90 results on '"Donald S. Grant"'
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2. Upper Airway Epithelial Tissue Transcriptome Analysis Reveals Immune Signatures Associated with COVID-19 Severity in Ghanaians
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John Demby Sandi, Joshua I. Levy, Kesego Tapela, Mark Zeller, Joshua Afari Yeboah, Daniel Frimpong Saka, Donald S. Grant, Gordon A. Awandare, Peter K. Quashie, Kristian G. Andersen, and Lily Paemka
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Immunologic diseases. Allergy ,RC581-607 - Abstract
The immunological signatures driving the severity of coronavirus disease 19 (COVID-19) in Ghanaians remain poorly understood. We performed bulk transcriptome sequencing of nasopharyngeal samples from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected Ghanaians with mild and severe COVID-19, as well as healthy controls to characterize immune signatures at the primary SARS-CoV-2 infection site and identify drivers of disease severity. Generally, a heightened antiviral response was observed in SARS-CoV-2-infected Ghanaians compared with uninfected controls. COVID-19 severity was associated with immune suppression, overexpression of proinflammatory cytokines, including CRNN, IL1A, S100A7, and IL23A, and activation of pathways involved in keratinocyte proliferation. SAMD9L was among the differentially regulated interferon-stimulated genes in our mild and severe disease cohorts, suggesting that it may play a critical role in SARS-CoV-2 pathogenesis. By comparing our data with a publicly available dataset from a non-African (Indians) (GSE166530), an elevated expression of antiviral response-related genes was noted in COVID-19-infected Ghanaians. Overall, the study describes immune signatures driving COVID-19 severity in Ghanaians and identifies immune drivers that could serve as potential prognostic markers for future outbreaks or pandemics. It further provides important preliminary evidence suggesting differences in antiviral response at the upper respiratory interface in sub-Saharan Africans (Ghanaians) and non-Africans, which could be contributing to the differences in disease outcomes. Further studies using larger datasets from different populations will expand on these findings.
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- 2024
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3. 344 Understanding drivers of post-Ebola syndrome (PES) in pediatric survivors of Ebolavirus disease: characterization and the way forward.
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Nell G Bond, Emily J. Engel, Lansana Kanneh, Robert J. Samuels, Donald S. Grant, and John S. Schieffelin
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Medicine - Abstract
OBJECTIVES/GOALS: Ebolavirus disease survivors report persistent, debilitating health concerns dubbed Post-Ebola Syndrome (PES). Attention to PES in young survivors is lacking, we describe PES in pediatric EVD survivors in Eastern Sierra Leone. Additionally, we introduce our proposal investigating differential presentations of PES in pediatric survivors. METHODS/STUDY POPULATION: EVD survivors were enrolled a median of 2.5 years after resolution of disease. Survivors were eligible if listed in a national register maintained by the Sierra Leone Association of Ebola Survivors. Household contacts (HCs) were identified by survivors. Participants were assigned into three comparison groups: pediatric (7-11), adolescent (12-17) and young adult (18-25). A self-reported symptom questionnaire, and a physical exam were conducted. Variables were clustered within organ system and compared across groups. RESULTS/ANTICIPATED RESULTS: Pediatric survivors had lower levels of long-term sequelae compared to adolescents and young adults. Symptoms and abnormal physical exam signs increase with age. Musculoskeletal, psychiatric, ophthalmologic, and GI signs and symptoms were significantly different between groups. Pediatric survivors had significantly more persistent sequelae than age-matched HCs with no history of EVD; particularly within the cardiac/GI (p=.006) and psychiatric/neurological (p=.025) clusters. PES is heterogeneous with respect to age, calling for a deeper understanding of age-based differences. Even the youngest group of survivors experienced significantly more sequelae than HCs, highlighting the elevated symptom burden in these children over their peers. DISCUSSION/SIGNIFICANCE: Understanding mechanistic drivers will ultimately improve targeted treatments for PES. We will characterize symptom groups defining PES in children, determine the relationship between accelerated aging and PES in this population, and test how immune profiles associated with accelerated aging relate to the development of PES in children.
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- 2024
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4. Predicting the evolution of the Lassa virus endemic area and population at risk over the next decades
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Raphaëlle Klitting, Liana E. Kafetzopoulou, Wim Thiery, Gytis Dudas, Sophie Gryseels, Anjali Kotamarthi, Bram Vrancken, Karthik Gangavarapu, Mambu Momoh, John Demby Sandi, Augustine Goba, Foday Alhasan, Donald S. Grant, Sylvanus Okogbenin, Ephraim Ogbaini-Emovo, Robert F. Garry, Allison R. Smither, Mark Zeller, Matthias G. Pauthner, Michelle McGraw, Laura D. Hughes, Sophie Duraffour, Stephan Günther, Marc A. Suchard, Philippe Lemey, Kristian G. Andersen, and Simon Dellicour
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Science - Abstract
It is currently unknown how climate and land use changes could affect the endemic area of Lassa virus, a zoonotic pathogen responsible for Lassa fever. Here, the authors show that by 2070, new regions in Africa will likely become ecologically suitable for Lassa virus, drastically increasing the population living in conditions favourable for virus circulation.
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- 2022
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5. The prevalence of Post-Ebola Syndrome hearing loss, Sierra Leone
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Samuel C. Ficenec, Donald S. Grant, Ibrahim Sumah, Foday Alhasan, Mohamed S. Yillah, Jenneh Brima, Edwin Konuwa, Michael A. Gbakie, Fatima K. Kamara, Nell G. Bond, Emily J. Engel, Jeffrey G. Shaffer, William A. Fischer, David A. Wohl, Susan D. Emmett, and John S. Schieffelin
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Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Globally, hearing loss is the second leading cause of disability, affecting approximately 18.7% of the world’s population. However, the burden of hearing loss is unequally distributed, with the majority of affected individuals located in Asia or Sub-Saharan Africa. Following the 2014 West African Ebola Outbreak, disease survivors began to describe hearing loss as part of the constellation of symptoms known as Post-Ebola Syndrome. The goal of this study was to more fully characterize hearing loss among Ebola Virus Disease (EVD) survivors. Methodology and principal findings EVD survivors and their household contacts were recruited (n = 1,12) from Eastern Sierra Leone. Each individual completed a symptom questionnaire, physical exam, and a two-step audiometry process measuring both air and bone conduction thresholds. In comparison to contacts, EVD survivors were more likely to have complaints or abnormal findings affecting every organ system. A significantly greater percentage of EVD survivors were found to have hearing loss in comparison to contacts (23% vs. 9%, p
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- 2022
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6. Respiratory virus surveillance in hospitalized children less than two-years of age in Kenema, Sierra Leone during the COVID-19 pandemic (October 2020- October 2021)
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Robert J. Samuels, Ibrahim Sumah, Foday Alhasan, Rendie McHenry, Laura Short, James D. Chappell, Zaid Haddadin, Natasha B. Halasa, Inaê D. Valério, Gustavo Amorim, Donald S. Grant, John S. Schieffelin, and Troy D. Moon
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Medicine ,Science - Published
- 2023
7. Elevated l-threonine is a biomarker for Lassa fever and Ebola
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Trevor V. Gale, John S. Schieffelin, Luis M. Branco, Robert F. Garry, and Donald S. Grant
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Lassa fever ,Ebola ,Viral hemorrhagic fevers ,Liquid Chromatography Mass Spectrometry ,l-Threonine ,Metabolomics ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Lassa fever and Ebola are characterized by non-specific initial presentations that can progress to severe multisystem illnesses with high fatality rates. Samples from additional subjects are examined to extend and corroborate biomarkers with prognostic value for these diseases. Methods Liquid Chromatography Mass Spectrometry metabolomics was used to identify and confirm metabolites disrupted in the blood of Lassa fever and Ebola patients. Authenticated standards are used to confirm the identify of key metabolites. Results We confirm prior results by other investigators that the amino acid l-threonine is elevated during Ebola virus infection. l-Threonine is also elevated during Lassa virus infection. We also confirmed that platelet-activating factor (PAF) and molecules with PAF moiety are reduced in the blood of patients with fatal Lassa fever. Similar changes in PAF and PAF-like molecules were not observed in the blood of Ebola patients. Conclusions Metabolomics may provide tools to identify pathways that are differentially affected during viral hemorrhagic fevers and guide development of diagnostics to monitor and predict outcome.
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- 2020
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8. Endotheliopathy and Platelet Dysfunction as Hallmarks of Fatal Lassa Fever
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Lucy E. Horton, Robert W. Cross, Jessica N. Hartnett, Emily J. Engel, Saori Sakabe, Augustine Goba, Mambu Momoh, John Demby Sandi, Thomas W. Geisbert, Robert F. Garry, John S. Schieffelin, Donald S. Grant, and Brian M. Sullivan
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Lassa fever ,hemostasis ,platelet ,protein C ,coagulation ,fibrinolysis ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
Lassa fever (LF) causes multisystem disease and has a fatality rate
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- 2020
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9. Deployable CRISPR-Cas13a diagnostic tools to detect and report Ebola and Lassa virus cases in real-time
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Kayla G. Barnes, Anna E. Lachenauer, Adam Nitido, Sameed Siddiqui, Robin Gross, Brett Beitzel, Katherine J. Siddle, Catherine A. Freije, Bonnie Dighero-Kemp, Samar B. Mehta, Amber Carter, Jessica Uwanibe, Fehintola Ajogbasile, Testimony Olumade, Ikponmwosa Odia, John Demby Sandi, Mambu Momoh, Hayden C. Metsky, Chloe K. Boehm, Aaron E. Lin, Molly Kemball, Daniel J. Park, Luis Branco, Matt Boisen, Brian Sullivan, Mihret F. Amare, Abdulwasiu B. Tiamiyu, Zahra F. Parker, Michael Iroezindu, Donald S. Grant, Kayvon Modjarrad, Cameron Myhrvold, Robert F. Garry, Gustavo Palacios, Lisa E. Hensley, Stephen F. Schaffner, Christian T. Happi, Andres Colubri, and Pardis C. Sabeti
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Science - Abstract
Outbreaks of viral hemorrhagic fevers highlight the need for sensitive, field-deployable diagnostics. Here the authors present a CRISPR-based SHERLOCK platform with field protocol and mobile app for Ebola and Lassa fever outbreaks.
