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  1. Article ; Online: Addressing the Burdens That Newborn Screening Imposes on Underserved Communities.

    Strenk, Meghan E / Berrios, Courtney / Garrett, Jeremy R

    The American journal of bioethics : AJOB

    2023  Volume 23, Issue 7, Page(s) 79–82

    MeSH term(s) Infant, Newborn ; Humans ; Neonatal Screening ; Rare Diseases ; Health Services Accessibility ; Social Justice
    Language English
    Publishing date 2023-06-20
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 2060433-6
    ISSN 1536-0075 ; 1526-5161
    ISSN (online) 1536-0075
    ISSN 1526-5161
    DOI 10.1080/15265161.2023.2207542
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: phippery: a software suite for PhIP-Seq data analysis.

    Galloway, Jared G / Sung, Kevin / Minot, Samuel S / Garrett, Meghan E / Stoddard, Caitlin I / Willcox, Alexandra C / Yaffe, Zak A / Yucha, Ryan / Overbaugh, Julie / Matsen, Frederick A

    Bioinformatics (Oxford, England)

    2023  Volume 39, Issue 10

    Abstract: Summary: We present the phippery software suite for analyzing data from phage display methods that use immunoprecipitation and deep sequencing to capture antibody binding to peptides, often referred to as PhIP-Seq. It has three main components that can ... ...

    Abstract Summary: We present the phippery software suite for analyzing data from phage display methods that use immunoprecipitation and deep sequencing to capture antibody binding to peptides, often referred to as PhIP-Seq. It has three main components that can be used separately or in conjunction: (i) a Nextflow pipeline, phip-flow, to process raw sequencing data into a compact, multidimensional dataset format and allows for end-to-end automation of reproducible workflows. (ii) a Python API, phippery, which provides interfaces for tasks such as count normalization, enrichment calculation, multidimensional scaling, and more, and (iii) a Streamlit application, phip-viz, as an interactive interface for visualizing the data as a heatmap in a flexible manner.
    Availability and implementation: All software packages are publicly available under the MIT License. The phip-flow pipeline: https://github.com/matsengrp/phip-flow. The phippery library: https://github.com/matsengrp/phippery. The phip-viz Streamlit application: https://github.com/matsengrp/phip-viz.
    MeSH term(s) Software ; Imidazoles ; Gene Library ; Peptides
    Chemical Substances 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (909C6UN66T) ; Imidazoles ; Peptides
    Language English
    Publishing date 2023-09-23
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1422668-6
    ISSN 1367-4811 ; 1367-4803
    ISSN (online) 1367-4811
    ISSN 1367-4803
    DOI 10.1093/bioinformatics/btad583
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Comprehensive characterization of the antibody responses to SARS-CoV-2 Spike protein finds additional vaccine-induced epitopes beyond those for mild infection.

    Garrett, Meghan E / Galloway, Jared G / Wolf, Caitlin / Logue, Jennifer K / Franko, Nicholas / Chu, Helen Y / Matsen, Frederick A / Overbaugh, Julie M

    eLife

    2022  Volume 11

    Abstract: Background: Control of the COVID-19 pandemic will rely on SARS-CoV-2 vaccine-elicited antibodies to protect against emerging and future variants; an understanding of the unique features of the humoral responses to infection and vaccination, including ... ...

