DR51.1 DataRelease
Release Date: April 2024
New Studies: 25
Updated Studies: 8
New Studies
| SDY2509: A chimeric haemagglutinin-based universal influenza virus vaccine boosts human cellular immune responses directed towards the conserved haemagglutinin stalk domain and the viral nucleoprotein. | |||||||
| Status: | New | ||||||
| Description: | The authors sought to determine whether the vaccines utilized in the observer-blind, randomized placebo-controlled phase I trial (NCT03300050) could, in addition to elicit durable HA stalk specific antibodies, boost T-cell responses against HA stalk, and nucleoprotein (NP). | ||||||
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| DOI: | 10.21430/M35DPFGEQJ | ||||||
| Subjects: | 40 | ||||||
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| SDY2532: Germinal centre-driven maturation of B cell response to SARS-CoV-2 vaccination | |||||||||
| Status: | New | ||||||||
| Description: | The maturation dynamics of GC B cells and propagation of their progeny throughout the B cell diaspora have not been elucidated, therefore, here we show that anti-SARS-CoV-2 spike (S)-binding GC B cells were detectable in draining lymph nodes in those that were vaccinated against SARS-CoV-2. Using a combined approach of single-cell RNA sequencing of responding blood and lymph node B cells from eight participants and expression of the corresponding monoclonal antibodies, we tracked the evolution of 1540 S-specific B cell clones. This study documents the induction of affinity-matured BMPCs after two doses of SARS-CoV-2 mRNA vaccination in humans, providing a foundation for the sustained high efficacy observed with these vaccines. | ||||||||
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| DOI: | 10.21430/M3818VPQQM | ||||||||
| Subjects: | 43 | ||||||||
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| SDY2533: The TLR2/TLR6 ligand FSL-1 mitigates radiation-induced hematopoietic injury in mice and nonhuman primates | |||||||||||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||||||||||
| Description: | Thrombocytopenia, hemorrhage, anemia, and infection are life-threatening issues following accidental or intentional radiation exposure. Since few therapeutics are available, safe and efficacious small molecules to mitigate radiation-induced injury need to be developed. Our previous study showed the synthetic TLR2/TLR6 ligand fibroblast stimulating lipopeptide (FSL-1) prolonged survival and provided MyD88-dependent mitigation of hematopoietic acute radiation syndrome (H-ARS) in mice. Although mice and humans differ in TLR number, expression, and function, nonhuman primate (NHP) TLRs are like those of humans; therefore, studying both animal models is critical for drug development. The objectives of this study were to determine the efficacy of FSL-1 on hematopoietic recovery in small and large animal models subjected to sublethal total body irradiation and investigate its mechanism of action. In mice, we demonstrate a lack of adverse effects, an easy route of delivery (subcutaneous) and efficacy in promoting hematopoietic progenitor cell proliferation by FSL-1. NHP given radiation, followed a day later with a single subcutaneous administration of FSL-1, displayed no adversity but showed elevated hematopoietic cells. Our analyses revealed that FSL-1 promoted red blood cell development and induced soluble effectors following radiation exposure. Cytologic analysis of bone marrow aspirates revealed a striking enhancement of mononuclear progenitor cells in FSL-1-treated NHP. Combining the efficacy of FSL-1 in promoting hematopoietic cell recovery with the lack of adverse effects induced by a single administration supports the application of FSL-1 as a viable countermeasure against H-ARS. | ||||||||||||||||||||||||||||||
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| DOI: | 10.21430/M3WMW4268C | ||||||||||||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||||||||||||||
| SDY2586: Mouse Blood Gene signature | |||||||
| Status: | New | ||||||
| Description: | In the search for biological markers after a large-scale exposure of the human population to radiation, gene expression is a sensitive endpoint easily translatable to in-field high throughput applications. Primarily, the ex-vivo irradiated healthy human blood model has been used to generate available gene expression datasets. This model has limitations i.e., lack of signaling from other irradiated tissues and deterioration of blood cells cultures over time. In vivo models are needed; therefore, we present our novel approach to define a gene signature in mouse blood cells that quantitatively correlates with radiation dose (at 1 Gy/min). Starting with available microarray datasets, we selected 30 radiation-responsive genes and performed cross-validation/training-testing data splits to downselect 16 radiation-responsive genes. We then tested these genes in an independent cohort of irradiated adult C57BL/6 mice (50:50 both sexes) and measured mRNA by quantitative RT-PCR in whole blood at 24 h. Dose reconstruction using net signal (difference between geometric means of top 3 positively correlated and top 4 negatively correlated genes with dose), was highly improved over the microarrays, with a root mean square error of +/- 1.1 Gy in male and female mice combined. There were no significant sex-specific differences in mRNA or cell counts after irradiation. | ||||||
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| DOI: | 10.21430/M3X0W5SUWP | ||||||
| Subjects: | 80 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2591: COVID-19 vaccine induced poor neutralization titers for SARS-CoV-2 omicron variants in maternal and cord blood | ||||||||||
| Status: | New | |||||||||
