two principal components according to their gestational age. Pathways of bile secretion, steroid hormone biosynthesis, pantohenate, and CoA biosynthesis, benzoate degradation, and phenylpropanoid biosynthesis were significantly regulated, which was collectively applied to discover and validate a predictive model that accurately captures the chronology of pregnancy. With six urine metabolites (acetylcholine, estriol-3-glucuronide, dehydroepiandrosterone sulfate, ?-lactose, hydroxyexanoy-carnitine, and l-carnitine), models were constructed based on gradient-boosting decision trees to date gestational age in high accordance with ultrasound results, and to accurately predict time to delivery. Conclusion: Our study characterizes the weekly baseline profile of the human pregnancy metabolome, which provides a high-resolution molecular reference for future studies of adverse pregnancy outcomes. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3GYLHG31L | ||||||
| Subjects: | 29 | ||||||
| Study PI, contact: |
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| Publications: | None | ||||||
| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY1962: Does a lack of vaccine side effects correlate with reduced BNT162b2 mRNA vaccine response among healthcare workers and nursing home residents? | |||||||
| Status: | New | ||||||
| Description: | Background: The BNT162b2 SARS-CoV-2 mRNA vaccination has mitigated the burden of COVID-19 among residents of long-term care facilities considerably, despite being excluded from the vaccine trials. Data on reactogenicity (vaccine side effects) in this population are limited.Aims: To assess reactogenicity among nursing home (NH) residents. To provide a plausible proxy for predicting vaccine response among this population.Methods: We enrolled and sampled NH residents and community-dwelling healthcare workers who received the BNT162b2 mRNA vaccine, to assess local or systemic reactogenicity and antibody levels (immunogenicity).Results: NH residents reported reactions at a much lower frequency and lesser severity than the community-dwelling healthcare workers. These reactions were mild and transient with all subjects experiencing more local than systemic reactions. Based on our reactogenicity and immunogenicity data, we developed a linear regression model predicting log-transformed anti-spike, anti-receptor-binding domain (RBD), and neutralizing titers, with a dichotomous variable indicating the presence or absence of reported reactions which revealed a statistically significant effect, with estimated shifts in log-transformed titers ranging from 0.32 to 0.37 (all p < 0.01) indicating greater immunogenicity in subjects with one or more reported reactions of varying severity.Discussion: With a significantly lower incidence of post-vaccination reactions among NH residents as reported in this study, the BNT162b2 mRNA vaccine appears to be well-tolerated among this vulnerable population. If validated in larger populations, absence of reactogenicity could help guide clinicians in prioritizing vaccine boosters.Conclusions: Reactogenicity is significantly mild among nursing home residents and overall, subjects who reported post-vaccination reactions developed higher antibody titers. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3KRZ9GLCR | ||||||
| Subjects: | 4 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY1963: Protective efficacy of Ad26.COV2.S against SARS-CoV-2 B.1.351 in macaques | |||||||||||
| Status: | New | ||||||||||
| Description: | The emergence of SARS-CoV-2 variants that partially evade neutralizing antibodies poses a threat to the efficacy of current COVID-19 vaccines1,2. The Ad26.COV2.S vaccine expresses a stabilized spike protein from the WA1/2020 strain of SARS-CoV-2, and has recently demonstrated protective efficacy against symptomatic COVID-19 in humans in several geographical regions?including in South Africa, where 95% of sequenced viruses in cases of COVID-19 were the B.1.351 variant3. Here we show that Ad26.COV2.S elicits humoral and cellular immune responses that cross-react with the B.1.351 variant and protects against B.1.351 challenge in rhesus macaques. Ad26.COV2.S induced lower binding and neutralizing antibodies against B.1.351 as compared to WA1/2020, but elicited comparable CD8 and CD4 T cell responses against the WA1/2020, B.1.351, B.1.1.7, P.1 and CAL.20C variants. B.1.351 infection of control rhesus macaques resulted in higher levels of virus replication in bronchoalveolar lavage and nasal swabs than did WA1/2020 infection. Ad26.COV2.S provided robust protection against both WA1/2020 and B.1.351, although we observed higher levels of virus in vaccinated macaques after B.1.351 challenge. These data demonstrate that Ad26.COV2.S provided robust protection against B.1.351 challenge in rhesus macaques. Our findings have important implications for vaccine control of SARS-CoV-2 variants of concern. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3I9MMZOGZ | ||||||||||