    Abstract Background: Control of the COVID-19 pandemic will rely on SARS-CoV-2 vaccine-elicited antibodies to protect against emerging and future variants; an understanding of the unique features of the humoral responses to infection and vaccination, including different vaccine platforms, is needed to achieve this goal.
    Methods: The epitopes and pathways of escape for Spike-specific antibodies in individuals with diverse infection and vaccination history were profiled using Phage-DMS. Principal component analysis was performed to identify regions of antibody binding along the Spike protein that differentiate the samples from one another. Within these epitope regions, we determined potential sites of escape by comparing antibody binding of peptides containing wild-type residues versus peptides containing a mutant residue.
    Results: Individuals with mild infection had antibodies that bound to epitopes in the S2 subunit within the fusion peptide and heptad-repeat regions, whereas vaccinated individuals had antibodies that additionally bound to epitopes in the N- and C-terminal domains of the S1 subunit, a pattern that was also observed in individuals with severe disease due to infection. Epitope binding appeared to change over time after vaccination, but other covariates such as mRNA vaccine dose, mRNA vaccine type, and age did not affect antibody binding to these epitopes. Vaccination induced a relatively uniform escape profile across individuals for some epitopes, whereas there was much more variation in escape pathways in mildly infected individuals. In the case of antibodies targeting the fusion peptide region, which was a common response to both infection and vaccination, the escape profile after infection was not altered by subsequent vaccination.
    Conclusions: The finding that SARS-CoV-2 mRNA vaccination resulted in binding to additional epitopes beyond what was seen after infection suggests that protection could vary depending on the route of exposure to Spike antigen. The relatively conserved escape pathways to vaccine-induced antibodies relative to infection-induced antibodies suggests that if escape variants emerge they may be readily selected for across vaccinated individuals. Given that the majority of people will be first exposed to Spike via vaccination and not infection, this work has implications for predicting the selection of immune escape variants at a population level.
    Funding: This work was supported by NIH grants AI138709 (PI JMO) and AI146028 (PI FAM). JMO received support as the Endowed Chair for Graduate Education (FHCRC). The research of FAM was supported in part by a Faculty Scholar grant from the Howard Hughes Medical Institute and the Simons Foundation. Scientific Computing Infrastructure at Fred Hutch was funded by ORIP grant S10OD028685.
    MeSH term(s) Antigenic Drift and Shift ; COVID-19/immunology ; COVID-19 Vaccines/immunology ; Epitopes ; Humans ; Mass Vaccination ; SARS-CoV-2/immunology ; Spike Glycoprotein, Coronavirus/immunology
    Chemical Substances COVID-19 Vaccines ; Epitopes ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
    Language English
    Publishing date 2022-01-24
    Publishing country England
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.73490
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The S2 subunit of spike encodes diverse targets for functional antibody responses to SARS-CoV-2

    Guenthoer, Jamie / Garrett, Meghan E / Lilly, Michelle / Depierreux, Delphine M / Ruiz, Felicitas / Chi, Margaret / Stoddard, Caitlin I / Chohan, Vrasha / Sung, Kevin / Ralph, Duncan / Chu, Helen Y / Matsen, Frederick A / Overbaugh, Julie

    bioRxiv

    Abstract: The SARS-CoV-2 virus responsible for the COVID-19 global pandemic has exhibited a striking capacity for viral evolution that drives continued evasion from vaccine and infection-induced immune responses. Mutations in the receptor binding domain of the S1 ... ...

    Abstract The SARS-CoV-2 virus responsible for the COVID-19 global pandemic has exhibited a striking capacity for viral evolution that drives continued evasion from vaccine and infection-induced immune responses. Mutations in the receptor binding domain of the S1 subunit of the spike glycoprotein have led to considerable escape from antibody responses, reducing the efficacy of vaccines and monoclonal antibody (mAb) therapies. Therefore, there is a need to interrogate more constrained regions of Spike, such as the S2 subdomain. Here, we describe a collection of S2 mAbs from two SARS-CoV-2 convalescent individuals that target multiple regions in the S2 subdomain and can be grouped into at least five epitope classes. Most did not neutralize SARS-CoV-2 with the exception of C20.119, which bound to a highly conserved epitope in the fusion peptide and showed broad binding and neutralization activity across SARS-CoV-2, SARS-CoV-1, and closely related zoonotic sarbecoviruses. Several of the S2 mAbs tested mediated antibody-dependent cellular cytotoxicity (ADCC) at levels similar to the S1 mAb S309 that was previously authorized for treatment of SARS-CoV-2 infections. Three of the mAbs with ADCC function also bound to spike trimers from HCoVs, such as MERS-CoV and HCoV-HKU1. Our findings suggest there are diverse epitopes in S2, including functional S2 mAbs with HCoV and sarbecovirus breadth that likely target functionally constrained regions of spike. These mAbs could be developed for potential future pandemics, while also providing insight into ideal epitopes for eliciting a broad HCoV response.
    Keywords covid19
    Language English
    Publishing date 2024-02-28
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2024.02.26.582219
    Database COVID19

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  5. Article ; Online: Tractography-Based Modeling Explains Treatment Outcomes in Patients Undergoing Deep Brain Stimulation for Obsessive-Compulsive Disorder.