| Description: | Introduction: Maternally derived antibodies are crucial for neonatal immunity. Understanding the binding and cross-neutralization capacity of maternal and cord antibody responses to SARS-CoV-2 variants following COVID-19 vaccination in pregnancy can inform neonatal immunity. Methods: Here we characterized the binding and neutralizing antibody profile at delivery in 24 pregnant individuals following two doses of Moderna mRNA-1273 or Pfizer BNT162b2 vaccination. We analyzed for SARS-CoV-2 multivariant cross-neutralizing antibody levels for wildtype Wuhan, Delta, Omicron BA1, BA2, and BA4/BA5 variants. In addition, we evaluated the transplacental antibody transfer by profiling maternal and umbilical cord blood. Results: Our results reveal that the current COVID-19 vaccination induced significantly higher RBD-specific binding IgG titers in cord blood compared to maternal blood for both the Wuhan and Omicron BA1 strain. Interestingly, the binding IgG antibody levels for the Omicron BA1 strain were significantly lower when compared to the Wuhan strain in both maternal and cord blood. In contrast to the binding, the Omicron BA1, BA2, and BA4/5 specific neutralizing antibody levels were significantly lower compared to the Wuhan and Delta variants. It is interesting to note that the BA4/5 neutralizing capacity was not detected in either maternal or cord blood. Discussion: Our data suggest that the initial series of COVID-19 mRNA vaccines were immunogenic in pregnant women, and vaccine-elicited binding antibodies were detectable in cord blood at significantly higher levels for the Wuhan and Delta variants but not for the Omicron variants. Interestingly, the vaccination did not induce neutralizing antibodies for Omicron variants. These results provide novel insight into the impact of vaccination on maternal humoral immune response and transplacental antibody transfer for SARS-CoV-2 variants and support the need for bivalent boosters as new variants emerge. | |||||||||
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| DOI: | 10.21430/M3Q9XHM545 | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2592: Estimating epidemiologic dynamics from cross-sectional viral load distributions | ||||||||||
| Status: | New | |||||||||
| Description: | Estimating an epidemic's trajectory is crucial for developing public health responses to infectious diseases, but case data used for such estimation are confounded by variable testing practices. We show that the population distribution of viral loads observed under random or symptom-based surveillance-in the form of cycle threshold (Ct) values obtained from reverse transcription quantitative polymerase chain reaction testing-changes during an epidemic. Thus, Ct values from even limited numbers of random samples can provide improved estimates of an epidemic's trajectory. Combining data from multiple such samples improves the precision and robustness of this estimation. We apply our methods to Ct values from surveillance conducted during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in a variety of settings and offer alternative approaches for real-time estimates of epidemic trajectories for outbreak management and response. | |||||||||
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| DOI: | 10.21430/M315H3WLDQ | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2593: Severe acute respiratory coronavirus virus 2 (SARS-CoV-2) seroprevalence in healthcare personnel in northern California early in the coronavirus disease 2019 (COVID-19) pandemic | ||||||||||
| Status: | New | |||||||||
| Description: | Objective: We assessed the magnitude of unidentified coronavirus disease 2019 (COVID-19) in our healthcare personnel (HCP) early in the COVID-19 pandemic, and we evaluated risk factors for infection to identify areas for improvement in infection control practice in a northern California academic medical center. Methods: We reviewed anti-severe acute respiratory coronavirus virus 2 (SARS-CoV-2) receptor-binding domain (RBD) IgG serologic test results and self-reported risk factors for seropositivity among 10,449 asymptomatic HCP who underwent voluntary serology testing between April 20 and May 20, 2020. Results: In total, 136 employees (1.3%) tested positive for SARS-CoV-2 IgG. This included 41 individuals (30.1%) who had previously tested positive for SARS-CoV-2 by nasopharyngeal reverse-transcription polymerase chain reaction (RT-PCR) between March 13 and April 16, 2020. In multivariable analysis, employees of Hispanic ethnicity (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.22-3.46) and those working in environmental services, food services, or patient transport (OR, 4.81; 95% CI, 2.08-10.30) were at increased risk for seropositivity compared to other groups. Employees reporting a household contact with COVID-19 were also at higher risk for seropositivity (OR, 3.25; 95% CI, 1.47-6.44), but those with a work, exposure alone were not (OR, 1.27; 95% CI, 0.58-2.47). Importantly, one-third of seropositive individuals reported no prior symptoms, no suspected exposures, and no prior positive RT-PCR test. Conclusion: In this study, SARS-CoV-2 seropositivity among HCP early in the northern California epidemic appeared to be quite low and was more likely attributable to community rather than occupational exposure. | |||||||||
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| DOI: | 10.21430/M33M7MRTHO | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2594: A phase II randomized trial with autologous polyclonal expanded regulatory T cells in children with new onset type 1 diabetes | |||||||
| Status: | New | ||||||