| Subjects: | 6 | ||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||
| SDY1964: Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine | |||||||||||||
| Status: | New | ||||||||||||
| Description: | The CVnCoV (CureVac) mRNA vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was recently evaluated in a phase 2b/3 efficacy trial in humans1. CV2CoV is a second-generation mRNA vaccine containing non-modified nucleosides but with optimized non-coding regions and enhanced antigen expression. Here we report the results of a head-to-head comparison of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in non-human primates. We immunized 18 cynomolgus macaques with two doses of 12??g lipid nanoparticle-formulated CVnCoV or CV2CoV or with sham (n?=?6 per group). Compared with CVnCoV, CV2CoV induced substantially higher titres of binding and neutralizing antibodies, memory B cell responses and T cell responses as well as more potent neutralizing antibody responses against SARS-CoV-2 variants, including the Delta variant. Moreover, CV2CoV was found to be comparably immunogenic to the BNT162b2 (Pfizer) vaccine in macaques. Although CVnCoV provided partial protection against SARS-CoV-2 challenge, CV2CoV afforded more robust protection with markedly lower viral loads in the upper and lower respiratory tracts. Binding and neutralizing antibody titres were correlated with protective efficacy. These data demonstrate that optimization of non-coding regions can greatly improve the immunogenicity and protective efficacy of a non-modified mRNA SARS-CoV-2 vaccine in non-human primates. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3YD38IFGB | ||||||||||||
| Subjects: | 3 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY1965: Virological Characteristics ofHospitalized Children WithSARS-CoV-2 Infection | |||||
| Status: | New | ||||
| Description: | In children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, virological characteristics and correlation with disease severity have not been extensively studied. The primary objective in this study is to determine the correlation between SARS-CoV-2 viral load (VL) in infected children with age, disease severity, and underlying comorbidities.Children ,21 years, screened for SARS-CoV-2 at the time of hospitalization, who tested positive by polymerase chain reaction were included in this study. VL at different sites was determined and compared between groups. Of the 102 children included in this study, 44% of the cohort had asymptomatic infection, and children with .1 comorbidity were the most at risk for severe disease. VL in children with symptomatic infection was significantly higher than in children with asymptomatic infection (3.0 3 105 vs 7.2 3 103 copies per mL; P = .001). VL in the respiratory tract was significantly higher in children ,1 year, compared with older children (3.3 3 107 vs 1.3 3 104 copies per mL respectively; P , .0001), despite most infants presenting with milder illness. Besides the respiratory tract, SARS-CoV-2 RNA was also detectable in samples from the gastrointestinal tract (saliva and rectum) and blood. In 13 children for whom data on duration of polymerase chain reaction positivity was available, 12 of 13 tested positive 2 weeks after initial diagnosis, and 6 of 13 continued to test positive 4 weeks after initial diagnosis. In hospitalized children with SARS-CoV-2, those with .1 comorbid condition experienced severe disease. SARS-CoV-2 VL in the respiratory tract is significantly higher in children with symptomatic disease and children ,1 year of age. | ||||
| Program/Contract: |
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| DOI: | 10.21430/M3OBTZVHIQ | ||||
| Subjects: | 3 | ||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||
| SDY1966: A combination of two human neutralizing antibodies prevents SARS-CoV-2 infection in cynomolgus macaques | |||||||||
| Status: | New | ||||||||
| Description: | Background: Human monoclonal antibody (mAb) treatments are promising for COVID-19 prevention or therapy. The pre-exposure prophylactic efficacy of neutralizing antibodies that are engineered with mutations to extend their persistence in human serum and the neutralizing antibody titer in serum required for protection against SARS-CoV-2 infection remain poorly characterized.Methods: The Fc region of two neutralizing mAbs (COV2-2130 and COV2-2381) targeting non-overlapping epitopes on the receptor binding domain of SARS-CoV-2 spike protein was engineered to extend their persistence in humans and reduce interactions with Fc gamma receptors. We assessed protection by individual antibodies or a combination of the two antibodies (designated ADM03820) given prophylactically by an intravenous or intramuscular route in a non-human primate (NHP) model of SARS-CoV-2 infection.Findings: Passive transfer of individual mAbs or ADM03820 conferred virological protection in the NHP respiratory tract in a dose-dependent manner, and ADM03820 potently neutralized SARS-CoV-2 variants of concern in vitro. We defined a protective serum-neutralizing antibody titer and concentration in NHPs for passively transferred human antibodies that acted by direct viral neutralization.Conclusions: In summary, we demonstrate that neutralizing antibodies with extended half-life and lacking Fc-mediated effector functions are efficient for pre-exposure prophylaxis of SARS-CoV-2 infection in NHPs. These results support clinical development of ADM03820 for COVID-19 prevention. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3G3GC8IIZ | ||||||||