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- 2020
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10. Machine-learning Prognostic Models from the 2014–16 Ebola Outbreak: Data-harmonization Challenges, Validation Strategies, and mHealth Applications
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Andres Colubri, Mary-Anne Hartley, Matthew Siakor, Vanessa Wolfman, August Felix, Tom Sesay, Jeffrey G. Shaffer, Robert F. Garry, Donald S. Grant, Adam C. Levine, and Pardis C. Sabeti
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Medicine (General) ,R5-920 - Abstract
Background: Ebola virus disease (EVD) plagues low-resource and difficult-to-access settings. Machine learning prognostic models and mHealth tools could improve the understanding and use of evidence-based care guidelines in such settings. However, data incompleteness and lack of interoperability limit model generalizability. This study harmonizes diverse datasets from the 2014–16 EVD epidemic and generates several prognostic models incorporated into the novel Ebola Care Guidelines app that provides informed access to recommended evidence-based guidelines. Methods: Multivariate logistic regression was applied to investigate survival outcomes in 470 patients admitted to five Ebola treatment units in Liberia and Sierra Leone at various timepoints during 2014–16. We generated a parsimonious model (viral load, age, temperature, bleeding, jaundice, dyspnea, dysphagia, and time-to-presentation) and several fallback models for when these variables are unavailable. All were externally validated against two independent datasets and compared to further models including expert observational wellness assessments. Models were incorporated into an app highlighting the signs/symptoms with the largest contribution to prognosis. Findings: The parsimonious model approached the predictive power of observational assessments by experienced clinicians (Area-Under-the-Curve, AUC = 0.70–0.79, accuracy = 0.64–0.74) and maintained its performance across subcohorts with different healthcare seeking behaviors. Age and viral load contributed >5-fold the weighting of other features and including them in a minimal model had a similar AUC, albeit at the cost of specificity. Interpretation: Clinically guided prognostic models can recapitulate clinical expertise and be useful when such expertise is unavailable. Incorporating these models into mHealth tools may facilitate their interpretation and provide informed access to comprehensive clinical guidelines. Funding: Howard Hughes Medical Institute, US National Institutes of Health, Bill & Melinda Gates Foundation, International Medical Corps, UK Department for International Development, and GOAL Global. Keywords: Ebola virus disease, Prognostic models, Machine learning, Data visualization, Severity score, mHealth, Supportive care guidelines, Clinical intuition
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- 2019
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11. Ebola Virus Persistence in Ocular Tissues and Fluids (EVICT) Study: Reverse Transcription-Polymerase Chain Reaction and Cataract Surgery Outcomes of Ebola Survivors in Sierra Leone
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Jessica G. Shantha, John G. Mattia, Augustine Goba, Kayla G. Barnes, Faiqa K. Ebrahim, Colleen S. Kraft, Brent R. Hayek, Jessica N. Hartnett, Jeffrey G. Shaffer, John S. Schieffelin, John D. Sandi, Mambu Momoh, Simbirie Jalloh, Donald S. Grant, Kerry Dierberg, Joyce Chang, Sharmistha Mishra, Adrienne K. Chan, Rob Fowler, Tim O'Dempsey, Erick Kaluma, Taylor Hendricks, Roger Reiners, Melanie Reiners, Lowell A. Gess, Kwame ONeill, Sarian Kamara, Alie Wurie, Mohamed Mansaray, Nisha R. Acharya, William J. Liu, Sina Bavari, Gustavo Palacios, Moges Teshome, Ian Crozier, Paul E. Farmer, Timothy M. Uyeki, Daniel G. Bausch, Robert F. Garry, Matthew J. Vandy, and Steven Yeh
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Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Ebola virus disease (EVD) survivors are at risk for uveitis during convalescence. Vision loss has been observed following uveitis due to cataracts. Since Ebola virus (EBOV) may persist in the ocular fluid of EVD survivors for an unknown duration, there are questions about the safety and feasibility of vision restorative cataract surgery in EVD survivors. Methods: We conducted a cross-sectional study of EVD survivors anticipating cataract surgery and patients with active uveitis to evaluate EBOV RNA persistence in ocular fluid, as well as vision outcomes post cataract surgery. Patients with aqueous humor that tested negative for EBOV RNA were eligible to proceed with manual small incision cataract surgery (MSICS). Findings: We screened 137 EVD survivors from June 2016 – August 2017 for enrolment. We enrolled 50 EVD survivors; 46 with visually significant cataract, 1 with a subluxated lens, 2 with active uveitis and 1 with a blind painful eye due to uveitis. The median age was 24.0 years (IQR 17–35) and 35 patients (70%) were female. The median logMAR visual acuity (VA) was 3.0 (Snellen VA Hand motions; Interquartile Range, IQR: 1.2-3.0, Snellen VA 20/320 – Hand motions). All patients tested negative for EBOV RNA by RT-PCR in aqueous humor/vitreous fluid and conjunctiva at a median of 19 months (IQR 18-20) from EVD diagnosis in Phase 1 of ocular fluid sampling and 34 months (IQR 32-36) from EVD diagnosis in Phase 2 of ocular fluid sampling. Thirty-four patients underwent MSICS, with a preoperative median VA improvement from hand motions to 20/30 at three-month postoperative follow-up (P
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- 2018
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12. Cross-Reactive Antibodies to SARS-CoV-2 and MERS-CoV in Pre-COVID-19 Blood Samples from Sierra Leoneans
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Rodrigo Borrega, Diana K. S. Nelson, Anatoliy P. Koval, Nell G. Bond, Megan L. Heinrich, Megan M. Rowland, Raju Lathigra, Duane J. Bush, Irina Aimukanova, Whitney N. Phinney, Sophia A. Koval, Andrew R. Hoffmann, Allison R. Smither, Antoinette R. Bell-Kareem, Lilia I. Melnik, Kaylynn J. Genemaras, Karissa Chao, Patricia Snarski, Alexandra B. Melton, Jaikin E. Harrell, Ashley A. Smira, Debra H. Elliott, Julie A. Rouelle, Gilberto Sabino-Santos, Arnaud C. Drouin, Mambu Momoh, John Demby Sandi, Augustine Goba, Robert J. Samuels, Lansana Kanneh, Michael Gbakie, Zoe L. Branco, Jeffrey G. Shaffer, John S. Schieffelin, James E. Robinson, Dahlene N. Fusco, Pardis C. Sabeti, Kristian G. Andersen, Donald S. Grant, Matthew L. Boisen, Luis M. Branco, and Robert F. Garry
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COVID-19 caseloads and deaths ,sub-Saharan Africa ,pre-existing immunity to coronaviruses ,recombinant antigens ,enzyme-linked immunosorbent assays ,pseudovirus neutralizing antibodies ,Microbiology ,QR1-502 - Abstract
Many countries in sub-Saharan Africa have experienced lower COVID-19 caseloads and fewer deaths than countries in other regions worldwide. Under-reporting of cases and a younger population could partly account for these differences, but pre-existing immunity to coronaviruses is another potential factor. Blood samples from Sierra Leonean Lassa fever and Ebola survivors and their contacts collected before the first reported COVID-19 cases were assessed using enzyme-linked immunosorbent assays for the presence of antibodies binding to proteins of coronaviruses that infect humans. Results were compared to COVID-19 subjects and healthy blood donors from the United States. Prior to the pandemic, Sierra Leoneans had more frequent exposures than Americans to coronaviruses with epitopes that cross-react with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), SARS-CoV, and Middle Eastern respiratory syndrome coronavirus (MERS-CoV). The percentage of Sierra Leoneans with antibodies reacting to seasonal coronaviruses was also higher than for American blood donors. Serological responses to coronaviruses by Sierra Leoneans did not differ by age or sex. Approximately a quarter of Sierra Leonian pre-pandemic blood samples had neutralizing antibodies against SARS-CoV-2 pseudovirus, while about a third neutralized MERS-CoV pseudovirus. Prior exposures to coronaviruses that induce cross-protective immunity may contribute to reduced COVID-19 cases and deaths in Sierra Leone.
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- 2021
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13. The Origins and Future of Sentinel: An Early-Warning System for Pandemic Preemption and Response
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Yolanda Botti-Lodovico, Parvathy Nair, Dolo Nosamiefan, Matthew Stremlau, Stephen Schaffner, Sebastian V. Agignoae, John Oke Aiyepada, Fehintola V. Ajogbasile, George O. Akpede, Foday Alhasan, Kristian G. Andersen, Danny A. Asogun, Oladele Oluwafemi Ayodeji, Aida S. Badiane, Kayla Barnes, Matthew R. Bauer, Antoinette Bell-Kareem, Muoebonam Ekene Benard, Ebo Ohomoime Benevolence, Osiemi Blessing, Chloe K. Boehm, Matthew L. Boisen, Nell G. Bond, Luis M. Branco, Michael J. Butts, Amber Carter, Andres Colubri, Awa B. Deme, Katherine C. DeRuff, Younousse Diédhiou, Akhilomen Patience Edamhande, Siham Elhamoumi, Emily J. Engel, Philomena Eromon, Mosoka Fallah, Onikepe A. Folarin, Ben Fry, Robert Garry, Amy Gaye, Michael Gbakie, Sahr M. Gevao, Gabrielle Gionet, Adrianne Gladden-Young, Augustine Goba, Jules Francois Gomis, Anise N. Happi, Mary Houghton, Chikwe Ihekwuazu, Christopher Ojemiega Iruolagbe, Jonathan Jackson, Simbirie Jalloh, Jeremy Johnson, Lansana Kanneh, Adeyemi Kayode, Molly Kemball, Ojide Chiedozie Kingsley, Veronica Koroma, Dylan Kotliar, Samar Mehta, Hayden C. Metsky, Airende Michael, Marzieh Ezzaty Mirhashemi, Kayvon Modjarrad, Mambu Momoh, Cameron A. Myhrvold, Okonofua Grace Naregose, Tolla Ndiaye, Mouhamadou Ndiaye, Aliou Ndiaye, Erica Normandin, Ikponmwosa Odia, Judith Uche Oguzie, Sylvanus A. Okogbenin, Peter O. Okokhere, Johnson Okolie, Idowu B. Olawoye, Testimony J. Olumade, Paul E. Oluniyi, Omigie Omoregie, Daniel J. Park, Mariétou Faye Paye, Brittany Petros, Anthony A. Philippakis, Abechi Priscilla, Alan Ricks, Anne Rimoin, John Demby Sandi, John S. Schieffelin, Monica Schreiber, Mame Cheikh Seck, Sameed Siddiqui, Katherine Siddle, Allison R. Smither, Mouhamad Sy, Ngayo Sy, Christopher H. Tomkins-Tinch, Oyewale Tomori, Chinedu Ugwu, Jessica N. Uwanibe, Eghosasere Anthonia Uyigue, Dada Ireti Victoria, Anika Vinzé, Megan E. Vodzak, Nicole Welch, Haja Isatta Wurie, Daba Zoumarou, Donald S. Grant, Daouda Ndiaye, Bronwyn MacInnis, Pardis C. Sabeti, and Christian Happi
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pandemic preemption ,pandemic response ,diagnostic tools ,bioinformatics ,genomic surveillance ,infectious disease ,Microbiology ,QR1-502 - Abstract
While investigating a signal of adaptive evolution in humans at the gene LARGE, we encountered an intriguing finding by Dr. Stefan Kunz that the gene plays a critical role in Lassa virus binding and entry. This led us to pursue field work to test our hypothesis that natural selection acting on LARGE—detected in the Yoruba population of Nigeria—conferred resistance to Lassa Fever in some West African populations. As we delved further, we conjectured that the “emerging” nature of recently discovered diseases like Lassa fever is related to a newfound capacity for detection, rather than a novel viral presence, and that humans have in fact been exposed to the viruses that cause such diseases for much longer than previously suspected. Dr. Stefan Kunz’s critical efforts not only laid the groundwork for this discovery, but also inspired and catalyzed a series of events that birthed Sentinel, an ambitious and large-scale pandemic prevention effort in West Africa. Sentinel aims to detect and characterize deadly pathogens before they spread across the globe, through implementation of its three fundamental pillars: Detect, Connect, and Empower. More specifically, Sentinel is designed to detect known and novel infections rapidly, connect and share information in real time to identify emerging threats, and empower the public health community to improve pandemic preparedness and response anywhere in the world. We are proud to dedicate this work to Stefan Kunz, and eagerly invite new collaborators, experts, and others to join us in our efforts.
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- 2021
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14. Data set on Lassa fever in post-conflict Sierra Leone
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Jeffrey G. Shaffer, John S. Schieffelin, Donald S. Grant, Augustine Goba, Mambu Momoh, Lansana Kanneh, Danielle C. Levy, Jessica N. Hartnett, Matt L. Boisen, Luis M. Branco, and Robert F. Garry
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Computer applications to medicine. Medical informatics ,R858-859.7 ,Science (General) ,Q1-390 - Abstract
Lassa fever is a rodent-borne illness that is endemic to parts of sub-Saharan Africa, including Sierra Leone, Nigeria, and Guinea. The disease is named after the town of Lassa, Nigeria where it was discovered in 1969. This data article focuses on the epidemiology of Lassa fever in Sierra Leone following a decade-long civil war that ended in 2002. The data were collected at Kenema Government Hospital (KGH) in Kenema, Sierra Leone, which maintains the country׳s only Lassa fever treatment facility and a biosafety level 3 (BSL-3) laboratory. The key data set variables include Lassa fever serostatus determined using antigen (Ag), immunoglobulin M (IgM), and immunoglobulin G (IgG) ELISA diagnostic techniques; and patient demographics, survival outcome, and treatment (ribavirin) status. The individual data used to generate the graphs and tables in the corresponding research manuscript published in PLOS Neglected Tropical Diseases in 2014 and its coding guide are provided as Supplementary material (Shaffer et al., 2014) [1]. Keywords: Infectious disease, Lassa fever, Epidemiology, Enzyme-linked immunosorbent assay (ELISA), Sierra Leone
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- 2019
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15. Space-Time Trends in Lassa Fever in Sierra Leone by ELISA Serostatus, 2012–2019
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Jeffrey G. Shaffer, John S. Schieffelin, Mambu Momoh, Augustine Goba, Lansana Kanneh, Foday Alhasan, Michael Gbakie, Emily J. Engel, Nell G. Bond, Jessica N. Hartnett, Diana K. S. Nelson, Duane J. Bush, Matthew L. Boisen, Megan L. Heinrich, Megan M. Rowland, Luis M. Branco, Robert J. Samuels, Robert F. Garry, Donald S. Grant, and the Viral Hemorrhagic Fever Consortium
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Lassa fever ,Lassa virus ,case-fatality rate ,enzyme-linked immunosorbent assay ,Ebola virus disease ,Sierra Leone ,Biology (General) ,QH301-705.5 - Abstract
Lassa fever (LF) is a viral hemorrhagic disease found in Sub-Saharan Africa and is responsible for up to 300,000 cases and 5000 deaths annually. LF is highly endemic in Sierra Leone, particularly in its Eastern Province. Kenema Government Hospital (KGH) maintains one of only a few LF isolation facilities in the world with year-round diagnostic testing. Here we focus on space-time trends for LF occurring in Sierra Leone between 2012 and 2019 to provide a current account of LF in the wake of the 2014–2016 Ebola epidemic. Data were analyzed for 3277 suspected LF cases and classified as acute, recent, and non-LF or prior LF exposure using enzyme-linked immunosorbent assays (ELISAs). Presentation rates for acute, recent, and non-LF or prior LF exposure were 6.0% (195/3277), 25.6% (838/3277), and 68.4% (2244/3277), respectively. Among 2051 non-LF or prior LF exposures, 33.2% (682/2051) tested positive for convalescent LF exposure. The overall LF case-fatality rate (CFR) was 78.5% (106/135). Both clinical presentations and confirmed LF cases declined following the Ebola epidemic. These declines coincided with an increased duration between illness onset and clinical presentation, perhaps suggesting more severe disease or presentation at later stages of illness. Acute LF cases and their corresponding CFRs peaked during the dry season (November to April). Subjects with recent (but not acute) LF exposure were more likely to present during the rainy season (May to October) than the dry season (p < 0.001). The findings here suggest that LF remains endemic in Sierra Leone and that caseloads are likely to resume at levels observed prior to the Ebola epidemic. The results provide insight on the current epidemiological profile of LF in Sierra Leone to facilitate LF vaccine studies and accentuate the need for LF cohort studies and continued advancements in LF diagnostics.
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- 2021
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16. Most neutralizing human monoclonal antibodies target novel epitopes requiring both Lassa virus glycoprotein subunits
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James E. Robinson, Kathryn M. Hastie, Robert W. Cross, Rachael E. Yenni, Deborah H. Elliott, Julie A. Rouelle, Chandrika B. Kannadka, Ashley A. Smira, Courtney E. Garry, Benjamin T. Bradley, Haini Yu, Jeffrey G. Shaffer, Matt L. Boisen, Jessica N. Hartnett, Michelle A. Zandonatti, Megan M. Rowland, Megan L. Heinrich, Luis Martínez-Sobrido, Benson Cheng, Juan C. de la Torre, Kristian G. Andersen, Augustine Goba, Mambu Momoh, Mohamed Fullah, Michael Gbakie, Lansana Kanneh, Veronica J. Koroma, Richard Fonnie, Simbirie C. Jalloh, Brima Kargbo, Mohamed A. Vandi, Momoh Gbetuwa, Odia Ikponmwosa, Danny A. Asogun, Peter O. Okokhere, Onikepe A. Follarin, John S. Schieffelin, Kelly R. Pitts, Joan B. Geisbert, Peter C. Kulakoski, Russell B. Wilson, Christian T. Happi, Pardis C. Sabeti, Sahr M. Gevao, S. Humarr Khan, Donald S. Grant, Thomas W. Geisbert, Erica Ollmann Saphire, Luis M. Branco, and Robert F. Garry
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Science - Abstract
Lassa virus can cause haemorrhagic fever for which no specific treatment currently exists. Here the authors have cloned 113 monoclonal antibodies from the survivors of Lassa infection and show that the majority of neutralizing antibodies target a complex of GP1 and GP2 viral proteins.