| Description: | CD4+CD25hiCD127lo/-FOXP3+ regulatory T cells (Tregs) play a key role in preventing autoimmunity. In autoimmune type 1 diabetes (T1D), adoptive transfer of autologous polyclonal Tregs has been shown to be safe in adults in Phase I clinical trials. We explored factors contributing to efficacy of autologous polyclonal expanded Tregs (expTregs) in a randomized Phase II multi-center, double-blind, clinical trial in 110 treated children and adolescents with new-onset T1D (Sanford/Lisata Therapeutics T-Rex Phase II trial) randomized 1:1:1 to high- (24*10^6 cells/kg) or low- (1*10^6 cells/kg) dose treatments or to matching placebo. Cytometry, bulk and single-cell RNA-sequencing were performed on selected expTregs and peripheral blood samples from participants. The single doses of expTregs were safe but did not prevent the decline in residual beta cell function over one year compared to placebo (P = 0.94 low dose, P = 0.21 high dose), regardless of age or baseline C-peptide. ExpTregs were highly activated and suppressive in vitro. A transient increase of activated memory Tregs was detectable one week after infusion in the high dose cohort suggesting effective transfer of expTregs. However, in vitro fold expansion of expTregs varied across participants even when accounting for age and lower fold expansion and its associated gene signature were linked with better C-peptide preservation regardless of Treg dose. These results suggest that a single dose of polyclonal expTregs does not alter progression in T1D; instead, Treg quality may be an important factor. | ||||||
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| DOI: | 10.21430/M3O7O5SQZT | ||||||
| Subjects: | 69 | ||||||
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| Publications: | None | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2596: H1N1 Infection | |||||||
| Status: | New | ||||||
| Description: | Mice were infected with H1N1 with examination of how pH and lung cells interact | ||||||
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| DOI: | 10.21430/M3PF29LBXZ | ||||||
| Subjects: | 48 | ||||||
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| SDY2597: Altering the Immunogenicity of Hemagglutinin Immunogens by Hyperglycosylation and Disulfide Stabilization | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Influenza virus alters glycosylation patterns on its surface exposed glycoproteins to evade host adaptive immune responses. The viral hemagglutinin (HA), in particular the H3 subtype, has increased its overall surface glycosylation since its introduction in 1968. We previously showed that modulating predicted N-linked glycosylation sites on H3 A/Hong Kong/1/1968 HA identified a conserved epitope at the HA interface. This epitope is occluded on the native HA trimer but is likely exposed during HA breathing on the virion surface. Antibodies directed to this site are protective via an ADCC-mediated mechanism. This glycan engineering strategy made an otherwise subdominant epitope dominant in the murine model. Here, we asked whether cysteine stabilization of the hyperglycosylated HA trimer could reverse this immunodominance by preventing access to the interface epitope and focus responses to the HA receptor binding site (RBS). While analysis of serum responses from immunized mice did not show a redirection to the RBS, cysteine stabilization did result in an overall reduction in immunogenicity of the interface epitope. Thus, glycan engineering and cysteine stabilization are two strategies that can be used together to alter immunodominance patterns to HA. These results add to rational immunogen design approaches used to manipulate immune responses for the development of next-generation influenza vaccines. | ||||||||||||
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| DOI: | 10.21430/M3JN37U7PR | ||||||||||||
| Subjects: | 39 | ||||||||||||
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| SDY2598: Mutation L319Q in the PB1 Polymerase Subunit Improves Attenuation of a Candidate Live-Attenuated Influenza A Virus Vaccine. | |||||||
| Status: | New | ||||||
| Description: | Three to five 4-month-old castrated male Fitch ferrets were inoculated with 107 PFU of the indicated WT and mutant pH1N1 viruses. Viral titers were then measured by plaque assay in multiple biosamples. | ||||||
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| DOI: | 10.21430/M3AGCBEAPM | ||||||
| Subjects: | 70 | ||||||
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| SDY2599: Mutations in SARS-CoV-2 variants of concern link to increased spike cleavage and virus transmission | |||||||||||||||||
| Status: | New | ||||||||||||||||
| Description: | SARS-CoV-2 lineages have diverged into highly prevalent variants termed ""variants of concern"" (VOCs). Here, we characterized emerging SARS-CoV-2 spike polymorphisms in vitro and in vivo to understand their impact on transmissibility and virus pathogenicity and fitness. We demonstrate that the substitution S:655Y, represented in the gamma and omicron VOCs, enhances viral replication and spike protein cleavage. The S:655Y substitution was transmitted more efficiently than its ancestor S:655H in the hamster infection model and was able to outcompete S:655H in the hamster model and in a human primary airway system. Finally, we analyzed a set of emerging SARS-CoV-2 variants to investigate how different sets of mutations may impact spike processing. All VOCs tested exhibited increased spike cleavage and fusogenic capacity. Taken together, our study demonstrates that the spike mutations present in VOCs that become epidemiologically prevalent in humans are linked to an increase in spike processing and virus transmission. | ||||||||||||||||
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| DOI: | 10.21430/M38A71XWCO | ||||||||||||||||
| Subjects: | 0 | ||||||||||||||||
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| SDY2600: Paradoxical sex-specific patterns of autoantibody response to SARS-CoV-2 infection | ||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||