| Subjects: | 6 | ||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||
| SDY1967: Longitudinal SARS-CoV-2 mRNA Vaccine-Induced Humoral Immune Responses in Patients with Cancer | |||||
| Status: | New | ||||
| Description: | Longitudinal studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced immune responses in patients with cancer are needed to optimize clinical care. In a prospective cohort study of 366 (291 vaccinated) patients, we measured antibody levels [anti-spike (IgG-(S-RBD) and anti-nucleocapsid immunoglobulin] at three time points. Antibody level trajectories and frequency of breakthrough infections were evaluated by tumor type and timing of treatment relative to vaccination. IgG-(S-RBD) at peak response (median = 42 days after dose 2) was higher (P = 0.002) and remained higher after 4 to 6 months (P = 0.003) in patients receiving mRNA-1273 compared with BNT162b2. Patients with solid tumors attained higher peak levels (P = 0.001) and sustained levels after 4 to 6 months (P < 0.001) compared with those with hematologic malignancies. B-cell targeted treatment reduced peak (P = 0.001) and sustained antibody responses (P = 0.003). Solid tumor patients receiving immune checkpoint inhibitors before vaccination had lower sustained antibody levels than those who received treatment after vaccination (P = 0.043). Two (0.69%) vaccinated and one (1.9%) unvaccinated patient had severe COVID-19 illness during follow-up. Our study shows variation in sustained antibody responses across cancer populations receiving various therapeutic modalities, with important implications for vaccine booster timing and patient selection. SIGNIFICANCE: Long-term studies of immunogenicity of SARS-CoV-2 vaccines in patients with cancer are needed to inform evidence-based guidelines for booster vaccinations and to tailor sequence and timing of vaccinations to elicit improved humoral responses. | ||||
| Program/Contract: |
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| DOI: | 10.21430/M3BGVPR3CN | ||||
| Subjects: | 3 | ||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||
| SDY1969: Mathematical Modeling to Inform Vaccination Strategies and Testing Approaches for Coronavirus Disease 2019 (COVID-19) in Nursing Homes | |||||
| Status: | New | ||||
| Description: | Background: Nursing home residents and staff were included in the first phase of coronavirus disease 2019 vaccination in the United States. Because the primary trial endpoint was vaccine efficacy (VE) against symptomatic disease, there are limited data on the extent to which vaccines protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the ability to infect others (infectiousness). Assumptions about VE against infection and infectiousness have implications for changes to infection prevention guidance for vaccinated populations, including testing strategies.Methods: We use a stochastic agent-based Susceptible-Exposed-Infectious (Asymptomatic/Symptomatic)-Recovered model of a nursing home to simulate SARS-CoV-2 transmission. We model 3 scenarios, varying VE against infection, infectiousness, and symptoms, to understand the expected impact of vaccination in nursing homes, increasing staff vaccination coverage, and different screening testing strategies under each scenario.Results: Increasing vaccination coverage in staff decreases total symptomatic cases in the nursing home (among staff and residents combined) in each VE scenario. In scenarios with 50% and 90% VE against infection and infectiousness, increasing staff coverage reduces symptomatic cases among residents. If vaccination only protects against symptoms, and asymptomatic cases remain infectious, increased staff coverage increases symptomatic cases among residents. However, this is outweighed by the reduction in symptomatic cases among staff. Higher frequency testing-more than once weekly-is needed to reduce total symptomatic cases if the vaccine has lower efficacy against infection and infectiousness, or only protects against symptoms.Conclusions: Encouraging staff vaccination is not only important for protecting staff, but might also reduce symptomatic cases in residents if a vaccine confers at least some protection against infection or infectiousness. | ||||
| Program/Contract: |
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| DOI: | 10.21430/M31WZ81NLC | ||||
| Subjects: | 0 | ||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: | None | ||||
| Clinical Assessments: | None | ||||
| SDY1971: Early prediction of preeclampsia in pregnancy with cfRNA | |||||||