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- 2016
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17. Association of cancer and outcomes of patients hospitalized for COVID-19 between 2020 and 2023 [version 1; peer review: awaiting peer review]
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Abdulai Tejan Jalloh, Laura Merson, Divya Nair, Shermarke Hassan, Ibrahim Franklyn Kamara, Innocent Nuwagira, Sia Morenike Tengbe, Yusuf Sheku Tejan, Mustapha Kabba, Sulaiman Lakoh, Donald S Grant, Robert J Samuels, Rugiatu Z Kamara, and Robert F Terry
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Research Article ,Articles ,COVID-19 ,cancer ,comorbidities ,mortality ,hazard ratio ,risk factor ,ISARIC ,SORT IT - Abstract
Background The coronavirus disease 2019 (COVID-19) has caused substantial morbidity and mortality on a global scale. A strong correlation has been found between COVID-19 treatment outcomes and noncommunicable diseases such as cancers. However, there is limited information on the outcomes of cancer patients who were hospitalised for COVID-19. Methods We conducted an analysis on data collected in a large prospective cohort study set-up by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). All patients with laboratory-confirmed or clinically-diagnosed SARS-CoV-2 infection were included. Cancer was defined as having a current solid organ or haematological malignancy. The following outcomes were assessed; 30-day in-hospital mortality, intensive care unit (ICU) admission, length of hospitalization and receipt of higher-level care. Results Of the 560,547 hospitalised individuals who were analysed, 27,243 (4.9%) had cancer. Overall, cancer patients were older and had more comorbidities than non-cancer patients. Patients with cancer had higher 30-day in-hospital mortality than non-cancer patients (29.1.3% vs 18.0%) and longer hospital stays (median of 12 days vs 8 days). However, patients with cancer were admitted less often to intensive care units than non-cancer patients (12.6% vs 17.1%) and received less invasive mechanical ventilation than non-cancer patients (4.5% vs 7.6%). The hazard ratio of dying from cancer, adjusted for age, sex and country income level was 1.18 (95%CI: 1.15-1.2). Conclusions This study’s findings underscore the heightened vulnerability of hospitalized COVID-19 patients with cancer, revealing a higher mortality rate, longer hospital stays, and an unstructured pattern of care that reflects the complexity of managing severely ill patients during a public health crisis like the COVID-19 pandemic.
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- 2024
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18. Female Genital Mutilation in Sierra Leone: Forms, Reliability of Reported Status, and Accuracy of Related Demographic and Health Survey Questions
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Owolabi Bjälkander, Donald S. Grant, Vanja Berggren, Heli Bathija, and Lars Almroth
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Gynecology and obstetrics ,RG1-991 - Abstract
Objective. To determine forms of female genital mutilation (FGM), assess consistency between self-reported and observed FGM status, and assess the accuracy of Demographic and Health Surveys (DHS) FGM questions in Sierra Leone. Methods. This cross-sectional study, conducted between October 2010 and April 2012, enrolled 558 females aged 12–47 from eleven antenatal clinics in northeast Sierra Leone. Data on demography, FGM status, and self-reported anatomical descriptions were collected. Genital inspection confirmed the occurrence and extent of cutting. Results. All participants reported FGM status; 4 refused genital inspection. Using the WHO classification of FGM, 31.7% had type Ib; 64.1% type IIb; and 4.2% type IIc. There was a high level of agreement between reported and observed FGM prevalence (81.2% and 81.4%, resp.). There was no correlation between DHS FGM responses and anatomic extent of cutting, as 2.7% reported pricking; 87.1% flesh removal; and 1.1% that genitalia was sewn closed. Conclusion. Types I and II are the main forms of FGM, with labia majora alterations in almost 5% of cases. Self-reports on FGM status could serve as a proxy measurement for FGM prevalence but not for FGM type. The DHS FGM questions are inaccurate for determining cutting extent.
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- 2013
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19. Virus genomes reveal factors that spread and sustained the Ebola epidemic.
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Gytis Dudas, Luiz Max Carvalho, Trevor Bedford, Andrew J. Tatem, Guy Baele, Nuno R. Faria, Daniel J. Park, Jason T. Ladner, Armando Arias, Danny Asogun, Filip Bielejec, Sarah L. Caddy, Matthew Cotten, Jonathan D'Ambrozio, Simon Dellicour, Antonino Di Caro, Joseph W. Diclaro, Sophie Duraffour, Michael J. Elmore, Lawrence S. Fakoli, Ousmane Faye, Merle L. Gilbert, Sahr M. Gevao, Stephen Gire, Adrianne Gladden-Young, Andreas Gnirke, Augustine Goba, Donald S. Grant, Bart L. Haagmans, Julian A. Hiscox, Umaru Jah, Jeffrey R. Kugelman, Di Liu, Jia Lu, Christine M. Malboeuf, Suzanne Mate, David A. Matthews, Christian B. Matranga, Luke W. Meredith, James Qu, Joshua Quick, Suzan D. Pas, My V. T. Phan, Georgios Pollakis, Chantal B. Reusken, Mariano Sanchez-Lockhart, Stephen F. Schaffner, John S. Schieffelin, Rachel S. G. Sealfon, Etienne Simon-Loriere, Saskia L. Smits, Kilian Stoecker, Lucy Thorne, Ekaete Alice Tobin, Mohamed A. Vandi, Simon J. Watson 0002, Kendra West, Shannon Whitmer, Michael R. Wiley, Sarah M. Winnicki, Shirlee Wohl, Roman Wölfel, Nathan L. Yozwiak, Kristian G. Andersen, Sylvia O. Blyden, Fatorma Bolay, Miles W. Carroll, Bernice Dahn, Boubacar Diallo, Pierre Formenty, Christophe Fraser, George F. Gao, Robert F. Garry, Ian Goodfellow, Stephan Günther, Christian T. Happi, Edward C. Holmes, Brima Kargbo, Sakoba Keïta, Paul Kellam, Marion Koopmans, Jens H. Kuhn, Nicholas J. Loman, N'Faly Magassouba, Dhamari Naidoo, Stuart T. Nichol, Tolbert Nyenswah, Gustavo F. Palacios, Oliver G. Pybus, Pardis C. Sabeti, Amadou Sall, Ute Ströher, Isatta Wurie, Marc A. Suchard, Philippe Lemey, and Andrew Rambaut
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- 2017
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20. Novel Tools for Lassa Virus Surveillance in Peri-domestic Rodents
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Allison R. Smither, James Koninga, Franklyn B. Kanneh, Momoh Foday, Matthew L. Boisen, Nell G. Bond, Mambu Momoh, John Demby Sandi, Lansana Kanneh, Foday Alhasan, Ibrahim Mustapha Kanneh, Mohamed S. Yillah, Donald S. Grant, Duane J. Bush, Diana K. S. Nelson, Kaitlin M. Cruz, Raphaëlle Klitting, Matthias Pauthner, Kristian G. Andersen, Jeffrey G. Shaffer, Robert W. Cross, John S. Schieffelin, and Robert F. Garry
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Article - Abstract
BackgroundLassa fever (LF) is a rodent-borne disease endemic to West Africa. In the absence of licensed therapeutics or vaccines, rodent exclusion from living spaces remains the primary method of preventing LF. Zoonotic surveillance of Lassa virus (LASV), the etiologic agent of LF, can assess the burden of LASV in a region and guide public health measures against LF.MethodsIn this study, we adapted commercially available LASV human diagnostics to assess the prevalence of LASV in peri-domestic rodents in Eastern Sierra Leone. Small mammal trapping was conducted in Kenema district, Sierra Leone between November 2018-July 2019. LASV antigen was detected using a commercially available LASV NP antigen rapid diagnostic test. LASV IgG antibodies against LASV nucleoprotein (NP) and glycoprotein (GP) were tested by adapting a commercially available semi-quantitative enzyme linked immunosorbent assay (ELISA) for detection of mouse-related and rat-related species IgG.FindingsOf the 373 tested specimens, 74 (20%) tested positive for LASV antigen. 40 (11%) specimens tested positive for LASV NP IgG, while an additional 12 (3%) specimens only tested positive for LASV GP IgG. Simultaneous antigen presence and IgG antibody presence was linked inMastomys sp. specimens (p< 0.01), but notRattus sp. specimens (p= 1). Despite the link between antigen presence and IgG antibody presence inMastomys sp., the strength of antigen response did not correlate with the strength of IgG response to either GP IgG or NP IgG.InterpretationThe tools developed in this study can aid in the generation of valuable public health data for rapid field assessment of LASV burden during outbreak investigations and general LASV surveillance.FundingFunding for this work was supported by the National Institute of Allergy and Infectious Diseases National Institute of Health, Department of Health and Human Services under the following grants: International Collaboration in Infectious Disease Research on Lassa fever and Ebola - ICIDR - U19 AI115589, Consortium for Viral Systems Biology - CViSB - 5U19AI135995, West African Emerging Infectious Disease Research Center - WARN-ID - U01AI151812, West African Center for Emerging Infectious Diseases: U01AI151801.
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- 2023
21. Lassa Fever Natural History and Clinical Management
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Donald S. Grant, Robert J. Samuels, Robert F. Garry, and John S. Schieffelin
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- 2023
22. Seroprevalence of anti-Lassa Virus IgG antibodies in three districts of Sierra Leone: A cross-sectional, population-based study
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Donald S. Grant, Emily J. Engel, Nicole Roberts Yerkes, Lansana Kanneh, James Koninga, Michael A. Gbakie, Foday Alhasan, Franklyn B. Kanneh, Ibrahim Mustapha Kanneh, Fatima K. Kamara, Mambu Momoh, Mohamed S. Yillah, Momoh Foday, Adaora Okoli, Ashley Zeoli, Caroline Weldon, Christopher M. Bishop, Crystal Zheng, Jessica Hartnett, Karissa Chao, Kayla Shore, Lilia I. Melnik, Mallory Mucci, Nell G. Bond, Philip Doyle, Rachael Yenni, Rachel Podgorski, Samuel C. Ficenec, Lina Moses, Jeffrey G. Shaffer, Robert F. Garry, and John S. Schieffelin
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Infectious Diseases ,Public Health, Environmental and Occupational Health - Abstract
Background Lassa virus (LASV), the cause of the acute viral hemorrhagic illness Lassa fever (LF), is endemic in West Africa. Infections in humans occur mainly after exposure to infected excrement or urine of the rodent-host, Mastomys natalensis. The prevalence of exposure to LASV in Sierra Leone is crudely estimated and largely unknown. This cross-sectional study aimed to establish a baseline point seroprevalence of IgG antibodies to LASV in three administrative districts of Sierra Leone and identify potential risk factors for seropositivity and LASV exposure. Methodology and principal findings Between 2015 and 2018, over 10,642 participants from Kenema, Tonkolili, and Port Loko Districts were enrolled in this cross-sectional study. Previous LASV and LF epidemiological studies support classification of these districts as “endemic,” “emerging,” and “non-endemic”, respectively. Dried blood spot samples were tested for LASV antibodies by ELISA to determine the seropositivity of participants, indicating previous exposure to LASV. Surveys were administered to each participant to assess demographic and environmental factors associated with a higher risk of exposure to LASV. Overall seroprevalence for antibodies to LASV was 16.0%. In Kenema, Port Loko, and Tonkolili Districts, seroprevalences were 20.1%, 14.1%, and 10.6%, respectively. In a multivariate analysis, individuals were more likely to be LASV seropositive if they were living in Kenema District, regardless of sex, age, or occupation. Environmental factors contributed to an increased risk of LASV exposure, including poor housing construction and proximity to bushland, forested areas, and refuse. Conclusions and significance In this study we determine a baseline LASV seroprevalence in three districts which will inform future epidemiological, ecological, and clinical studies on LF and the LASV in Sierra Leone. The heterogeneity of the distribution of LASV and LF over both space, and time, can make the design of efficacy trials and intervention programs difficult. Having more studies on the prevalence of LASV and identifying potential hyper-endemic areas will greatly increase the awareness of LF and improve targeted control programs related to LASV.