| Description: | Background: Pronounced sex differences in the susceptibility and response to SARS-CoV-2 infection remain poorly understood. Emerging evidence has highlighted the potential importance of autoimmune activation in modulating the acute response and recovery trajectories following SARS-CoV-2 exposure. Given that immune-inflammatory activity can be sex-biased in the setting of severe COVID-19 illness, the aim of the study was to examine sex-specific autoimmune reactivity to SARS-CoV-2 in the absence of extreme clinical disease. Methods: In this study, we assessed autoantibody (AAB) reactivity to 91 autoantigens previously linked to a range of classic autoimmune diseases in a cohort of 177 participants (65% women, 35% men, mean age of 35) with confirmed evidence of prior SARS-CoV-2 infection based on presence of antibody to the nucleocapsid protein of SARS-CoV-2. Data were compared to 53 pre-pandemic healthy controls (49% women, 51% men). For each participant, sociodemographic data, serological analyses, SARS-CoV-2 infection status and COVID-19 related symptoms were collected by an electronic survey of questions. The symptoms burden score was constructed based on the total number of reported symptoms (N = 21) experienced within 6 months prior to the blood draw, wherein a greater number of symptoms corresponded to a higher score and assigned as more severe burden. Results: In multivariable analyses, we observed sex-specific patterns of autoreactivity associated with the presence or absence (as well as timing and clustering of symptoms) associated with prior COVID-19 illness. Whereas the overall AAB response was more prominent in women following asymptomatic infection, the breadth and extent of AAB reactivity was more prominent in men following at least mildly symptomatic infection. Notably, the observed reactivity included distinct antigens with molecular homology with SARS-CoV-2. Conclusion: Our results reveal that prior SARS-CoV-2 infection, even in the absence of severe clinical disease, can lead to a broad AAB response that exhibits sex-specific patterns of prevalence and antigen selectivity. Further understanding of the nature of triggered AAB activation among men and women exposed to SARS-CoV-2 will be essential for developing effective interventions against immune-mediated sequelae of COVID-19. | |||||||||||||||||||||
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| DOI: | 10.21430/M3DDUQLRWL | |||||||||||||||||||||
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| SDY2601: Nucleocapsid Antigenemia in Patients Receiving Anti-CD20 Therapy With Protracted COVID-19 | |||||||||
| Status: | New | ||||||||
| Description: | Immunocompromised patients with prolonged coronavirus disease 2019 symptoms present diagnostic and therapeutic challenges. We measured viral nucleocapsid antigenemia in 3 patients treated with anti-CD20 immunotherapy who acquired severe acute respiratory syndrome coronavirus 2 infection and experienced protracted symptoms. Our results support nucleocapsid antigenemia as a marker of persistent infection and therapeutic response. | ||||||||
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| DOI: | 10.21430/M3PD7M007L | ||||||||
| Subjects: | 0 | ||||||||
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| SDY2602: Rapid, high throughput, automated detection of SARS-CoV-2 neutralizing antibodies against Wuhan-WT, delta and omicron BA1, BA2 spike trimers | |||||||||||||||||
| Status: | New | ||||||||||||||||
| Description: | Traditional cellular and live-virus methods for detection of SARS-CoV-2 neutralizing antibodies (nAbs) are labor- and time-intensive, and thus not suited for routine use in the clinical lab to predict vaccine efficacy and natural immune protection. Here, we report the development and validation of a rapid, high throughput method for measuring SARS-CoV-2 nAbs against native-like trimeric spike proteins. This assay uses a blockade of human angiotensin converting enzyme 2 (hACE-2) binding (BoAb) approach in an automated digital immunoassay on the Quanterix HD-X platform. BoAb assays using Wuhan-WT (vaccine strain), delta (B.1.167.2), omicron BA1 and BA2 variant viral strains showed strong correlation with cell-based pseudovirus neutralization activity (PNA) and live-virus neutralization activity. Importantly, we were able to detect similar patterns of delta and omicron variant resistance to neutralization in samples with paired vaccine strain and delta variant BoAb measurements. Finally, we screened clinical samples from patients with or without evidence of SARS-CoV-2 exposure by a single-dilution screening version of our assays, finding significant nAb activity only in exposed individuals. Importantly, this completely automated assay can be performed in 4 h to measure neutralizing antibody titers for 16 samples over 8 serial dilutions or, 128 samples at a single dilution with replicates. In principle, these assays offer a rapid, robust, and scalable alternative to time-, skill-, and cost-intensive standard methods for measuring SARS-CoV-2 nAb levels. | ||||||||||||||||
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| DOI: | 10.21430/M3G3JILIU6 | ||||||||||||||||
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| SDY2603: Pre-existing SARS-CoV-2 immunity influences potency, breadth, and durability of the humoral response to SARS-CoV-2 vaccination | |||||||||||||
| Status: | New | ||||||||||||
| Description: | The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic highlights the importance of determining the breadth and durability of humoral immunity to SARS-CoV-2 mRNA vaccination. Herein, we characterize the humoral response in 27 naive and 40 recovered vaccinees. SARS-CoV-2-specific antibody and memory B cell (MBC) responses are durable up to 6 months, although antibody half-lives are shorter for naive recipients. The magnitude of the humoral responses to vaccination strongly correlates with responses to initial SARS-CoV-2 infection. Neutralization titers are lower against SARS-CoV-2 variants in both recovered and naive vaccinees, with titers more reduced in naive recipients. While the receptor-binding domain (RBD) is the main neutralizing target of circulating antibodies, Moderna-vaccinated naives show a lesser reliance on RBDs, with >25% neutralization remaining after depletion of RBD-binding antibodies. Overall, we observe that vaccination induces higher peak titers and improves durability in recovered compared with naive vaccinees. These findings have broad implications for current vaccine strategies deployed against the SARS-CoV-2 pandemic. | ||||||||||||