| Status: | New | ||||||
| Description: | Liquid biopsies that measure circulating cell-free RNA (cfRNA) offer an opportunity to study the development of pregnancy-related complications in a non-invasive manner and to bridge gaps in clinical care. Here we used 404 blood samples from 199 pregnant mothers to identify and validate cfRNA transcriptomic changes that are associated with preeclampsia, a multi-organ syndrome that is the second largest cause of maternal death globally. We find that changes in cfRNA gene expression between normotensive and preeclamptic mothers are marked and stable early in gestation, well before the onset of symptoms. These changes are enriched for genes specific to neuromuscular, endothelial and immune cell types and tissues that reflect key aspects of preeclampsia physiology, suggest new hypotheses for disease progression and correlate with maternal organ health. This enabled the identification and independent validation of a panel of 18 genes that when measured between 5 and 16 weeks of gestation can form the basis of a liquid biopsy test that would identify mothers at risk of preeclampsia long before clinical symptoms manifest themselves. Tests based on these observations could help predict and manage who is at risk for preeclampsia?an important objective for obstetric care. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M31FWXIEU2 | ||||||
| Subjects: | 199 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY1972: Population impact of SARS-CoV-2 variants with enhanced transmissibility and/or partial immune escape | |||||||
| Status: | New | ||||||
| Description: | SARS-CoV-2 variants of concern exhibit varying degrees of transmissibility and, in some cases, escape from acquired immunity. Much effort has been devoted to measuring these phenotypes, but understanding their impact on the course of the pandemic-especially that of immune escape-has remained a challenge. Here, we use a mathematical model to simulate the dynamics of wild-type and variant strains of SARS-CoV-2 in the context of vaccine rollout and nonpharmaceutical interventions. We show that variants with enhanced transmissibility frequently increase epidemic severity, whereas those with partial immune escape either fail to spread widely or primarily cause reinfections and breakthrough infections. However, when these phenotypes are combined, a variant can continue spreading even as immunity builds up in the population, limiting the impact of vaccination and exacerbating the epidemic. These findings help explain the trajectories of past and present SARS-CoV-2 variants and may inform variant assessment and response in the future. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3EWP60HPZ | ||||||
| Subjects: | 0 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1973: Reduced BNT162b2 Messenger RNA Vaccine Response in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-Naive Nursing Home Residents | |||||||||
| Status: | New | ||||||||
| Description: | After BNT162b2 messenger RNA vaccination, antibody levels to spike, receptor-binding domain, and virus neutralization were examined in 149 nursing home residents and 110 healthcare worker controls. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-naive nursing home residents' median post-second vaccine dose antibody neutralization titers are one-quarter that of SARS-CoV-2-naive healthcare workers. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M31XBTVKKN | ||||||||
| Subjects: | 5 | ||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||
| SDY1974: Generation of human long-lived plasma cells by developmentally regulated epigenetic imprinting | |||||||||||
| Status: | New | ||||||||||
| Description: | Antibody secreting cells (ASCs) circulate after vaccination and infection and migrate to the BM where a subset known as long-lived plasma cells (LLPCs) persists and secrete antibodies for a lifetime. The mechanisms by which circulating ASCs become LLPCs are not well elucidated. Here, we show that human blood ASCs have distinct morphology, transcriptomes, and epigenetics compared with BM LLPCs. Compared with blood ASCs, BM LLPCs have decreased nucleus/cytoplasm ratio but increased endoplasmic reticulum and numbers of mitochondria. LLPCs up-regulate pro-survival genes MCL1, BCL2, and BCL-XL while simultaneously down-regulating pro-apoptotic genes HRK1, CASP3, and CASP8 Consistent with reduced gene expression, the pro-apoptotic gene loci are less accessible in LLPCs. Of the pro-survival genes, only BCL2 is concordant in gene up-regulation and loci accessibility. Using a novel in vitro human BM mimetic, we show that blood ASCs undergo similar morphological and molecular changes that resemble ex vivo BM LLPCs. Overall, our study demonstrates that early-minted blood ASCs in the BM microniche must undergo morphological, transcriptional, and epigenetic changes to mature into apoptotic-resistant LLPCs. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3W5SK65XI | ||||||||||
| Subjects: | 6 | ||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||