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- 2023
23. Endotheliopathy and Platelet Dysfunction as Hallmarks of Fatal Lassa Fever
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Robert W. Cross, Brian M. Sullivan, Saori Sakabe, Lucy E Horton, John S. Schieffelin, Mambu Momoh, Robert F. Garry, Emily J Engel, Thomas W. Geisbert, Jessica N. Hartnett, Donald S. Grant, Augustine Goba, and John Demby Sandi
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Male ,Epidemiology ,vector-borne infections ,lcsh:Medicine ,protein C ,chemistry.chemical_compound ,0302 clinical medicine ,Platelet ,030212 general & internal medicine ,Child ,platelet ,Endothelial protein C receptor ,Middle Aged ,Infectious Diseases ,Child, Preschool ,Plasminogen activator inhibitor-1 ,Female ,fibrinolysis ,hemorrhagic fever ,medicine.drug ,Lassa fever ,Adult ,Blood Platelets ,Microbiology (medical) ,medicine.medical_specialty ,Adolescent ,030231 tropical medicine ,Thrombomodulin ,Sierra Leone ,Sierra leone ,lcsh:Infectious and parasitic diseases ,Young Adult ,03 medical and health sciences ,Tissue factor ,Internal medicine ,medicine ,Humans ,viruses ,lcsh:RC109-216 ,Endothelium ,coagulation ,Blood Coagulation ,Aged ,business.industry ,Research ,lcsh:R ,Infant ,zoonoses ,Endocrinology ,chemistry ,Endotheliopathy and Platelet Dysfunction as Hallmarks of Fatal Lassa Fever ,Hemostasis ,hemostasis ,business ,Protein C - Abstract
Lassa fever (LF) causes multisystem disease and has a fatality rate
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- 2020
24. Lassa Fever among Children in Eastern Province, Sierra Leone: A 7-year Retrospective Analysis (2012–2018)
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Joseph R. Starnes, John S. Schieffelin, Donald S. Grant, Robert J. Samuels, Emily J Engel, Troy D. Moon, Augustine Goba, John Demby Sandi, Mambu Momoh, Robert F. Garry, Veronica J. Koroma, Foday Alhasan, Michael Gbakie, and Jeffrey G. Shaffer
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Male ,Pediatrics ,medicine.medical_specialty ,Time Factors ,Adolescent ,Antibodies, Viral ,Sierra leone ,Sierra Leone ,chemistry.chemical_compound ,Lassa Fever ,Virology ,Case fatality rate ,medicine ,Humans ,Lassa fever ,Child ,Lassa virus ,Antigens, Viral ,Retrospective Studies ,Creatinine ,Univariate analysis ,business.industry ,Ribavirin ,Infant, Newborn ,Infant ,Retrospective cohort study ,Odds ratio ,Articles ,medicine.disease ,Infectious Diseases ,chemistry ,Child, Preschool ,Parasitology ,Female ,business - Abstract
Pediatric Lassa fever (LF) usually presents as a nonspecific febrile illness, similar to other endemic diseases in countries like Sierra Leone, where LF is considered to be hyperendemic. The nonspecificity of presentation and lack of research have made it difficult to fully understand best practices for pediatric management. We aim to describe clinical characteristics of hospitalized pediatric patients suspected or diagnosed with LF and assess factors associated with hospital outcomes among those with LF antigen–positive results. We conducted a 7-year retrospective cohort study using routine data for all children younger than 18 years admitted at the Kenema Government Hospital’s LF ward. A total of 292 children with suspected or confirmed LF were analyzed. Overall, mortality was high (21%). Children with antigen-positive results had a high case fatality rate of 63% (P < 0.01). In univariate analyses, children who presented with unexplained bleeding (odds ratio [OR]: 3.58; 95% CI: 1.08–11.86; P = 0.040) and confusion (altered sensorium) (OR: 5.37; 95% CI: 1.34–21.48; P = 0.020) had increased odds of death. Abnormal serum levels of alanine aminotransferase (P = 0.001), creatinine (P = 0.004), and potassium (P = 0.003) were associated with increased likelihood of death in these children. Treatment with ribavirin was not significantly associated with survival (P = 0.916). Our findings provide insights into current pediatric LF clinical presentation and management. More evidence-based, high-quality research in creating predictive algorithms of antigen-positivity and hospital outcomes is needed in the management of pediatric LF.
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- 2020
25. Expansion of CD8+ T cell population in Lassa virus survivors with low T cell precursor frequency reveals durable immune response in most survivors
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Stephanie M. LaVergne, Saori Sakabe, Mambu Momoh, Lansana Kanneh, Nell Bond, Robert F. Garry, Donald S. Grant, Juan Carlos de la Torre, Michael B. A. Oldstone, John S. Schieffelin, and Brian M. Sullivan
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Precursor Cells, T-Lymphoid ,Infectious Diseases ,Lassa Fever ,Public Health, Environmental and Occupational Health ,Leukocytes, Mononuclear ,Immunity ,Humans ,CD8-Positive T-Lymphocytes ,Lassa virus - Abstract
Introduction Lassa virus is a priority pathogen for vaccine research and development, however the duration of cellular immunity and protection in Lassa fever (LF) survivors remains unclear. Methods We investigated Lassa virus specific CD8+ T cell responses in 93 LF survivors. Peripheral blood mononuclear cells from these individuals were infected with recombinant vesicular stomatitis virus encoding Lassa virus antigens and virus specific T cell responses were measured after 18-hour incubation. Participants who had undetectable CD8+ T cell response underwent further analysis using a 10-day T cell proliferation assays to evaluate for low T cell precursor frequency. Results Forty-five of the 93 LF survivors did not have a Lassa virus specific CD8+ T cell response. Of those with responses and a known date of onset of LF (N = 11), 9 had LF within the last ten years. Most participants without a measurable CD8+ T cell response were more than 10 years removed from a clinical history of LF (N = 14/16). Fourteen of 21 patients (67%) with undetectable CD8+ T cell response had a measurable Lassa virus specific CD8+ T cell response with the 10-day assay. Discussion Despite reports of strong CD8+ T cell responses during acute Lassa virus infection, circulating Lassa virus-specific CD8+ T cells declined to undetectable levels in most Lassa fever survivors after ten years when evaluated with an 18-hour T cell stimulation. However, when Lassa virus-specific T cells were expanded prior to restimulation, a Lassa virus-specific CD8+ T cell response could be detected in many if the samples that were negative in the 18-hour stimulation assay, suggesting that prolonged cellular immunity does exist in Lassa fever survivors at low frequencies.
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- 2022
26. Antibodies from Sierra Leonean and Nigerian Lassa fever survivors cross-react with recombinant proteins representing Lassa viruses of divergent lineages
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Olusola A Ogunsanya, Francis Baimba, Johan Holst, Simji S. Gomerep, Robert F. Garry, Erica Ollmann Saphire, Peter O. Okokhere, Raju Lathigra, Viktoriya Borisevich, Diana K. S. Nelson, Luis M. Branco, Benevolence Ebo, Sylvanus Okogbenin, John S. Schieffelin, John Aiyepada, Mambu Momoh, Robert W. Cross, Megan L. Heinrich, Anatoliy P. Koval, Matthew L. Boisen, Thomas W. Geisbert, Augustine Goba, Megan M. Rowland, Andrew R. Hoffmann, Onikepe A. Folarin, E. E. Ella, John Demby Sandi, Christian T. Happi, Chinedu A Ugwu, lkponmwosa Odia, Johnson Etafo, Brandon J. Beddingfield, Macdonald Nonso Onyechi, Donald S. Grant, Jeffrey G. Shaffer, Rashidat Adeyemi, M. Aminu, Sophia A. Koval, Kathryn M. Hastie, Duane J. Bush, George O. Akpede, Philomena Eromon, Matthew Afam Eke, Danny Asogun, Irina Aimukanova, and Testimony J. Olumade
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0301 basic medicine ,Immunology ,Nigeria ,lcsh:Medicine ,Cross Reactions ,medicine.disease_cause ,Antibodies, Viral ,Microbiology ,Neutralization ,Article ,Antibodies ,Sierra leone ,Sierra Leone ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Lassa Fever ,medicine ,Humans ,030212 general & internal medicine ,Survivors ,Lassa fever ,Lassa virus ,lcsh:Science ,Antigens, Viral ,Multidisciplinary ,biology ,lcsh:R ,Genetic Variation ,medicine.disease ,Virology ,Recombinant Proteins ,Nucleoprotein ,Immunity, Humoral ,030104 developmental biology ,Nucleoproteins ,Humoral immunity ,biology.protein ,Immunization ,lcsh:Q ,Antibody - Abstract
Lassa virus (LASV) is the causative agent of Lassa fever, an often-fatal hemorrhagic disease that is endemic in West Africa. Seven genetically distinct LASV lineages have been identified. As part of CEPI’s (Coalition for Epidemic Preparedness Innovations) Lassa vaccine development program, we assessed the potential of the human immune system to mount cross-reactive and cross-protective humoral immune responses to antigens from the most prevalent LASV lineages, which are lineages II and III in Nigeria and lineage IV in Sierra Leone. IgG and IgM present in the blood of Lassa fever survivors from Nigeria or Sierra Leone exhibited substantial cross-reactivity for binding to LASV nucleoprotein and two engineered (linked and prefusion) versions of the glycoproteins (GP) of lineages II–IV. There was less cross-reactivity for the Zinc protein. Serum or plasma from Nigerian Lassa fever survivors neutralized LASV pseudoviruses expressing lineage II GP better than they neutralized lineage III or IV GP expressing pseudoviruses. Sierra Leonean survivors did not exhibit a lineage bias. Neutralization titres determined using LASV pseudovirus assays showed significant correlation with titres determined by plaque reduction with infectious LASV. These studies provide guidance for comparison of humoral immunity to LASV of distinct lineages following natural infection or immunization.
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- 2020
27. Field evaluation of a Pan-Lassa rapid diagnostic test during the 2018 Nigerian Lassa fever outbreak
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Ekaete Alice Tobin, Matthew L. Boisen, Meike Pahlmann, Chris Aire, Diana K. S. Nelson, John S. Schieffelin, Adeyemi T. Kayode, Luis M. Branco, Solomon Ehikhametalor, Onikepe A. Folarin, Patience Akhilomen, Jacqueline Agbukor, Danny Asogun, Donatus I Adomeh, Ikponmwosa Odia, Grace Okonofua, John Aiyepada, Katherine J. Siddle, Blessing Osiemi, Augustine Goba, Ephraim Ogbaini-Emovan, Megan L. Heinrich, Kayla G. Barnes, Peter O. Okokhere, John Demby Sandi, Megan M. Rowland, Philomena Eromon, Pardis C. Sabeti, Robert F. Garry, Ekene B. Muoebonam, Samar B. Mehta, Eghosa Uyigue, Christian T. Happi, Michael Airende, Stephan Günther, Sophie Duraffour, Lisa Oestereich, Sylvanus Okogbenin, Omigie Omoregie, Donald S. Grant, Duane J. Bush, George O. Akpede, Mambu Momoh, and Wiebke Böhm
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Adult ,Male ,0301 basic medicine ,Point-of-Care Systems ,viruses ,Immunology ,Nigeria ,lcsh:Medicine ,Antibodies, Viral ,medicine.disease_cause ,Sensitivity and Specificity ,Microbiology ,Article ,Virus ,Disease Outbreaks ,Sierra leone ,Young Adult ,03 medical and health sciences ,Lassa Fever ,0302 clinical medicine ,Case fatality rate ,parasitic diseases ,Humans ,Medicine ,030212 general & internal medicine ,Lassa virus ,Lassa fever ,lcsh:Science ,Antigens, Viral ,Rapid diagnostic test ,Multidisciplinary ,biology ,Diagnostic Tests, Routine ,Sequence Analysis, RNA ,business.industry ,lcsh:R ,Outbreak ,Middle Aged ,medicine.disease ,Virology ,030104 developmental biology ,biology.protein ,RNA, Viral ,Female ,lcsh:Q ,Antibody ,business - Abstract
Lassa virus (LASV) is the causative agent of Lassa fever (LF), an often-fatal hemorrhagic disease. LF is endemic in Nigeria, Sierra Leone and other West African countries. Diagnosis of LASV infection is challenged by the genetic diversity of the virus, which is greatest in Nigeria. The ReLASV Pan-Lassa Antigen Rapid Test (Pan-Lassa RDT) is a point-of-care, in vitro diagnostic test that utilizes a mixture of polyclonal antibodies raised against recombinant nucleoproteins of representative strains from the three most prevalent LASV lineages (II, III and IV). We compared the performance of the Pan-LASV RDT to available quantitative PCR (qPCR) assays during the 2018 LF outbreak in Nigeria. For patients with acute LF (RDT positive, IgG/IgM negative) during initial screening, RDT performance was 83.3% sensitivity and 92.8% specificity when compared to composite results of two qPCR assays. 100% of samples that gave Ct values below 22 on both qPCR assays were positive on the Pan-Lassa RDT. There were significantly elevated case fatality rates and elevated liver transaminase levels in subjects whose samples were RDT positive compared to RDT negative.
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- 2020
28. Capturing sequence diversity in metagenomes with comprehensive and scalable probe design
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Sharon Isern, Onikepe A. Folarin, Philomena Eromon, Thiago Moreno L. Souza, Yasmine Rangel Vieira, Kimberly García, Christian B. Matranga, Douglas S. Kwon, Etienne Simon-Loriere, Shirlee Wohl, Ivette Lorenzana, Hayden C. Metsky, Patrick Brehio, Katherine J. Siddle, David K Yang, Scott F. Michael, Giselle Barbosa-Lima, Adrianne Gladden-Young, Leda Parham, Lauren M. Paul, Augustine Goba, Bjӧrn Corleis, Todd M. Allen, Andreas Gnirke, Pardis C. Sabeti, Scott Hennigan, Eva Harris, Jonathan A. Runstadler, Andrew Goldfarb, Lee Gehrke, Sandra Smole, Christian T. Happi, Amanda L Tan, Angel Balmaseda, Damien C. Tully, Anne Piantadosi, Fernando A. Bozza, Aaron E. Lin, Gregory D. Ebel, Daniel J. Park, Amber Carter, James Qu, Donald S. Grant, Ikponmwonsa Odia, Irene Bosch, Lisa E. Hensley, and Kayla G. Barnes
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Sequence analysis ,Computer science ,Oligonucleotides ,Biomedical Engineering ,Nigeria ,Genomics ,Bioengineering ,Genome, Viral ,Computational biology ,Full coverage ,Genome ,Applied Microbiology and Biotechnology ,Article ,Disease Outbreaks ,03 medical and health sciences ,Lassa Fever ,0302 clinical medicine ,Animals ,Humans ,Genomic library ,Gene Library ,030304 developmental biology ,Sequence (medicine) ,0303 health sciences ,Computational Biology ,Genetic Variation ,High-Throughput Nucleotide Sequencing ,Sequence Analysis, DNA ,Culicidae ,Virus Diseases ,Metagenomics ,Scalability ,Metagenome ,Molecular Medicine ,Oligonucleotide Probes ,030217 neurology & neurosurgery ,Biotechnology - Abstract
Metagenomic sequencing has the potential to transform microbial detection and characterization, but new tools are needed to improve its sensitivity. Here we present CATCH, a computational method to enhance nucleic acid capture for enrichment of diverse microbial taxa. CATCH designs optimal probe sets, with a specified number of oligonucleotides, that achieve full coverage of, and scale well with, known sequence diversity. We focus on applying CATCH to capture viral genomes in complex metagenomic samples. We design, synthesize, and validate multiple probe sets, including one that targets the whole genomes of the 356 viral species known to infect humans. Capture with these probe sets enriches unique viral content on average 18-fold, allowing us to assemble genomes that could not be recovered without enrichment, and accurately preserves within-sample diversity. We also use these probe sets to recover genomes from the 2018 Lassa fever outbreak in Nigeria and to improve detection of uncharacterized viral infections in human and mosquito samples. The results demonstrate that CATCH enables more sensitive and cost-effective metagenomic sequencing.