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| DOI: | 10.21430/M3D5XOQG82 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2604: Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation | |||||||||||||||||||||
| Status: | New | ||||||||||||||||||||
| Description: | Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1β production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration. | ||||||||||||||||||||
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| DOI: | 10.21430/M3UJYDAKKX | ||||||||||||||||||||
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| SDY2605: Examining Bias from Differential Depletion of Susceptibles in Vaccine Effectiveness Estimates in Settings of Waning | ||||||||||
| Status: | New | |||||||||
| Description: | Waning of the effectiveness of coronavirus disease 2019 (COVID-19) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and symptomatic disease has been observed in many settings (1–3). The documented ability of booster doses to restore vaccine effectiveness (VE) to higher levels suggests that at least some of the observed waning is real (3, 4). However, differential depletion of susceptible persons through infectioninduced immunity related to individuals’ vaccination status can create bias that induces spurious waning, complicating interpretation of VE estimates (5–8). In previous work (5), we showed that spurious waning was detectable but modest in settings without true waning where true VE was very high (0.95) and constant over time (i.e., no true waning), and more notable in settings where true VE was lower (0.70) and constant over time. This led us to the natural question: Is spurious waning modest or more notable in situations where true effectiveness wanes over time? Here we examine bias that can arise in settings in which true waning occurs. | |||||||||
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| DOI: | 10.21430/M315XLGPAR | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2606: COVID-19 mRNA vaccines drive differential antibody Fc-functional profiles in pregnant, lactating, and nonpregnant women | ||||||||||
| Status: | New | |||||||||
| Description: | Substantial immunological changes occur throughout pregnancy to render the mother immunologically tolerant to the fetus and allow fetal growth. However, additional local and systemic immunological adaptations also occur, allowing the maternal immune system to continue to protect the dyad against pathogens both during pregnancy and after birth through lactation. This fine balance of tolerance and immunity, along with physiological and hormonal changes, contributes to increased susceptibility to particular infections in pregnancy, including more severe coronavirus disease 2019 (COVID-19). Whether these changes also make pregnant women less responsive to vaccination or induce altered immune responses to vaccination remains incompletely understood. To define potential changes in vaccine response during pregnancy and lactation, we undertook deep sequencing of the humoral vaccine response in a group of pregnant and lactating women and nonpregnant age-matched controls. Vaccine-specific titers were comparable between pregnant women, lactating women, and nonpregnant controls. However, Fc receptor (FcR) binding and antibody effector functions were induced with delayed kinetics in both pregnant and lactating women compared with nonpregnant women after the first vaccine dose, which normalized after the second dose. Vaccine boosting resulted in high FcR-binding titers in breastmilk. These data suggest that pregnancy promotes resistance to generating proinflammatory antibodies and indicates that there is a critical need to follow prime-boost timelines in this vulnerable population to ensure full immunity is attained. | |||||||||
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| DOI: | 10.21430/M3ES2OLH9U | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2607: Humoral immunity to an endemic coronavirus is associated with postacute sequelae of COVID-19 in individuals with rheumatic diseases | ||||||||||
| Status: | New | |||||||||
| Description: | Beyond the acute illness caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) infection, about one-fifth of infections result in long-term persistence of symptoms despite the apparent clearance of infection. Insights into the mechanisms that underlie postacute sequelae of COVID-19 (PASC) will be critical for the prevention and clinical management of long-term complications of COVID-19. Several hypotheses have been proposed that may account for the development of PASC, including persistence of virus and dysregulation of immune responses. Among the immunological changes noted in PASC, alterations in humoral immunity have been observed in some patient subsets. To begin to determine whether SARS-CoV-2- or other pathogen-specific humoral immune responses evolve uniquely in PASC, we performed comprehensive antibody profiling against SARS-CoV-2, a panel of endemic pathogens, and a panel of routine vaccine antigens using systems serology in two cohorts of patients with preexisting systemic autoimmune rheumatic disease (SARD) who either developed or did not develop PASC. A distinct qualitative shift observed in Fcγ receptor (FcγR) binding was observed in individuals with PASC. Specifically, individuals with PASC harbored weaker FcγR-binding anti-SARS-CoV-2 antibodies and stronger FcγR-binding antibody responses against the endemic coronavirus OC43. Individuals with PASC developed an OC43 S2-specific antibody response with stronger FcγR binding, linked to cross-reactivity across SARS-CoV-2 and common coronaviruses. These findings identify previous coronavirus imprinting as a potential marker for the development of PASC in individuals with SARDs. | |||||||||