| SDY1975: Single-Dose Intranasal Administration of AdCOVID Elicits Systemic and Mucosal Immunity against SARS-CoV-2 and Fully Protects Mice from Lethal Challenge | |||||||||
| Status: | New | ||||||||
| Description: | The coronavirus disease 2019 (COVID-19) pandemic has highlighted the urgent need for effective prophylactic vaccination to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Intranasal vaccination is an attractive strategy to prevent COVID-19 as the nasal mucosa represents the first-line barrier to SARS-CoV-2 entry. The current intramuscular vaccines elicit systemic immunity but not necessarily high-level mucosal immunity. Here, we tested a single intranasal dose of our candidate adenovirus type 5-vectored vaccine encoding the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (AdCOVID) in inbred, outbred, and transgenic mice. A single intranasal vaccination with AdCOVID elicited a strong and focused immune response against RBD through the induction of mucosal IgA in the respiratory tract, serum neutralizing antibodies, and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile. A single AdCOVID dose resulted in immunity that was sustained for over six months. Moreover, a single intranasal dose completely protected K18-hACE2 mice from lethal SARS-CoV-2 challenge, preventing weight loss and mortality. These data show that AdCOVID promotes concomitant systemic and mucosal immunity and represents a promising vaccine candidate. | ||||||||
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| DOI: | 10.21430/M3O55DEMO6 | ||||||||
| Subjects: | 5 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY1976: Shared B cell memory to coronaviruses and other pathogens varies in human age groups and tissues | |||||||
| Status: | New | ||||||
| Description: | Vaccination and infection promote the formation, tissue distribution, and clonal evolution of B cells, which encode humoral immune memory. We evaluated pediatric and adult blood and deceased adult organ donor tissues to determine convergent antigen-specific antibody genes of similar sequences shared between individuals. B cell memory varied for different pathogens. Polysaccharide antigenspecific clones were not exclusive to the spleen. Adults had higher clone frequencies and greater class switching in lymphoid tissues than blood, while pediatric blood had abundant class-switched convergent clones. Consistent with reported serology, prepandemic children had class-switched convergent clones to severe acute respiratory syndrome coronavirus 2 with weak cross-reactivity to other coronaviruses, while adult blood or tissues showed few such clones. These results highlight the prominence of early childhood B cell clonal expansions and cross-reactivity for future responses to novel pathogens. | ||||||
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| DOI: | 10.21430/M3TGZSFQZZ | ||||||
| Subjects: | 4 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1977: SARS-CoV-2 vaccine uptake, perspectives, and adverse reactions following vaccination in patients with cancer undergoing treatment | |||||
| Status: | New | ||||
| Description: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines were developed, tested, and approved in record time. As patients with cancer were excluded from vaccine trials, some patients may be hesitant,1 given unanswered questions around safety and adverse reactions, especially those undergoing treatment. One study conducted among 134 patients receiving immune checkpoint inhibitors (ICIs) reported an 81% BNT162b2 vaccine uptake rate with similar rates of acute adverse reactions as reported among healthy individuals, except for higher frequency of myalgias among patients with cancer.2 Further research is needed by tumor type and treatment to better inform clinicians and patients during the vaccine decision-making process.We report data on uptake and perspectives on SARS-CoV-2 vaccination and postvaccination adverse reactions in 208 recently diagnosed patients with cancer (median age 63 years, 52.4% women, 33.2% non-White minorities, Table 1 ) at a large healthcare system in Los Angeles spanning the timeline from limited vaccine availability to broader dissemination (November 2020 to July 2021). Vaccine hesitancy and perspectives were measured using a modified version of the World Health Organization Vaccine Hesitancy Scale (Supplementary Material, available at https://doi.org/10.1016/j.annonc.2021.10.005).3 A self-administered symptoms questionnaire was given to vaccinated recipients after dose 1 (D1) and D2 for messenger RNA (mRNA) SARS-CoV-2 vaccines. Electronic medical records provided correlative clinical information. Chi-square tests were used to assess differences for categorical variables and a Wilcoxon rank-sum test for continuous variables (Stata v. 15.1). All tests were two-sided and considered statistically significant at P < 0.05. | ||||
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| DOI: | 10.21430/M36ER193HY | ||||
| Subjects: | 2 | ||||