    Gadot, Ron / Li, Ningfei / Shofty, Ben / Avendano-Ortega, Michelle / McKay, Sarah / Bijanki, Kelly R / Robinson, Meghan E / Banks, Garrett / Provenza, Nicole / Storch, Eric A / Goodman, Wayne K / Horn, Andreas / Sheth, Sameer A

    Biological psychiatry

    2023  

    Abstract: Background: Deep brain stimulation (DBS) is an established and expanding therapy for treatment-refractory obsessive-compulsive disorder. Previous work has suggested that a white matter circuit providing hyperdirect input from the dorsal cingulate and ... ...

    Abstract Background: Deep brain stimulation (DBS) is an established and expanding therapy for treatment-refractory obsessive-compulsive disorder. Previous work has suggested that a white matter circuit providing hyperdirect input from the dorsal cingulate and ventrolateral prefrontal regions to the subthalamic nucleus could be an effective neuromodulatory target.
    Methods: We tested this concept by attempting to retrospectively explain through predictive modeling the ranks of clinical improvement as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) in 10 patients with obsessive-compulsive disorder who underwent DBS to the ventral anterior limb of internal capsule with subsequent programming uninformed by the putative target tract.
    Results: Rank predictions were carried out using the tract model by a team that was completely uninvolved in DBS planning and programming. Predicted Y-BOCS improvement ranks significantly correlated with actual Y-BOCS improvement ranks at the 6-month follow-up (r = 0.75, p = .013). Predicted score improvements correlated with actual Y-BOCS score improvements (r = 0.72, p = .018).
    Conclusions: Here, we provide data in a first-of-its-kind report suggesting that normative tractography-based modeling can blindly predict treatment response in DBS for obsessive-compulsive disorder.
    Language English
    Publishing date 2023-01-31
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209434-4
    ISSN 1873-2402 ; 0006-3223
    ISSN (online) 1873-2402
    ISSN 0006-3223
    DOI 10.1016/j.biopsych.2023.01.017
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  6. Article: Comprehensive characterization of the antibody responses to SARS-CoV-2 Spike protein after infection and/or vaccination.

    Garrett, Meghan E / Galloway, Jared G / Wolf, Caitlin / Logue, Jennifer K / Franko, Nicholas / Chu, Helen Y / Matsen, Frederick A / Overbaugh, Julie

    bioRxiv : the preprint server for biology

    2021  

    Abstract: Background: Control of the COVID-19 pandemic will rely on SARS-CoV-2 vaccine-elicited antibodies to protect against emerging and future variants; an understanding of the unique features of the humoral responses to infection and vaccination, including ... ...

    Abstract Background: Control of the COVID-19 pandemic will rely on SARS-CoV-2 vaccine-elicited antibodies to protect against emerging and future variants; an understanding of the unique features of the humoral responses to infection and vaccination, including different vaccine platforms, is needed to achieve this goal.
    Methods: The epitopes and pathways of escape for Spike-specific antibodies in individuals with diverse infection and vaccination history were profiled using Phage-DMS. Principal component analysis was performed to identify regions of antibody binding along the Spike protein that differentiate the samples from one another. Within these epitope regions we determined potential escape mutations by comparing antibody binding of peptides containing wildtype residues versus peptides containing a mutant residue.
    Results: Individuals with mild infection had antibodies that bound to epitopes in the S2 subunit within the fusion peptide and heptad-repeat regions, whereas vaccinated individuals had antibodies that additionally bound to epitopes in the N- and C-terminal domains of the S1 subunit, a pattern that was also observed in individuals with severe disease due to infection. Epitope binding appeared to change over time after vaccination, but other covariates such as mRNA vaccine dose, mRNA vaccine type, and age did not affect antibody binding to these epitopes. Vaccination induced a relatively uniform escape profile across individuals for some epitopes, whereas there was much more variation in escape pathways in in mildly infected individuals. In the case of antibodies targeting the fusion peptide region, which was a common response to both infection and vaccination, the escape profile after infection was not altered by subsequent vaccination.
    Conclusions: The finding that SARS-CoV-2 mRNA vaccination resulted in binding to additional epitopes beyond what was seen after infection suggests protection could vary depending on the route of exposure to Spike antigen. The relatively conserved escape pathways to vaccine-induced antibodies relative to infection-induced antibodies suggests that if escape variants emerge, they may be readily selected for across vaccinated individuals. Given that the majority of people will be first exposed to Spike via vaccination and not infection, this work has implications for predicting the selection of immune escape variants at a population level.
    Funding: This work was supported by NIH grants AI138709 (PI Overbaugh) and AI146028 (PI Matsen). Julie Overbaugh received support as the Endowed Chair for Graduate Education (FHCRC). The research of Frederick Matsen was supported in part by a Faculty Scholar grant from the Howard Hughes Medical Institute and the Simons Foundation. Scientific Computing Infrastructure at Fred Hutch was funded by ORIP grant S10OD028685.
    Language English
    Publishing date 2021-10-05
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2021.10.05.463210
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Detailed analysis of antibody responses to SARS-CoV-2 vaccination and infection in macaques.