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| DOI: | 10.21430/M32BIF6Z4Z | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2608: mRNA-1273 but not BNT162b2 induces antibodies against polyethylene glycol (PEG) contained in mRNA-based vaccine formulations | ||||||||||
| Status: | New | |||||||||
| Description: | In this study, we determined if any of the components of mRNA-1273 or BNT162b2 formulations elicited PEG-specific antibody responses in serum by enzyme linked immunosorbent assay (ELISA). Using sera from participants selected based on the vaccine-associated side effects experienced after vaccination, including delayed onset, injection site or severe allergic reactions, we found no obvious association between PEG antibodies and adverse reactions. | |||||||||
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| DOI: | 10.21430/M393Q1VZXO | |||||||||
| Subjects: | 133 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2609: Extracellular vesicles carry SARS-CoV-2 spike protein and serve as decoys for neutralizing antibodies | |||||||||||||||
| Status: | New | ||||||||||||||
| Description: | In late 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China. SARS-CoV-2 and the disease it causes, coronavirus disease 2019 (COVID-19), spread rapidly and became a global pandemic in early 2020. SARS-CoV-2 spike protein is responsible for viral entry and binds to angiotensin converting enzyme 2 (ACE2) on host cells, making it a major target of the immune system - particularly neutralizing antibodies (nAbs) that are induced by infection or vaccines. Extracellular vesicles (EVs) are small membraned particles constitutively released by cells, including virally-infected cells. EVs and viruses enclosed within lipid membranes share some characteristics: they are small, sub-micron particles and they overlap in cellular biogenesis and egress routes. Given their shared characteristics, we hypothesized that EVs released from spike-expressing cells could carry spike and serve as decoys for anti-spike nAbs, promoting viral infection. Here, using mass spectrometry and nanoscale flow cytometry (NFC) approaches, we demonstrate that SARS-CoV-2 spike protein can be incorporated into EVs. Furthermore, we show that spike-carrying EVs act as decoy targets for convalescent patient serum-derived nAbs, reducing their effectiveness in blocking viral entry. These findings have important implications for the pathogenesis of SARS-CoV-2 infection in vivo and highlight the complex interplay between viruses, extracellular vesicles, and the immune system that occurs during viral infections. | ||||||||||||||
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| DOI: | 10.21430/M3QY2WPPLJ | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
| SDY2610: Antibodies elicited in humans upon chimeric hemagglutinin-based influenza virus vaccination confer FcgR-dependent protection in vivo | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | To characterize the role of Fc-FcgR interactions to the in vivo protective activity of IgG antibodies elicited in participants in a phase I trial of a cHA vaccine candidate, passive transfer studies of vaccine-elicited IgG antibodies in mice humanized for all classes of FcgRs were conducted, as well as in mice deficient for FcgRs. | |||||||||||||||
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| DOI: | 10.21430/M3KRCJ7M05 | |||||||||||||||
| Subjects: | 110 | |||||||||||||||
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| SDY2611: Intranasal priming induces local lung-resident B cell populations | ||||||||||
| Status: | New | |||||||||
| Description: | Secretory immunoglobulin A (IgA) is a predominant Ig isotype at mucosal surfaces whose epithelial cells express polymeric Ig receptor capable of transporting dimeric IgA to the lumen. Although the role of IgA in intestinal mucosa has been extensively studied, the cell types responsible for secreting the IgA that protects the host against pathogens in the lower respiratory tract are less clear. Here, using a mouse model of influenza virus infection, we demonstrate that intranasal, but not systemic, immunization induces local IgA secretion in the bronchoalveolar space. | |||||||||
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| DOI: | 10.21430/M3QR5QXSPQ | |||||||||
| Subjects: | 169 | |||||||||
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| SDY2612: ChAdOx1 nCoV-19 (AZD1222) vaccine-induced Fc receptor binding tracks with differential susceptibility to COVID-19 | |||||||||||||||
| Status: | New | ||||||||||||||
| Description: | Despite the success of COVID-19 vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern have emerged that can cause breakthrough infections. Although protection against severe disease has been largely preserved, the immunological mediators of protection in humans remain undefined. We performed a substudy on the ChAdOx1 nCoV-19 (AZD1222) vaccinees enrolled in a South African clinical trial. At peak immunogenicity, before infection, no differences were observed in immunoglobulin (Ig)G1-binding antibody titers; however, the vaccine induced different Fc-receptor-binding antibodies across groups. Vaccinees who resisted COVID-19 exclusively mounted FcγR3B-binding antibodies. In contrast, enhanced IgA and IgG3, linked to enriched FcγR2B binding, was observed in individuals who experienced breakthrough. Antibodies unable to bind to FcγR3B led to immune complex clearance and resulted in inflammatory cascades. Differential antibody binding to FcγR3B was linked to Fc-glycosylation differences in SARS-CoV-2-specific antibodies. These data potentially point to specific FcγR3B-mediated antibody functional profiles as critical markers of immunity against COVID-19. | ||||||||||||||