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- 2019
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29. Evaluation of Three Clinical Prediction Tools to Predict Mortality in Hospitalized Patients with Lassa Fever
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John J. Chiosi, John S. Schieffelin, Jeffrey G. Shaffer, and Donald S. Grant
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Infectious Diseases ,Lassa Fever ,Immunoglobulin M ,Virus Diseases ,Virology ,Humans ,Parasitology ,Antibodies, Viral ,Lassa virus ,Retrospective Studies - Abstract
Lassa fever is a viral hemorrhagic illness with a case fatality rate for hospitalized patients as high as 69%. Identifying cases before they progress to serious illness can lead to earlier treatment and improved clinical outcomes. Three existing clinical prediction tools were evaluated on their ability to predict the in-hospital mortality in Lassa fever: the quick Sequential Organ Failure Assessment (qSOFA), the Modified Early Warning System (MEWS), and the Universal Vital Assessment (UVA). This was a retrospective cohort study of patients admitted to the dedicated Lassa fever ward of the Kenema Government Hospital in Sierra Leone between May 2013 and December 2019. Data among three serology groups were analyzed: Lassa antigen-positive (Ag+) regardless of IgM status, Lassa Ag- and IgM+, and Lassa Ag- and IgM- cases. There were 123 cases of suspected Lassa fever included in this study. Abnormalities in respiratory rate, oxygenation status, mental status, and serum markers of kidney and liver dysfunction were more likely seen in the Ag+ group, which had an in-hospital mortality of 85.7%. For the Lassa Ag+ group, the sensitivity and positive predictive value of qSOFA ≥ 2 was 70.6% and 92.3%, MEWS ≥ 5 was 96.9% and 86.1%, and UVA ≥ 5 was 60.0% and 100.0%. The MEWS and UVA scores show potential for use in Lassa fever, but there is opportunity for future development of a tool that includes the clinical and laboratory markers specific to Lassa fever.
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- 2020
30. Development of a qualitative real-time RT-PCR assay for the detection of SARS-CoV-2: A guide and case study in setting up an emergency-use, laboratory-developed molecular assay
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Jochen K. Lennerz, Jacob E. Lemieux, Lauren L. Ritterhouse, Virginia M. Pierce, Julia Thierauf, Rebecca Pellerin, Sylvia Signorelli, Tasos Gogakos, Bennett M. Shaw, Graham McGrath, Christian T. Happi, Sarah E Turbett, Stephen F. Schaffner, Jacqueline S. Eversley, Damien Slater, Donald S. Grant, N Zeke Georgantas, Katherine J. Siddle, Jason B. Harris, Molly Kemball, Edward T. Ryan, Regina C. LaRocque, John A. Branda, Daouda Ndiaye, Hetal D. Marble, Pardis C. Sabeti, Julie M. Batten, Melis N. Anahtar, Elizabeth H Byrne, Samar B. Mehta, Eric S. Rosenberg, Gordon Adams, and Yolanda Botti-Lodovico
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Flexibility (engineering) ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Computer science ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Economic shortage ,medicine.disease ,Real-time polymerase chain reaction ,Health care ,Pandemic ,medicine ,Medical emergency ,business ,Effective response - Abstract
Developing and deploying new diagnostic tests is difficult, but the need to do so in response to a rapidly emerging pandemic such as COVID-19 is crucially important for an effective response. In the early stages of a pandemic, laboratories play a key role in helping health care providers and public health authorities detect active infection, a task most commonly achieved using nucleic acid-based assays. While the landscape of diagnostics is rapidly evolving, polymerase chain reaction (PCR) remains the gold-standard of nucleic acid-based diagnostic assays, in part due to its reliability, flexibility, and wide deployment. To address a critical local shortage of testing capacity persisting during the COVID-19 outbreak, our hospital set up a molecular based laboratory developed test (LDT) to accurately and safely diagnose SARS-CoV-2. We describe here the process of developing an emergency-use LDT, in the hope that our experience will be useful to other laboratories in future outbreaks and will help to lower barriers to fast and accurate diagnostic testing in crisis conditions.
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- 2020
31. Identification of Common CD8 + T Cell Epitopes from Lassa Fever Survivors in Nigeria and Sierra Leone
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Christian T. Happi, Beatrice Cubitt, Karthik Gangavarapu, Brian M. Sullivan, Peter O. Okokhere, Onikepe A. Folarin, Brian C. Ware, Saori Sakabe, Pardis C. Sabeti, Nhi Ngo, Jessica N. Hartnett, Sylvanus Okogbenin, Juan Carlos de la Torre, Luis M. Branco, Ikponmwosa Odia, Donald S. Grant, Philomena Eromon, John S. Schieffelin, Augustine Goba, John Demby Sandi, Refugio Robles-Sikisaka, Mambu Momoh, Kristian G. Andersen, Dylan Kotliar, Ephraim Ogbaini-Emovon, Selma D. Garcia, Robert F. Garry, Lansana Kanneh, and Michael B. A. Oldstone
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Male ,viruses ,Epitopes, T-Lymphocyte ,CD8-Positive T-Lymphocytes ,Antibodies, Viral ,medicine.disease_cause ,Epitope ,0302 clinical medicine ,Viral Envelope Proteins ,Genes, Reporter ,Cytotoxic T cell ,Survivors ,arenavirus ,Child ,Lassa fever ,Antigens, Viral ,0303 health sciences ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Host-Pathogen Interactions ,Female ,Adolescent ,T cell ,Green Fluorescent Proteins ,Immunology ,Nigeria ,Biology ,Microbiology ,Sierra Leone ,Sierra leone ,Young Adult ,03 medical and health sciences ,Lassa Fever ,memory T cells ,HLA-DQ Antigens ,Virology ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Lassa virus ,030304 developmental biology ,Arenavirus ,Immune Sera ,epitopes ,biology.organism_classification ,medicine.disease ,Nucleoproteins ,Haplotypes ,Insect Science ,Pathogenesis and Immunity ,Immunologic Memory ,CD8 - Abstract
The high morbidity and mortality associated with clinical cases of Lassa fever, together with the lack of licensed vaccines and limited and partially effective interventions, make Lassa virus (LASV) an important health concern in its regions of endemicity in West Africa. Previous infection with LASV protects from disease after subsequent exposure, providing a framework for designing vaccines to elicit similar protective immunity. Multiple major lineages of LASV circulate in West Africa, and therefore, ideal vaccine candidates should elicit immunity to all lineages. We therefore sought to identify common T cell epitopes between Lassa fever survivors from Sierra Leone and Nigeria, where distinct lineages circulate. We identified three such epitopes derived from highly conserved regions within LASV proteins. In this process, we also identified nine other T cell epitopes. These data should help in the design of an effective pan-LASV vaccine., Early and robust T cell responses have been associated with survival from Lassa fever (LF), but the Lassa virus-specific memory responses have not been well characterized. Regions within the virus surface glycoprotein (GPC) and nucleoprotein (NP) are the main targets of the Lassa virus-specific T cell responses, but, to date, only a few T cell epitopes within these proteins have been identified. We identified GPC and NP regions containing T cell epitopes and HLA haplotypes from LF survivors and used predictive HLA-binding algorithms to identify putative epitopes, which were then experimentally tested using autologous survivor samples. We identified 12 CD8-positive (CD8+) T cell epitopes, including epitopes common to both Nigerian and Sierra Leonean survivors. These data should be useful for the identification of dominant Lassa virus-specific T cell responses in Lassa fever survivors and vaccinated individuals as well as for designing vaccines that elicit cell-mediated immunity. IMPORTANCE The high morbidity and mortality associated with clinical cases of Lassa fever, together with the lack of licensed vaccines and limited and partially effective interventions, make Lassa virus (LASV) an important health concern in its regions of endemicity in West Africa. Previous infection with LASV protects from disease after subsequent exposure, providing a framework for designing vaccines to elicit similar protective immunity. Multiple major lineages of LASV circulate in West Africa, and therefore, ideal vaccine candidates should elicit immunity to all lineages. We therefore sought to identify common T cell epitopes between Lassa fever survivors from Sierra Leone and Nigeria, where distinct lineages circulate. We identified three such epitopes derived from highly conserved regions within LASV proteins. In this process, we also identified nine other T cell epitopes. These data should help in the design of an effective pan-LASV vaccine.
- Published
- 2020
32. Ebola-Specific CD8(+) and CD4(+) T-Cell Responses in Sierra Leonean Ebola Virus Survivors With or Without Post-Ebola Sequelae
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K. Michael Pollard, Donald S. Grant, Kayla Shore, Michael B. A. Oldstone, Luis M. Branco, Robert F. Garry, Augustine Goba, Jessica M Mayeux, Mambu Momoh, John Demby Sandi, Mohamed Yilah, Lansana Kanneh, John S. Schieffelin, Matthew L. Boisen, Saori Sakabe, Foday Al-Hassan, Stephanie LaVergne, Juan Carlos de la Torre, Iris Bica, Michael Gbakie, Ashley A. Smira, Brian M Sullivan, and Beatrice Cubitt
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Male ,Anti-nuclear antibody ,Fluorescent Antibody Technique ,CD8-Positive T-Lymphocytes ,medicine.disease_cause ,Antibodies, Viral ,Immunoglobulin G ,Sierra Leone ,Major Articles and Brief Reports ,Immune system ,Antigen ,Immunology and Allergy ,Medicine ,Rheumatoid factor ,Humans ,Survivors ,Antigens, Viral ,Immunity, Cellular ,Ebola virus ,biology ,business.industry ,Hemorrhagic Fever, Ebola ,biology.organism_classification ,Ebolavirus ,Infectious Diseases ,Vesicular stomatitis virus ,Immunology ,biology.protein ,Female ,Antibody ,business - Abstract
BackgroundEbola virus (EBOV) disease has killed thousands of West and Central Africans over the past several decades. Many who survive the acute disease later experience post-Ebola syndrome, a constellation of symptoms whose causative pathogenesis is unclear.MethodsWe investigated EBOV-specific CD8+ and CD4+ T-cell responses in 37 Sierra Leonean EBOV disease survivors with (n = 19) or without (n = 18) sequelae of arthralgia and ocular symptoms. Peripheral blood mononuclear cells were infected with recombinant vesicular stomatitis virus encoding EBOV antigens. We also studied the presence of EBOV-specific immunoglobulin G, antinuclear antibodies, anti–cyclic citrullinated peptide antibodies, rheumatoid factor, complement levels, and cytokine levels in these 2 groups.ResultsSurvivors with sequelae had a significantly higher EBOV-specific CD8+ and CD4+ T-cell response. No differences in EBOV-specific immunoglobulin G, antinuclear antibody, or anti–cyclic citrullinated peptide antibody levels were found. Survivors with sequelae showed significantly higher rheumatoid factor levels.ConclusionEBOV-specific CD8+ and CD4+ T-cell responses were significantly higher in Ebola survivors with post-Ebola syndrome. These findings suggest that pathogenesis may occur as an immune-mediated disease via virus-specific T-cell immune response or that persistent antigen exposure leads to increased and sustained T-cell responses.
- Published
- 2020
33. High crossreactivity of human T cell responses between Lassa virus lineages
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Brian M. Sullivan, Selma D. Garcia, Robert F. Garry, Saori Sakabe, Refugio Robles-Sikisaka, Dylan Kotliar, Christian T. Happi, John S. Schieffelin, Luís C. Branco, Beatrice Cubitt, Brian C. Ware, Michael B. A. Oldstone, Lansana Kanneh, Juan Carlos de la Torre, Onikepe A. Folarin, Peter O. Okokhere, Ikponmwosa Odia, Kristian G. Andersen, Jessica N. Hartnett, Nhi Ngo, Karthik Gangavarapu, Philomena Eromon, Mambu Momoh, Pardis C. Sabeti, Ephraim Ogbaini-Emovon, Augustine Goba, John Demby Sandi, Sylvanus Okogbenin, and Donald S. Grant
- Subjects
RNA viruses ,Male ,Viral Diseases ,Physiology ,viruses ,Epitopes, T-Lymphocyte ,CD8-Positive T-Lymphocytes ,Pathology and Laboratory Medicine ,medicine.disease_cause ,Biochemistry ,White Blood Cells ,Animal Cells ,Immune Physiology ,Medicine and Health Sciences ,Biology (General) ,Lassa fever ,Immune Response ,Antigens, Viral ,Vaccines ,0303 health sciences ,Immune System Proteins ,biology ,T Cells ,030302 biochemistry & molecular biology ,3. Good health ,Africa, Western ,Infectious Diseases ,medicine.anatomical_structure ,Vesicular Stomatitis Virus ,Medical Microbiology ,Vesicular stomatitis virus ,Viral Pathogens ,Viruses ,Female ,Cellular Types ,Pathogens ,Research Article ,Neglected Tropical Diseases ,Infectious Disease Control ,QH301-705.5 ,Immune Cells ,T cell ,Immunology ,Cytotoxic T cells ,Cross Reactions ,Microbiology ,Rhabdoviruses ,Antibodies ,Sierra leone ,03 medical and health sciences ,Lassa Fever ,Immune system ,Species Specificity ,Glycoprotein complex ,Virology ,Genetics ,medicine ,Humans ,Lassa virus ,Microbial Pathogens ,Molecular Biology ,030304 developmental biology ,Blood Cells ,Organisms ,Biology and Life Sciences ,Proteins ,Cell Biology ,RC581-607 ,Tropical Diseases ,biology.organism_classification ,medicine.disease ,Arenaviruses ,Nucleoprotein ,Parasitology ,Immunologic diseases. Allergy - Abstract
Lassa virus infects hundreds of thousands of people each year across rural West Africa, resulting in a high number of cases of Lassa fever (LF), a febrile disease associated with high morbidity and significant mortality. The lack of approved treatments or interventions underscores the need for an effective vaccine. At least four viral lineages circulate in defined regions throughout West Africa with substantial interlineage nucleotide and amino acid diversity. An effective vaccine should be designed to elicit Lassa virus specific humoral and cell mediated immunity across all lineages. Most current vaccine candidates use only lineage IV antigens encoded by Lassa viruses circulating around Sierra Leone, Liberia, and Guinea but not Nigeria where lineages I-III are found. As previous infection is known to protect against disease from subsequent exposure, we sought to determine whether LF survivors from Nigeria and Sierra Leone harbor memory T cells that respond to lineage IV antigens. Our results indicate a high degree of cross-reactivity of CD8+ T cells from Nigerian LF survivors to lineage IV antigens. In addition, we identified regions within the Lassa virus glycoprotein complex and nucleoprotein that contributed to these responses while T cell epitopes were not widely conserved across our study group. These data are important for current efforts to design effective and efficient vaccine candidates that can elicit protective immunity across all Lassa virus lineages., Author summary Lassa virus (LASV), the causative agent of the hemorrhagic illness Lassa fever (LF), is found throughout West Africa. Humans are usually infected after contact with infected rodent excreta or aerosolized virus. The mortality rate among hospitalized LF cases is high and no effective treatments or vaccines exist. A vaccine effective against the four main lineages of LASV is needed to protect susceptible individuals across West Africa. To understand how this protection could occur, we examined the immune responses of LF survivors from two different regions of West Africa. As previous infection with Lassa virus protects from disease after subsequent exposure, the immune response of LF survivors provides a model of protective immunity that could be induced after vaccination. We found that LASV strains from lineages different from those that infected the LF survivors efficiently activated memory CD8+ T cell responses. We identified regions within LASV proteins that elicit memory responses in the majority of individuals. From these data, we propose that an effective vaccine that protects against lineages across West Africa should be designed to elicit memory CD8+ T cell responses in addition to antibody responses.