    Willcox, Alexandra C / Sung, Kevin / Garrett, Meghan E / Galloway, Jared G / Erasmus, Jesse H / Logue, Jennifer K / Hawman, David W / Chu, Helen Y / Hasenkrug, Kim J / Fuller, Deborah H / Matsen Iv, Frederick A / Overbaugh, Julie

    PLoS pathogens

    2022  Volume 18, Issue 4, Page(s) e1010155

    Abstract: Macaques are a commonly used model for studying immunity to human viruses, including for studies of SARS-CoV-2 infection and vaccination. However, it is unknown whether macaque antibody responses resemble the response in humans. To answer this question, ... ...

    Abstract Macaques are a commonly used model for studying immunity to human viruses, including for studies of SARS-CoV-2 infection and vaccination. However, it is unknown whether macaque antibody responses resemble the response in humans. To answer this question, we employed a phage-based deep mutational scanning approach (Phage-DMS) to compare which linear epitopes are targeted on the SARS-CoV-2 Spike protein in convalescent humans, convalescent (re-infected) rhesus macaques, mRNA-vaccinated humans, and repRNA-vaccinated pigtail macaques. We also used Phage-DMS to determine antibody escape pathways within each epitope, enabling a granular comparison of antibody binding specificities at the locus level. Overall, we identified some common epitope targets in both macaques and humans, including in the fusion peptide (FP) and stem helix-heptad repeat 2 (SH-H) regions. Differences between groups included a response to epitopes in the N-terminal domain (NTD) and C-terminal domain (CTD) in vaccinated humans but not vaccinated macaques, as well as recognition of a CTD epitope and epitopes flanking the FP in convalescent macaques but not convalescent humans. There was also considerable variability in the escape pathways among individuals within each group. Sera from convalescent macaques showed the least variability in escape overall and converged on a common response with vaccinated humans in the SH-H epitope region, suggesting highly similar antibodies were elicited. Collectively, these findings suggest that the antibody response to SARS-CoV-2 in macaques shares many features with humans, but with substantial differences in the recognition of certain epitopes and considerable individual variability in antibody escape profiles, suggesting a diverse repertoire of antibodies that can respond to major epitopes in both humans and macaques. Differences in macaque species and exposure type may also contribute to these findings.
    MeSH term(s) Animals ; Antibodies, Neutralizing ; Antibodies, Viral ; Antibody Formation ; COVID-19/prevention & control ; COVID-19 Vaccines ; Epitopes ; Humans ; Macaca mulatta ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; Vaccination
    Chemical Substances Antibodies, Neutralizing ; Antibodies, Viral ; COVID-19 Vaccines ; Epitopes ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
    Language English
    Publishing date 2022-04-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1010155
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  8. Article ; Online: Phage-DMS: A Comprehensive Method for Fine Mapping of Antibody Epitopes.

    Garrett, Meghan E / Itell, Hannah L / Crawford, Katharine H D / Basom, Ryan / Bloom, Jesse D / Overbaugh, Julie

    iScience

    2020  Volume 23, Issue 10, Page(s) 101622

    Abstract: Understanding the antibody response is critical to developing vaccine and antibody-based therapies and has inspired the recent development of new methods to isolate antibodies. Methods to define the antibody-antigen interactions that determine ... ...