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| DOI: | 10.21430/M3U2ME6QLL | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
Updated Studies
| SDY1025: Asthma Phenotypes in the Inner City (APIC/ICAC-19) | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | This study looks to define the phenotypic characteristics of Difficult-to-Treat asthma, among 650 children between the ages of 6 to 17 years, receiving one year of guidelines-based therapy for asthma and rhinitis/rhinosinusitis. | ||||||||||||||||||
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| DOI: | 10.21430/M39SEUM79K | ||||||||||||||||||
| Subjects: | 717 | ||||||||||||||||||
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| SDY1481: Genetic and Environmental Factors in the Response to Influenza Vaccination 2014 | |||||||||
| Status: | Updated | ||||||||
| Description: | This is a phase IV study of 120 healthy 12-49 year old adolescents and adult volunteers who are given licensed seasonal influenza vaccine. There are no exclusions for gender, ethnicity or race. The volunteers will be enrolled into one of 3 groups: Group A: Up to 40 healthy monozygotic (MZ) twin volunteers, 12-49 years old, will be given inactivated influenza vaccine quadrivalent (IIV4). Each volunteer will complete a total of 3 visits: Day 0 (pre-immunization), Day 6-8 and Day 28+ 7 post-immunization. All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). Group B: Up to 40 healthy dizygotic (DZ) twin volunteers, 12-49 years old, will be given inactivated influenza vaccine quadrivalent (IIV4). Each volunteer will complete a total of 3 visits: Day 0 (pre-immunization), Day 6-8 and Day 28+7 post-immunization. All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). Group C: Up to 40 healthy monozygotic (MZ) twin volunteers, 12-49 years old, will be randomized within the twin pair to receive either inactivated influenza vaccine quadrivalent (IIV4) or live, attenuated influenza vaccine quadrivalent (LAIV4). Each volunteer will complete a total of 3 visits: Day 0 (pre-immunization), Day 6-8 and Day 28+7 post-immunization. All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). This group was discontinued in 2016 due to ACIP recommendations against the use of LAIV but may be reopened in 2018 pending LAIV4 availability. Each twin is counted as a single participant. All reporting numbers reflect the number of participants, not the number of twin pairs. | ||||||||
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| DOI: | 10.21430/M3KVQXST4E | ||||||||
| Subjects: | 114 | ||||||||
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| SDY1644: Urban Environmental Factors and Childhood Asthma (URECA) (ICAC-07) | ||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||
| Description: | The purpose of this study is to determine the way environmental factors (like the components of inner-city household dust) affect immune system development and symptoms of asthma in inner city children. The study is divided into three periods, as the subjects age from birth to 10 years old. Each age bracket will explore different objectives and endpoints. Study Objectives/Hypotheses: Subjects age 0 to 3 years old: Environmental factors in the inner city adversely influence the development of the immune system to promote cytokine dysregulation, allergy, and recurrent wheezing by age 3. Children who have had a viral lower respiratory infection and have developed cytokine dysregulation by age 3 are at increased risk for the development of asthma by age 6. Subjects age 4 to 7 years old: There is a unique pattern of immune development that is driven by specific urban exposures in early life, and this pattern of immune development is characterized by: 1) impairment of antiviral responses and 2) accentuation of Th2-like responses (e.g. cockroach-specific Interleukin-13(IL-13)). The clinical effects of these changes in immune development are frequent virus-induced wheezing and allergic sensitization by 3-4 years of age, and these characteristics synergistically increase the risk of asthma at age 7 years. Subjects age 7 to 10 years old: There are unique combinations of environmental exposures (cockroach allergens, indoor pollutants [Environmental Tobacco Smoke (ETS) and Nitrogen Dioxide (NO2)], lack of microbial exposure), and family characteristics (stress, genetic factors related to innate immunity) that synergistically promote asthma onset, persistence, and morbidity in urban neighborhoods. These exposures and characteristics influence immune expression and lung development during critical periods of growth, resulting in specific asthma phenotypes. Subjects age 10 to 16 years old: To determine the wheezing, asthma and atopy phenotypes in minority children growing up in poor urban neighborhoods as they develop from birth through adolescence. | |||||||||||||||||||||||||||
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| DOI: | 10.21430/M3H1YHLR5Z | |||||||||||||||||||||||||||
| Subjects: | 1218 | |||||||||||||||||||||||||||
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| SDY2015: Mass cytometry analysis of PBMCs from peanut-sensitized tolerant and clinically allergic infants | ||||||||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||||||||