- Published
- 2020
34. Ebola Virus Persistence in Ocular Tissues and Fluids (EVICT) Study: Reverse Transcription-Polymerase Chain Reaction and Cataract Surgery Outcomes of Ebola Survivors in Sierra Leone☆
- Author
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Moges Teshome, Gustavo Palacios, Joyce Chang, Sina Bavari, Nisha R. Acharya, John G. Mattia, Steven Yeh, Colleen S. Kraft, Adrienne K. Chan, Timothy M. Uyeki, Simbirie Jalloh, Jeffrey G. Shaffer, Kerry Dierberg, Roger Reiners, Erick Kaluma, Mambu Momoh, Lowell A. Gess, Faiqa K. Ebrahim, John S. Schieffelin, Robert F. Garry, Jessica N. Hartnett, Sarian Kamara, Mohamed Mansaray, Jessica G. Shantha, Kwame O’Neill, Tim O'Dempsey, Kayla G. Barnes, Matthew J. Vandy, Paul Farmer, William J. Liu, Daniel G. Bausch, Alie H. Wurie, Melanie Reiners, Rob Fowler, Ian Crozier, Sharmistha Mishra, Augustine Goba, Brent Hayek, Taylor Hendricks, John Demby Sandi, and Donald S. Grant
- Subjects
medicine.medical_specialty ,Visual acuity ,genetic structures ,medicine.medical_treatment ,media_common.quotation_subject ,lcsh:Medicine ,Ebola virus disease ,medicine.disease_cause ,Global Health ,General Biochemistry, Genetics and Molecular Biology ,Cataract ,Sierra leone ,Uveitis ,03 medical and health sciences ,0302 clinical medicine ,Interquartile range ,Ophthalmology ,medicine ,030212 general & internal medicine ,Eye surgery ,media_common ,lcsh:R5-920 ,Ebola virus ,business.industry ,Convalescence ,lcsh:R ,General Medicine ,Cataract surgery ,medicine.disease ,Ebolavirus ,eye diseases ,3. Good health ,030221 ophthalmology & optometry ,sense organs ,medicine.symptom ,business ,lcsh:Medicine (General) ,Research Paper - Abstract
Background Ebola virus disease (EVD) survivors are at risk for uveitis during convalescence. Vision loss has been observed following uveitis due to cataracts. Since Ebola virus (EBOV) may persist in the ocular fluid of EVD survivors for an unknown duration, there are questions about the safety and feasibility of vision restorative cataract surgery in EVD survivors. Methods We conducted a cross-sectional study of EVD survivors anticipating cataract surgery and patients with active uveitis to evaluate EBOV RNA persistence in ocular fluid, as well as vision outcomes post cataract surgery. Patients with aqueous humor that tested negative for EBOV RNA were eligible to proceed with manual small incision cataract surgery (MSICS). Findings We screened 137 EVD survivors from June 2016 – August 2017 for enrolment. We enrolled 50 EVD survivors; 46 with visually significant cataract, 1 with a subluxated lens, 2 with active uveitis and 1 with a blind painful eye due to uveitis. The median age was 24.0 years (IQR 17–35) and 35 patients (70%) were female. The median logMAR visual acuity (VA) was 3.0 (Snellen VA Hand motions; Interquartile Range, IQR: 1.2-3.0, Snellen VA 20/320 – Hand motions). All patients tested negative for EBOV RNA by RT-PCR in aqueous humor/vitreous fluid and conjunctiva at a median of 19 months (IQR 18-20) from EVD diagnosis in Phase 1 of ocular fluid sampling and 34 months (IQR 32-36) from EVD diagnosis in Phase 2 of ocular fluid sampling. Thirty-four patients underwent MSICS, with a preoperative median VA improvement from hand motions to 20/30 at three-month postoperative follow-up (P, Highlights • Ebola virus disease (EVD) survivors are at-risk for severe vision impairment due to uveitis and subsequent cataract development. • Fifty EVD survivors underwent ocular fluid sampling and tested negative for Ebola virus by RT-PCR. • Thirty-four survivors underwent cataract surgery with excellent safety measures and vision restorative outcomes. Ebola virus disease (EVD) survivors are at high risk for uveitis, an inflammatory condition affecting the eye that may lead to severe vision impairment, often from cataract. Because persistent Ebola virus (EBOV) has been identified within the immune privileged eye, understanding the prevalence of intraocular EBOV persistence is significant for patients, providers, and public health policy. In this study, 50 EVD survivors tested negative for EBOV by RT-PCR of their intraocular fluid. Thirty-four underwent cataract surgery with vision restorative outcomes. These findings improve our ability to impact vision care and quality-of-life for thousands of EVD survivors at-risk for eye disease.
- Published
- 2018
35. Internet Gaming Disorder in Children and Adolescents
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Daphne Bavelier, Elizabeth Woolley, Jeanne Funk Brockmyer, Tracy Markle, Cosette D. Rae, Kimberly S. Young, Andrew P. Doan, Mark D. Griffiths, Michael Rich, Sarah M. Coyne, Douglas A. Gentile, Florian Rehbein, Donald S. Grant, C. Shawn Green, Sara Prot, Dave Sullivan, Kira Bailey, Hilarie Cash, and Nancy M. Petry
- Subjects
Pediatrics ,medicine.medical_specialty ,Adolescent ,MEDLINE ,Child Behavior ,Child Behavior Disorders ,law.invention ,Digital media ,03 medical and health sciences ,0302 clinical medicine ,ddc:150 ,Randomized controlled trial ,law ,Humans ,Medicine ,030212 general & internal medicine ,Child ,Association (psychology) ,Internet ,business.industry ,Additional research ,030227 psychiatry ,3. Good health ,Behavior, Addictive ,Diagnostic and Statistical Manual of Mental Disorders ,Video Games ,Adolescent Behavior ,Pediatrics, Perinatology and Child Health ,Etiology ,The Internet ,business ,Patient education ,Clinical psychology - Abstract
The American Psychiatric Association recently included Internet gaming disorder (IGD) as a potential diagnosis, recommending that further study be conducted to help illuminate it more clearly. This paper is a summary of the review undertaken by the IGD Working Group as part of the 2015 National Academy of Sciences Sackler Colloquium on Digital Media and Developing Minds. By using measures based on or similar to the IGD definition, we found that prevalence rates range between ∼1% and 9%, depending on age, country, and other sample characteristics. The etiology of IGD is not well-understood at this time, although it appears that impulsiveness and high amounts of time gaming may be risk factors. Estimates for the length of time the disorder can last vary widely, but it is unclear why. Although the authors of several studies have demonstrated that IGD can be treated, no randomized controlled trials have yet been published, making any definitive statements about treatment impossible. IGD does, therefore, appear to be an area in which additional research is clearly needed. We discuss several of the critical questions that future research should address and provide recommendations for clinicians, policy makers, and educators on the basis of what we know at this time.
- Published
- 2017
36. The Origins and Future of Sentinel: An Early-Warning System for Pandemic Preemption and Response
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John Aiyepada, Michael Gbakie, Sameed Siddiqui, Hayden C. Metsky, Foday Alhasan, Johnson C. Okolie, Amber Carter, Bronwyn MacInnis, Christopher Tomkins-Tinch, Airende Michael, Marzieh Ezzaty Mirhashemi, Parvathy Nair, A.R. Ndiaye, D. Asogun, Daniel J. Park, Siham Elhamoumi, Awa B. Deme, Adrianne Gladden-Young, Brittany A. Petros, Omigie Omoregie, Alan Ricks, Dolo Nosamiefan, Luis M. Branco, Amy Gaye, Kayla G. Barnes, Adeyemi T. Kayode, Osiemi Blessing, Yolanda Botti-Lodovico, Michael J Butts, Jonathan Jackson, Augustine Goba, Nell G Bond, Christian T. Happi, Anika Vinze, Erica Normandin, Ben Fry, Chinedu A Ugwu, Okonofua Grace Naregose, Katherine C. DeRuff, Matthew R. Bauer, Peter O. Okokhere, Robert F. Garry, Andrés Colubri, Megan E. Vodzak, Matthew Stremlau, Anne W. Rimoin, Philomena Eromon, Samar Mehta, Daba Zoumarou, Oyewale Tomori, John Demby Sandi, Haja Isatta Wurie, Aida Sadikh Badiane, Tolla Ndiaye, Mouhamad Sy, Sylvanus Okogbenin, Veronica J. Koroma, Allison R. Smither, Mambu Momoh, Abechi Priscilla, Emily J Engel, Paul E. Oluniyi, Judith U. Oguzie, Donald S. Grant, Molly Kemball, Anthony A. Philippakis, Idowu B. Olawoye, Katherine Siddle, Monica Schreiber, Chloe K. Boehm, Mary Houghton, Dada Ireti Victoria, Testimony J. Olumade, Younousse Diédhiou, Fehintola V. Ajogbasile, Mariétou Faye Paye, Ebo Ohomoime Benevolence, Antoinette R. Bell-Kareem, Ikponmwosa Odia, Daouda Ndiaye, Pardis C. Sabeti, Jessica N. Uwanibe, Mame Cheikh Seck, Oladele Oluwafemi Ayodeji, Kayvon Modjarrad, Kristian G. Andersen, Jeremy A. Johnson, Ngayo Sy, Sahr M. Gevao, Dylan Kotliar, Akhilomen Patience Edamhande, Stephen F. Schaffner, Anise N Happi, George O. Akpede, Simbirie Jalloh, Matthew L. Boisen, Muoebonam Ekene Benard, Sebastian V Agignoae, Nicole L. Welch, Ojide Chiedozie Kingsley, Mouhamadou Mansour Ndiaye, Gabrielle Gionet, Lansana Kanneh, Onikepe A. Folarin, Eghosasere Anthonia Uyigue, Jules F. Gomis, Chikwe Ihekwuazu, Mosoka Fallah, John S. Schieffelin, Cameron Myhrvold, and Christopher Ojemiega Iruolagbe
- Subjects
medicine.medical_specialty ,History ,infectious disease ,Population ,Preemption ,Nigeria ,Disaster Planning ,LARGE ,N-Acetylglucosaminyltransferases ,medicine.disease_cause ,Microbiology ,Article ,diagnostic tools ,pandemic preemption ,pandemic response ,Virology ,Pandemic ,medicine ,Humans ,Lassa virus ,education ,Lassa fever ,Pandemics ,education.field_of_study ,Polymorphism, Genetic ,business.industry ,Public health ,bioinformatics ,Public relations ,medicine.disease ,QR1-502 ,genomic surveillance ,Africa, Western ,Infectious Diseases ,Infectious disease (medical specialty) ,Ebola ,Receptors, Virus ,Early warning system ,business - Abstract
While investigating a signal of adaptive evolution in humans at the gene LARGE, we encountered an intriguing finding by Dr. Stefan Kunz that the gene plays a critical role in Lassa virus binding and entry. This led us to pursue field work to test our hypothesis that natural selection acting on LARGE—detected in the Yoruba population of Nigeria—conferred resistance to Lassa Fever in some West African populations. As we delved further, we conjectured that the “emerging” nature of recently discovered diseases like Lassa fever is related to a newfound capacity for detection, rather than a novel viral presence, and that humans have in fact been exposed to the viruses that cause such diseases for much longer than previously suspected. Dr. Stefan Kunz’s critical efforts not only laid the groundwork for this discovery, but also inspired and catalyzed a series of events that birthed Sentinel, an ambitious and large-scale pandemic prevention effort in West Africa. Sentinel aims to detect and characterize deadly pathogens before they spread across the globe, through implementation of its three fundamental pillars: Detect, Connect, and Empower. More specifically, Sentinel is designed to detect known and novel infections rapidly, connect and share information in real time to identify emerging threats, and empower the public health community to improve pandemic preparedness and response anywhere in the world. We are proud to dedicate this work to Stefan Kunz, and eagerly invite new collaborators, experts, and others to join us in our efforts.