    Abstract Understanding the antibody response is critical to developing vaccine and antibody-based therapies and has inspired the recent development of new methods to isolate antibodies. Methods to define the antibody-antigen interactions that determine specificity or allow escape have not kept pace. We developed Phage-DMS, a method that combines two powerful approaches-immunoprecipitation of phage peptide libraries and deep mutational scanning (DMS)-to enable high-throughput fine mapping of antibody epitopes. As an example, we designed sequences encoding all possible amino acid variants of HIV Envelope to create phage libraries. Using Phage-DMS, we identified sites of escape predicted using other approaches for four well-characterized HIV monoclonal antibodies with known linear epitopes. In some cases, the results of Phage-DMS refined the epitope beyond what was determined in previous studies. This method has the potential to rapidly and comprehensively screen many antibodies in a single experiment to define sites essential for binding interactions.
    Language English
    Publishing date 2020-09-29
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2020.101622
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Comprehensive characterization of the antibody responses to SARS-CoV-2 Spike protein finds additional vaccine-induced epitopes beyond those for mild infection

    Meghan E Garrett / Jared G Galloway / Caitlin Wolf / Jennifer K Logue / Nicholas Franko / Helen Y Chu / Frederick A Matsen IV / Julie M Overbaugh

    eLife, Vol

    2022  Volume 11

    Abstract: Background: Control of the COVID-19 pandemic will rely on SARS-CoV-2 vaccine-elicited antibodies to protect against emerging and future variants; an understanding of the unique features of the humoral responses to infection and vaccination, including ... ...

    Abstract Background: Control of the COVID-19 pandemic will rely on SARS-CoV-2 vaccine-elicited antibodies to protect against emerging and future variants; an understanding of the unique features of the humoral responses to infection and vaccination, including different vaccine platforms, is needed to achieve this goal. Methods: The epitopes and pathways of escape for Spike-specific antibodies in individuals with diverse infection and vaccination history were profiled using Phage-DMS. Principal component analysis was performed to identify regions of antibody binding along the Spike protein that differentiate the samples from one another. Within these epitope regions, we determined potential sites of escape by comparing antibody binding of peptides containing wild-type residues versus peptides containing a mutant residue. Results: Individuals with mild infection had antibodies that bound to epitopes in the S2 subunit within the fusion peptide and heptad-repeat regions, whereas vaccinated individuals had antibodies that additionally bound to epitopes in the N- and C-terminal domains of the S1 subunit, a pattern that was also observed in individuals with severe disease due to infection. Epitope binding appeared to change over time after vaccination, but other covariates such as mRNA vaccine dose, mRNA vaccine type, and age did not affect antibody binding to these epitopes. Vaccination induced a relatively uniform escape profile across individuals for some epitopes, whereas there was much more variation in escape pathways in mildly infected individuals. In the case of antibodies targeting the fusion peptide region, which was a common response to both infection and vaccination, the escape profile after infection was not altered by subsequent vaccination. Conclusions: The finding that SARS-CoV-2 mRNA vaccination resulted in binding to additional epitopes beyond what was seen after infection suggests that protection could vary depending on the route of exposure to Spike antigen. The relatively conserved escape pathways to ...
    Keywords SARS-CoV-2 ; antibody epitope ; escape mutations ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Phage-DMS

    Meghan E. Garrett / Hannah L. Itell / Katharine H.D. Crawford / Ryan Basom / Jesse D. Bloom / Julie Overbaugh

    iScience, Vol 23, Iss 10, Pp 101622- (2020)

    A Comprehensive Method for Fine Mapping of Antibody Epitopes

    2020  

    Abstract: Summary: Understanding the antibody response is critical to developing vaccine and antibody-based therapies and has inspired the recent development of new methods to isolate antibodies. Methods to define the antibody-antigen interactions that determine ... ...

    Abstract Summary: Understanding the antibody response is critical to developing vaccine and antibody-based therapies and has inspired the recent development of new methods to isolate antibodies. Methods to define the antibody-antigen interactions that determine specificity or allow escape have not kept pace. We developed Phage-DMS, a method that combines two powerful approaches—immunoprecipitation of phage peptide libraries and deep mutational scanning (DMS)—to enable high-throughput fine mapping of antibody epitopes. As an example, we designed sequences encoding all possible amino acid variants of HIV Envelope to create phage libraries. Using Phage-DMS, we identified sites of escape predicted using other approaches for four well-characterized HIV monoclonal antibodies with known linear epitopes. In some cases, the results of Phage-DMS refined the epitope beyond what was determined in previous studies. This method has the potential to rapidly and comprehensively screen many antibodies in a single experiment to define sites essential for binding interactions.
    Keywords Virology ; Genomic Library ; Science ; Q
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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