| Description: | Not all individuals who produce peanut-specific IgE will react upon consumption of peanut. Infants with detectable peanut sIgE who can eat the food without adverse consequences are referred to as peanut sensitized tolerant (PST). Understanding the immune mechanisms that govern why some individuals go on to develop clinical peanut allergy (PA), whilst others do not, despite the presence of peanut-specific IgE, is central in diagnostic, prevention and early management strategies. This study used mass cytometry-based immune profiling to define the circulating immune cell signatures associated with PST vs. PA vs. non allergic healthy controls (NA) in the first year of life. Resting PBMCs and PBMCs after stimulation with endotoxin-free pure peanut solution or PMA/ionomycin were studied. A sub group of infants from the HealthNuts cohort (total n=5000 children) were used in this study. PA infants (n=12) were defined as having a peanut skin prick test (SPT) wheal diameter of ≥2mm or a peanut-specific IgE level of ≥0.35 kUA/L, and an unequivocal objective allergic reaction during peanut OFC at age 1 year. PST infants (n=12) had a peanut SPT≥2 mm and peanut-specific IgE level of ≥0.35 kUA/L and a negative peanut OFC at age 1 year. The NA group infants (n=12) were non-sensitized and non-allergic, with a negative SPT to peanut, egg, sesame, and cow’s milk together with a negative peanut OFC outcome at age 1 year. | |||||||||||||||||||||||||||||||||
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| DOI: | 10.21430/M3VPY49EGU | |||||||||||||||||||||||||||||||||
| Subjects: | 36 | |||||||||||||||||||||||||||||||||
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| SDY2209: CD8 Depletion | |||||||||
| Status: | Updated | ||||||||
| 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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| SDY2350: A Combination Adjuvant for SARS-CoV-2 | |||||||||
| Status: | Updated | ||||||||
| Description: | Here, we demonstrate a rationally designed combination mucosal [intranasal (IN)] adjuvant that enhances the quality of the immune response to SARS-CoV-2 induced by an S protein subunit antigen. Adjuvants can facilitate induction of high levels of NAbs and robust protective T cell responses and help promote more durable immune memory. Furthermore, rational adjuvant design allows for shaping or skewing of vaccine responses towards effective, broader and more potent immunity against drifted viruses. The combined adjuvant integrates a nanoemulsion- based adjuvant (NE) that activates TLRs and NLRP3 with an RNA agonist of RIG-I (IVT DI). | ||||||||
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| DOI: | 10.21430/M3KWOY18SF | ||||||||
| Subjects: | 45 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY2576: Directed evolution of and structural insights into antibody-mediated disruption of a stable receptor-ligand complex | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Antibody drugs exert therapeutic effects via a range of mechanisms, including competitive inhibition, allosteric modulation, and immune effector mechanisms. Facilitated dissociation is an additional mechanism where antibody-mediated ""disruption"" of stable high-affinity macromolecular complexes can potentially enhance therapeutic efficacy. However, this mechanism is not well understood or utilized therapeutically. Here, we investigate and engineer the weak disruptive activity of an existing therapeutic antibody, omalizumab, which targets IgE antibodies to block the allergic response. We develop a yeast display approach to select for and engineer antibody disruptive efficiency and generate potent omalizumab variants that dissociate receptor-bound IgE. We determine a low resolution cryo-EM structure of a transient disruption intermediate containing the IgE-Fc, its partially dissociated receptor and an antibody inhibitor. Our results provide a conceptual framework for engineering disruptive inhibitors for other targets, insights into the failure in clinical trials of the previous high affinity omalizumab HAE variant and anti-IgE antibodies that safely and rapidly disarm allergic effector cells. | ||||||||||||
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| DOI: | 10.21430/m344a57hws | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2582: Large-scale proteomics in the first trimester of pregnancy predict psychopathology and temperament in preschool children | |||||||||
| Status: | Updated | ||||||||
| Description: | Background: Understanding the prenatal origins of children’s psychopathology is a fundamental goal in developmental and clinical science. Recent research suggests that inflammation during pregnancy can trigger a cascade of fetal programming changes that contribute to vulnerability for the emergence of psychopathology. Most studies, however, have focused on a handful of proinflammatory cytokines and have not explored a range of prenatal biological pathways that may be involved in increasing postnatal risk for emotional and behavioral difficulties. Methods: Using extreme gradient boosted machine learning models, we explored large-scale proteomics, considering over 1,000 proteins from first trimester blood samples, to predict behavior in early childhood. Mothers reported on their 3- to 5-year-old children’s (N = 89, 51% female) temperament (Child Behavior Questionnaire) and psychopathology (Child Behavior Checklist). Results: We found that machine learning models of prenatal proteomics predict 5%–10% of the variance in children’s sadness, perceptual sensitivity, attention problems, and emotional reactivity. Enrichment analyses identified immune function, nervous system development, and cell signaling pathways as being particularly important in predicting children’s outcomes. Conclusions: Our findings, though exploratory, suggest processes in early pregnancy that are related to functioning in early childhood. Predictive features included far more proteins than have been considered in prior work. Specifically, proteins implicated in inflammation, in the development of the central nervous system, and in key cell-signaling pathways were enriched in relation to child temperament and psychopathology measures. Keywords: Biomarkers; child development; machine learning; prenatal; prediction. | ||||||||
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| DOI: | 10.21430/m34sax8sjb | ||||||||
| Subjects: | 202 | ||||||||
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