- Published
- 2021
37. Human-monoclonal-antibody therapy protects nonhuman primates against advanced Lassa fever
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Karla A. Fenton, Megan L. Heinrich, Donald S. Grant, Robert F. Garry, Mathew L Boisen, Mohamed Fullah, Viktoriya Borisevich, Mambu Momoh, Sheik Humarr Khan, Luis M. Branco, Robert W. Cross, Megan M. Rowland, Thomas W. Geisbert, Chad E. Mire, Daniel J. Deer, James E. Robinson, Augustine Goba, Krystle N. Agans, and Joan B. Geisbert
- Subjects
0301 basic medicine ,medicine.drug_class ,viruses ,Enzyme-Linked Immunosorbent Assay ,Cross Reactions ,Biology ,Antibodies, Viral ,Monoclonal antibody ,medicine.disease_cause ,Article ,General Biochemistry, Genetics and Molecular Biology ,West africa ,Random Allocation ,03 medical and health sciences ,Lassa Fever ,0302 clinical medicine ,medicine ,Animals ,Humans ,030212 general & internal medicine ,Lassa virus ,Lassa fever ,Monoclonal antibody therapy ,Immune Evasion ,Advanced stage ,Antibodies, Monoclonal ,virus diseases ,General Medicine ,Viral Load ,medicine.disease ,Antibodies, Neutralizing ,Immunohistochemistry ,Virology ,Survival Rate ,Macaca fascicularis ,030104 developmental biology ,Immunology ,biology.protein ,RNA, Viral ,Antibody ,Viral load - Abstract
There are no approved treatments for Lassa fever, which is endemic to the same regions of West Africa that were recently devastated by Ebola. Here we show that a combination of human monoclonal antibodies that cross-react with the glycoproteins of all four clades of Lassa virus is able to rescue 100% of cynomolgus macaques when treatment is initiated at advanced stages of disease, including up to 8 d after challenge.
- Published
- 2017
38. Using social media for sobriety recovery: Beliefs, behaviors, and surprises from users of face-to-face and social media sobriety support
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Karen E. Dill-Shackleford and Donald S. Grant
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Cultural Studies ,Psychotherapist ,Communication ,05 social sciences ,030508 substance abuse ,Alcohol abuse ,050801 communication & media studies ,medicine.disease ,Substance abuse ,03 medical and health sciences ,Face-to-face ,Social support ,0508 media and communications ,Sobriety ,medicine ,Social media ,0305 other medical science ,Psychology ,Social psychology ,Applied Psychology - Published
- 2017
39. Treatment of Lassa virus infection in outbred guinea pigs with first-in-class human monoclonal antibodies
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James E. Robinson, Robert W. Cross, Mambu Momoh, Megan L. Heinrich, Chad E. Mire, Thomas W. Geisbert, Robert F. Garry, Donald S. Grant, Luis M. Branco, Mohamed Fullah, Joan B. Geisbert, Augustine Goba, Megan M. Rowland, and Sheik Humarr Khan
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0301 basic medicine ,medicine.drug_class ,viruses ,Guinea Pigs ,Biology ,Antibodies, Viral ,Monoclonal antibody ,medicine.disease_cause ,Article ,Neutralization ,Guinea pig ,Inhibitory Concentration 50 ,03 medical and health sciences ,chemistry.chemical_compound ,Lassa Fever ,0302 clinical medicine ,Neutralization Tests ,Virology ,medicine ,Animals ,Humans ,030212 general & internal medicine ,Lassa virus ,Lassa fever ,Pharmacology ,Dose-Response Relationship, Drug ,Ribavirin ,Antibodies, Monoclonal ,virus diseases ,medicine.disease ,Antibodies, Neutralizing ,3. Good health ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Immunology ,biology.protein ,Antiviral drug ,Antibody - Abstract
Lassa fever is a significant health threat to West African human populations with hundreds of thousands of annual cases. There are no approved medical countermeasures currently available. Compassionate use of the antiviral drug ribavirin or transfusion of convalescent serum has resulted in mixed success depending on when administered or the donor source, respectively. We previously identified several recombinant human monoclonal antibodies targeting the glycoprotein of Lassa virus with strong neutralization profiles in vitro. Here, we demonstrate remarkable therapeutic efficacy using first-in-class human antibodies in a guinea pig model of Lassa infection thereby presenting a promising treatment alternative.
- Published
- 2016
40. Field Validation of the ReEBOV Antigen Rapid Test for Point-of-Care Diagnosis of Ebola Virus Infection
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Matthew L. Boisen, Robert W. Cross, Jessica N. Hartnett, Augustine Goba, Mambu Momoh, Mohamed Fullah, Michael Gbakie, Sidiki Safa, Mbalu Fonnie, Francis Baimba, Veronica J. Koroma, Joan B. Geisbert, Stephanie McCormick, Diana K. S. Nelson, Molly M. Millett, Darin Oottamasathien, Abby B. Jones, Ha Pham, Bethany L. Brown, Jeffrey G. Shaffer, John S. Schieffelin, Brima Kargbo, Momoh Gbetuwa, Sahr M. Gevao, Russell B. Wilson, Kelly R. Pitts, Thomas W. Geisbert, Luis M. Branco, Sheik H. Khan, Donald S. Grant, and Robert F. Garry
- Subjects
Immunoassay ,Ebola Outbreak in West Africa ,Point-of-Care Systems ,030231 tropical medicine ,Reproducibility of Results ,Hemorrhagic Fever, Ebola ,Ebolavirus ,Real-Time Polymerase Chain Reaction ,Sensitivity and Specificity ,Hospitals ,Sierra Leone ,03 medical and health sciences ,0302 clinical medicine ,Infectious Diseases ,Humans ,RNA, Viral ,Immunology and Allergy ,Reagent Kits, Diagnostic ,030212 general & internal medicine ,Antigens, Viral - Abstract
The 2013-2016 West African Ebola virus disease (EVD) epidemic is the largest recorded. Triage on the basis of clinical signs had limited success, and the time to diagnosis by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) could exceed 5 days. Here we describe the development and field validation of the ReEBOV Antigen Rapid Test (ReEBOV RDT) to aid triage of individuals with suspected EVD.Samples from patients with suspected EVD were submitted to Kenema Government Hospital, Sierra Leone, for Lassa fever and EVD screening throughout 2014. Banked residual clinical samples were tested in November 2014 and January 2015 in a blinded field trial to estimate the clinical effectiveness of the ReEBOV RDT, compared with EBOV-specific qRT-PCR.Preliminary ReEBOV RDT performance demonstrated a positive percentage agreement (PPA) of 91.1% (195 of 214 results; 95% confidence interval [CI], 86.5%-94.6%) and a negative percentage agreement (NPA) of 90.2% (175 of 194; 95% CI, 85.1%-94.0%). The final estimates used by the Food and Drug Administration to determine whether to grant emergency use authorization for the test, which excluded a qRT-PCR reference method threshold cutoff, were a PPA of 62.1% (72 of 116 results; 95% CI, 52.6%-70.9%) and a NPA of 96.7% (58 of 60; 95% CI, 88.5%-99.6%), with a diagnostic likelihood of 18.6. A subsequent, independent evaluation by the World Health Organization generated results consistent with the preliminary performance estimates.The ReEBOV RDT demonstrated the potential to provide clinically effective rapid and accurate point-of-care test results and, thus, to be a powerful tool for increasing triage efficiency.
- Published
- 2016
41. An Outbreak of Ebola Virus Disease in the Lassa Fever Zone
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Rachael E. Yenni, Augustine Goba, Stephanie J. McCormick, Erica Ollmann Saphire, Brima Kargbo, John Demby Sandi, Jeffrey G. Shaffer, Robert F. Garry, Susan McLellan, Julie A. Rouelle, Edwin Konowu, Sonia Grillo, Issa French, Benjamin T. Bradley, Ibraham Mustapha, S. Humarr Khan, Vandi Sinnah, Shevin T. Jacob, Russell B. Wilson, Veronica J. Koroma, Josephine Sellu, Christian T. Happi, Momoh Foday, Helena McCarthy, Kelly R. Pitts, Peter C. Kulakosky, Jessica N. Hartnett, Mohamed Yillah, Nathan L. Yozwiak, Daniel J. Park, James E. Robinson, Christopher M. Bishop, Donald S. Grant, Siddiki Safai, Sylvia O. Blyden, James L. B. Massaly, Alex Moigboi, Matthew L. Boisen, Tiangay Kallon, Sahr M. Gevao, Joan B. Geisbert, Ian Crozier, Thomas W. Geisbert, Mustupha Kallon, Chandrika B. Kannadka, Ashley A. Reyna, Hawa Rogers, Haini Yu, Mbalu Fonnie, Mohamed Fullah, Courtney E Garry, Lansana Kanneh, John S. Schieffelin, Alice Kovoma, Allyson M. Haislip, Lilia I. Melnik, Luis M. Branco, David Kargbo, Pardis C. Sabeti, Jing He, Kristian G. Andersen, Fatima K. Kamara, Michael Gbakie, Mambu Momoh, Mohamed A. Vandi, Stephen K. Gire, Deborah H. Elliott, Franklyn Kanneh, Simbirie Jalloh, Ridhi Tariyal, Nancy Yoko, Kathryn M. Hastie, William R. Gallaher, Lee A. Henderson, Robert W. Cross, Brian M. Sullivan, Momoh Gbetuwa, Scott Oman, Donna Edwards, Jenneh Naiebu, Abdul A. Jalloh, Danny Asogun, Michael B. A. Oldstone, and William C. Wimley
- Subjects
Adult ,Male ,0301 basic medicine ,Adolescent ,viruses ,Genome, Viral ,medicine.disease_cause ,Disease Outbreaks ,Sierra Leone ,Sierra leone ,Viral hemorrhagic fever ,Young Adult ,03 medical and health sciences ,Lassa Fever ,0302 clinical medicine ,Humans ,Immunology and Allergy ,Medicine ,030212 general & internal medicine ,Child ,Lassa virus ,Lassa fever ,Ebolavirus ,Ebola Outbreak in West Africa ,Ebola virus ,business.industry ,Transmission (medicine) ,Outbreak ,Genomics ,Sequence Analysis, DNA ,Hemorrhagic Fever, Ebola ,Middle Aged ,medicine.disease ,Virology ,Africa, Western ,030104 developmental biology ,Infectious Diseases ,Child, Preschool ,Epidemiological Monitoring ,Female ,Guinea ,Medical emergency ,business - Abstract
Background.Kenema Government Hospital (KGH) has developed an advanced clinical and laboratory research capacity to manage the threat of Lassa fever, a viral hemorrhagic fever (VHF). The 2013–2016 Ebola virus (EBOV) disease (EVD) outbreak is the first to have occurred in an area close to a facility with established clinical and laboratory capacity for study of VHFs. Methods.Because of its proximity to the epicenter of the EVD outbreak, which began in Guinea in March 2014, the KGH Lassa fever Team mobilized to establish EBOV surveillance and diagnostic capabilities. Results.Augustine Goba, director of the KGH Lassa laboratory, diagnosed the first documented case of EVD in Sierra Leone, on 25 May 2014. Thereafter, KGH received and cared for numbers of patients with EVD that quickly overwhelmed the capacity for safe management. Numerous healthcare workers contracted and lost their lives to EVD. The vast majority of subsequent EVD cases in West Africa can be traced back to a single transmission chain that includes this first diagnosed case. Conclusions.Responding to the challenges of confronting 2 hemorrhagic fever viruses will require continued investments in the development of countermeasures (vaccines, therapeutic agents, and diagnostic assays), infrastructure, and human resources.
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- 2016
42. Roots, Not Parachutes: Research Collaborations Combat Outbreaks
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Donald S. Grant, Nathan L. Yozwiak, Pardis C. Sabeti, Robert F. Garry, Christian T. Happi, John S. Schieffelin, and Kristian G. Andersen
- Subjects
0301 basic medicine ,Biomedical Research ,Hemorrhagic Fevers, Viral ,International Cooperation ,Disease ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Disease Outbreaks ,03 medical and health sciences ,0302 clinical medicine ,Virology ,Environmental health ,Health care ,030212 general & internal medicine ,business.industry ,Environmental resource management ,food and beverages ,Outbreak ,Hemorrhagic Fever, Ebola ,3. Good health ,Africa, Western ,030104 developmental biology ,Infectious disease (medical specialty) ,Epidemiological Monitoring ,business ,Healthcare system - Abstract
Recent infectious disease epidemics illustrate how health systems failures anywhere can create disease vulnerabilities everywhere. We must therefore prioritize investments in health care infrastructure in outbreak-prone regions of the world. We describe how ‘rooted’ research collaborations can establish capacity for pathogen surveillance and facilitate rapid outbreak responses.
- Published
- 2016
43. Most neutralizing human monoclonal antibodies target novel epitopes requiring both Lassa virus glycoprotein subunits
- Author
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Robert W. Cross, Matthew L. Boisen, Mambu Momoh, Megan L. Heinrich, Michelle Zandonatti, Michael Gbakie, Joan B. Geisbert, Simbirie Jalloh, Juan Carlos de la Torre, Chandrika B. Kannadka, Momoh Gbetuwa, Julie A. Rouelle, Onikepe A. Follarin, S. Humarr Khan, Ashley A. Smira, Mohamed Fullah, Benjamin T. Bradley, Richard Fonnie, Kathryn M. Hastie, Luis M. Branco, Russell B. Wilson, Veronica J. Koroma, Danny Asogun, Mohamed A. Vandi, Christian T. Happi, Megan M. Rowland, Benson Yee Hin Cheng, Robert F. Garry, Deborah H. Elliott, Augustine Goba, Pardis C. Sabeti, Kristian G. Andersen, Brima Kargbo, Jeffrey G. Shaffer, James E. Robinson, Peter C. Kulakoski, Kelly R. Pitts, Thomas W. Geisbert, Luis Martinez-Sobrido, Donald S. Grant, Erica Ollmann Saphire, Peter O Okokhere, Odia Ikponmwosa, Lansana Kanneh, Courtney E Garry, Jessica N. Hartnett, John S. Schieffelin, Rachael E. Yenni, Sahr M. Gevao, and Haini Yu
- Subjects
0301 basic medicine ,Models, Molecular ,medicine.drug_class ,viruses ,Science ,General Physics and Astronomy ,Cross Reactions ,Monoclonal antibody ,medicine.disease_cause ,Antibodies, Viral ,General Biochemistry, Genetics and Molecular Biology ,Epitope ,Article ,03 medical and health sciences ,Epitopes ,Lassa Fever ,Viral Envelope Proteins ,Glycoprotein complex ,Antibody Specificity ,medicine ,Humans ,Lassa fever ,Lassa virus ,Antigens, Viral ,Sequence Deletion ,chemistry.chemical_classification ,Multidisciplinary ,biology ,Antibodies, Monoclonal ,virus diseases ,General Chemistry ,Arenavirus ,medicine.disease ,Virology ,Antibodies, Neutralizing ,3. Good health ,030104 developmental biology ,Epitope mapping ,chemistry ,biology.protein ,Mutagenesis, Site-Directed ,Antibody ,Glycoprotein ,Epitope Mapping - Abstract
Lassa fever is a severe multisystem disease that often has haemorrhagic manifestations. The epitopes of the Lassa virus (LASV) surface glycoproteins recognized by naturally infected human hosts have not been identified or characterized. Here we have cloned 113 human monoclonal antibodies (mAbs) specific for LASV glycoproteins from memory B cells of Lassa fever survivors from West Africa. One-half bind the GP2 fusion subunit, one-fourth recognize the GP1 receptor-binding subunit and the remaining fourth are specific for the assembled glycoprotein complex, requiring both GP1 and GP2 subunits for recognition. Notably, of the 16 mAbs that neutralize LASV, 13 require the assembled glycoprotein complex for binding, while the remaining 3 require GP1 only. Compared with non-neutralizing mAbs, neutralizing mAbs have higher binding affinities and greater divergence from germline progenitors. Some mAbs potently neutralize all four LASV lineages. These insights from LASV human mAb characterization will guide strategies for immunotherapeutic development and vaccine design., Lassa virus can cause haemorrhagic fever for which no specific treatment currently exists. Here the authors have cloned 113 monoclonal antibodies from the survivors of Lassa infection and show that the majority of neutralizing antibodies target a complex of GP1 and GP2 viral proteins.