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| Assays: | None | ||||
| Clinical Assessments: | None | ||||
| SDY1978: Roles of antiviral sensing and type I interferon signaling in the restriction of SARS-CoV-2 replication | |||||||
| Status: | New | ||||||
| Description: | We investigated the role of tissue type and antiviral genes during SARS-CoV-2 infection in nonhuman primate (kidney) and human (liver, respiratory epithelial, gastric) cell lines. We report different viral growth kinetics and release among the cell lines despite comparable ACE2 expression. Transcriptomics revealed that absence of STAT1 in nonhuman primate cells appeared to enhance inflammatory responses without effecting infectious viral titer. Deletion of RL-6 in respiratory epithelial cells increased viral replication. Impaired infectious virus release was detected in Huh7 but not Huh7.5 cells, suggesting a role for RIG1. Gastric cells MKN45 exhibited robust antiviral gene expression and supported viral replication. Data here provide insight into molecular pathogenesis of and alternative cell lines for studying SARS-CoV-2 infection. | ||||||
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| DOI: | 10.21430/M381LM05UM | ||||||
| Subjects: | 7 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1980: Direct on-swab metabolic profiling of vaginal microbiome host interactions | |||||||||||
| Status: | New | ||||||||||
| Description: | The pregnancy vaginal microbiome contributes to risk of preterm birth, the primary cause of death in children under 5 years of age. Here we describe direct on-swab metabolic profiling by Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) for sample preparation-free characterisation of the cervicovaginal metabolome in two independent pregnancy cohorts (VMET, n?=?160; 455 swabs; VMET II, n?=?205; 573 swabs). By integrating metataxonomics and immune profiling data from matched samples, we show that specific metabolome signatures can be used to robustly predict simultaneously both the composition of the vaginal microbiome and host inflammatory status. In these patients, vaginal microbiota instability and innate immune activation, as predicted using DESI-MS, associated with preterm birth, including in women receiving cervical cerclage for preterm birth prevention. These findings highlight direct on-swab metabolic profiling by DESI-MS as an innovative approach for preterm birth risk stratification through rapid assessment of vaginal microbiota-host dynamics. | ||||||||||
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| DOI: | 10.21430/M3ZXHXS7FV | ||||||||||
| Subjects: | 365 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY1990: Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection | |||||||||||||||
| Status: | New | ||||||||||||||
| Description: | SARS-CoV-2-specific antibodies, CD4+ T cells, and CD8+ T cells are made in response to SARS-CoV-2 infection. Understanding the kinetics and durability of immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines and assessing the likely future course of the COVID-19 pandemic. We assessed the immune memory of all three branches of adaptive immunity (CD4+ T cell, CD8+ T cell, and humoral immunity) in a predominantly cross-sectional study, including a longitudinal subset, extending for up to eight months post-infection. | ||||||||||||||
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| DOI: | 10.21430/M31TX0GFHU | ||||||||||||||
| Subjects: | 2 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
| SDY56: Systems Biology of 2010 trivalent Influenza vaccine (TIV) in young and elderly (see companion study SDY61 2007, SDY270 2009, SDY119 2011) | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Study Objective To identify innate signatures that correlate with the magnitude, quality and persistence of B cell responses after vaccination with TIV in the young versus the elderly. Study Design Single center, open label study in which adult healthy volunteers with no contraindications to immunization will be vaccinated with TIV. Blood samples will be collected on Days D0 (at enrollment) and D1, D3, D7, D14, D30, D180 post vaccination to study innate and/or adaptive immunity markers. Even though influenza vaccination is considered safe, volunteers will be asked to report any local or systemic AEs from Day 0 (vaccination) to Day 7 in memory aids. Reactogenicity events will also be evaluated by injection site examination on visits at D0, D1, D3 and D7. Volunteers will be also asked to report local and systemic AEs developing the day of a blood draw. Additionally, only AEs considered related (unlikely, possibly, probably or definitely related) will be collected and reported in this study from Day 0 (vaccination) to Day 180. After Day 30 only related SAEs will be collected and reported. Study Duration 12 months (6 months accrual and 6 months follow-up period) |
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| DOI: | 10.21430/M3X9SKF8RQ | ||||||||||||
| Subjects: | 70 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||