- Published
- 2016
44. Reevaluating HLA-A2-restricted Lassa epitopes in human Lassa fever survivors
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Brian Martin Sullivan, Saori Sakabe, Jessica N Hartnett, Nhi Nho, Augustine Goba, Mambu Momoh, John Demby Sandi, Lansana Kanneh, Beatrice Cubitt, Selma D Garcia, Brian C Ware, Dylan Kotliar, Refugio Robles-Sikisaka, Karthik Gangavarapu, Juan Carlos de la Torre, Pardis C Sabeti, Kristian G Andersen, Robert F Garry, Donald S Grant, John S Schieffelin, and Michael B Oldstone
- Subjects
Immunology ,Immunology and Allergy - Abstract
Many factors contribute to the selection of epitope-specific T cells. Often, candidate epitopes are generated through in silico prediction of various biological processes, mainly peptide generation and MHC binding, that are then tested in relevant biological assays. This is especially true of epitopes derived from BSL-4 pathogens or where relevant patient samples are difficult to obtain. Two previous studies identified CD8+ T cell epitopes from the Lassa virus glycoprotein through in silico prediction, experimental MHC binding assays, and epitope generation in HLA-A2 transgenic mice. Using samples from ten HLA-A*02:01 Lassa fever survivors, we tested whether these previously described epitope-specific CD8+ T cells were present and their relation to the broader Lassa virus-specific T cell response. Using overnight stimulation assays, we detected robust LASV-specific responses to the glycoprotein and nucleoprotein, but only one of the three epitopes (GP60–68)shown to be present and protective in mice made a substantial contribution to the overall LASV-specific response. Using a more sensitive proliferation assay, we detected the remaining two epitopes in some individuals at a very low frequency. Overall, this study shows the limitations of epitope discovery through in silico prediction, MHC binding and transgenic mouse models and highlights the complex nature of T cell selection during natural infection of humans.
- Published
- 2020
45. A medical records and data capture and management system for Lassa fever in Sierra Leone: Approach, implementation, and challenges
- Author
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Jeffrey G Shaffer, John S Schieffelin, Michael Gbakie, Foday Alhasan, Nicole B Roberts, Augustine Goba, Jessica Randazzo, Mambu Momoh, Troy D Moon, Lansana Kanneh, Danielle C Levy, Rachel M Podgorski, Jessica N Hartnett, Matt L Boisen, Luis M Branco, Robert Samuels, Donald S Grant, Robert F Garry, and Viral Hemorrhagic Fever Consortium
- Subjects
Viral Diseases ,Databases, Factual ,viruses ,Artificial Gene Amplification and Extension ,medicine.disease_cause ,Antibodies, Viral ,Polymerase Chain Reaction ,Medical Records ,Geographical locations ,Disease Outbreaks ,0302 clinical medicine ,Medicine and Health Sciences ,030212 general & internal medicine ,Computer Networks ,Enzyme-Linked Immunoassays ,Lassa fever ,Data Management ,Multidisciplinary ,Medical record ,3. Good health ,Survival Rate ,Infectious Diseases ,Medicine ,RNA, Viral ,Medical emergency ,Information Technology ,Research Article ,Neglected Tropical Diseases ,Computer and Information Sciences ,Science ,030231 tropical medicine ,Research and Analysis Methods ,Ebola Hemorrhagic Fever ,Viral hemorrhagic fever ,Sierra leone ,Sierra Leone ,03 medical and health sciences ,Databases ,Lassa Fever ,medicine ,Humans ,Lassa virus ,Immunoassays ,Molecular Biology Techniques ,Molecular Biology ,Internet ,Viral Hemorrhagic Fevers ,Ebola virus ,business.industry ,Information Dissemination ,Outbreak ,Biology and Life Sciences ,medicine.disease ,Hospitals, District ,Tropical Diseases ,Blood chemistry ,Africa ,Immunologic Techniques ,People and places ,business ,Blood Chemical Analysis ,Software - Abstract
Situated in southeastern Sierra Leone, Kenema Government Hospital (KGH) maintains one of the world's only Lassa fever isolation wards and was a strategic Ebola virus disease (EVD) treatment facility during the 2014 EVD outbreak. Since 2006, the Viral Hemorrhagic Fever Consortium (VHFC) has carried out research activities at KGH, capturing clinical and laboratory data for suspected cases of Lassa fever. Here we describe the approach, progress, and challenges in designing and maintaining a data capture and management system (DCMS) at KGH to assist infectious disease researchers in building and sustaining DCMS in low-resource environments. Results on screening patterns and case-fatality rates are provided to illustrate the context and scope of the DCMS covered in this study. A medical records system and DCMS was designed and implemented between 2010 and 2016 linking historical and prospective Lassa fever data sources across KGH Lassa fever units and its peripheral health units. Data were captured using a case report form (CRF) system, enzyme-linked immunosorbent assay (ELISA) plate readers, polymerase chain reaction (PCR) machines, blood chemistry analyzers, and data auditing procedures. Between 2008 and 2016, blood samples for 4,229 suspected Lassa fever cases were screened at KGH, ranging from 219 samples in 2008 to a peak of 760 samples in 2011. Lassa fever case-fatality rates before and following the Ebola outbreak were 65.5% (148/226) and 89.5% (17/19), respectively, suggesting that fewer, but more seriously ill subjects with Lassa fever presented to KGH following the 2014 EVD outbreak (p = .040). DCMS challenges included weak specificity of the Lassa fever suspected case definition, limited capture of patient survival outcome data, internet costs, lapses in internet connectivity, low bandwidth, equipment and software maintenance, lack of computer teaching laboratories, and workload fluctuations due to variable screening activity. DCMS are the backbone of international research efforts and additional literature is needed on the topic for establishing benchmarks and driving goal-based approaches for its advancement in developing countries.
- Published
- 2018
46. Analysis of CD8 + T cell response during the 2013–2016 Ebola epidemic in West Africa
- Author
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Mambu Momoh, Dylan Kotliar, Beatrice Cubitt, John S. Schieffelin, Augustine Goba, Brian M. Sullivan, John Demby Sandi, Michael B. A. Oldstone, Karthik Gangavarapu, Jessica N. Hartnett, Brian C. Ware, Donald S. Grant, Juan Carlos de la Torre, Kristian G. Andersen, Pardis C. Sabeti, Saori Sakabe, Refugio Robles-Sikisaka, Luis M. Branco, Robert F. Garry, and Lansana Kanneh
- Subjects
Adult ,Male ,0301 basic medicine ,Adolescent ,viruses ,T cell ,Epitopes, T-Lymphocyte ,Immunodominance ,CD8-Positive T-Lymphocytes ,Antibodies, Viral ,medicine.disease_cause ,Sierra Leone ,Sierra leone ,Viral Proteins ,Young Adult ,03 medical and health sciences ,VP40 ,Antigen ,HLA Antigens ,medicine ,Humans ,Cytotoxic T cell ,Survivors ,Epidemics ,Antigens, Viral ,Multidisciplinary ,Ebola virus ,business.industry ,Vaccination ,Hemorrhagic Fever, Ebola ,Ebolavirus ,Virology ,Nucleoproteins ,030104 developmental biology ,medicine.anatomical_structure ,PNAS Plus ,Female ,business ,CD8 - Abstract
The recent Ebola epidemic exemplified the importance of understanding and controlling emerging infections. Despite the importance of T cells in clearing virus during acute infection, little is known about Ebola-specific CD8+ T cell responses. We investigated immune responses of individuals infected with Ebola virus (EBOV) during the 2013–2016 West Africa epidemic in Sierra Leone, where the majority of the >28,000 EBOV disease (EVD) cases occurred. We examined T cell memory responses to seven of the eight Ebola proteins (GP, sGP, NP, VP24, VP30, VP35, and VP40) and associated HLA expression in survivors. Of the 30 subjects included in our analysis, CD8+ T cells from 26 survivors responded to at least one EBOV antigen. A minority, 10 of 26 responders (38%), made CD8+ T cell responses to the viral GP or sGP. In contrast, 25 of the 26 responders (96%) made response to viral NP, 77% to VP24 (20 of 26), 69% to VP40 (18 of 26), 42% (11 of 26) to VP35, with no response to VP30. Individuals making CD8+ T cells to EBOV VP24, VP35, and VP40 also made CD8+ T cells to NP, but rarely to GP. We identified 34 CD8+ T cell epitopes for Ebola. Our data indicate the immunodominance of the EBOV NP-specific T cell response and suggest that its inclusion in a vaccine along with the EBOV GP would best mimic survivor responses and help boost cell-mediated immunity during vaccination.
- Published
- 2018
47. Association of the Quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) score with excess hospital mortality in adults with suspected infection in low- and middle-income countries
- Author
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A. Pubudu De Silva, Adam C. Levine, Olivier Urayeneza, L. Nathalie Colas, François Nosten, Nicholas P. J. Day, John S. Schieffelin, Donald S. Grant, Derek C. Angus, Nguyen Van Hao, Martin W. Dünser, Marc E. Augustin, Duong Bich Thuy, Nicholas J. White, T. Eoin West, Jeffrey G. Shaffer, Andrew J. Patterson, Kristina E. Rudd, Jean Claude Byiringiro, Chung-Chou H. Chang, Direk Limmathurotsakul, Sanjib Mohanty, Jason Kennedy, C. Louise Thwaites, Arjen M. Dondorp, Rashan Haniffa, Adam R. Aluisio, Alfred Papali, Danstan Bagenda, Christopher W. Seymour, Abi Beane, and M. Abul Faiz
- Subjects
Predictive validity ,medicine.medical_specialty ,business.industry ,030208 emergency & critical care medicine ,Retrospective cohort study ,General Medicine ,Odds ratio ,medicine.disease ,law.invention ,Systemic inflammatory response syndrome ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Intensive care ,Internal medicine ,Cohort ,medicine ,030212 general & internal medicine ,business ,Cohort study - Abstract
Importance The quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) score has not been well-evaluated in low- and middle-income countries (LMICs). Objective To assess the association of qSOFA with excess hospital death among patients with suspected infection in LMICs and to compare qSOFA with the systemic inflammatory response syndrome (SIRS) criteria. Design, Settings, and Participants Retrospective secondary analysis of 8 cohort studies and 1 randomized clinical trial from 2003 to 2017. This study included 6569 hospitalized adults with suspected infection in emergency departments, inpatient wards, and intensive care units of 17 hospitals in 10 LMICs across sub-Saharan Africa, Asia, and the Americas. Exposures Low (0), moderate (1), or high (≥2) qSOFA score (range, 0 [best] to 3 [worst]) or SIRS criteria (range, 0 [best] to 4 [worst]) within 24 hours of presentation to study hospital. Main Outcomes and Measures Predictive validity (measured as incremental hospital mortality beyond that predicted by baseline risk factors, as a marker of sepsis or analogous severe infectious course) of the qSOFA score (primary) and SIRS criteria (secondary). Results The cohorts were diverse in enrollment criteria, demographics (median ages, 29-54 years; males range, 36%-76%), HIV prevalence (range, 2%-43%), cause of infection, and hospital mortality (range, 1%-39%). Among 6218 patients with nonmissing outcome status in the combined cohort, 643 (10%) died. Compared with a low or moderate score, a high qSOFA score was associated with increased risk of death overall (19% vs 6%; difference, 13% [95% CI, 11%-14%]; odds ratio, 3.6 [95% CI, 3.0-4.2]) and across cohorts (P Conclusions and Relevance When assessed among hospitalized adults with suspected infection in 9 LMIC cohorts, the qSOFA score identified infected patients at risk of death beyond that explained by baseline factors. However, the predictive validity varied among cohorts and settings, and further research is needed to better understand potential generalizability.
- Published
- 2018
48. Capturing diverse microbial sequence with comprehensive and scalable probe design
- Author
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James Qu, Ikponmwonsa Odia, Douglas S. Kwon, Yasmine Rangel Vieira, Etienne Simon-Loriere, Hayden C. Metsky, Patrick Brehio, Leda Parham, Giselle Barbosa-Lima, Scott F. Michael, Scott Hennigan, David K Yang, Andreas Gnirke, Gregory D. Ebel, Augustine Goba, Eva Harris, Shirlee Wohl, Adrianne Gladden-Young, Fernando A. Bozza, Kayla G. Barnes, Amber Carter, Katherine J. Siddle, Lauren M. Paul, Aaron E. Lin, Souza Tml, Sandra Smole, Jonathan A. Runstadler, Pardis C. Sabeti, Damien C. Tully, Anne Piantadosi, Daniel J. Park, Christian T. Happi, Sharon Isern, Ivette Lorenzana, Andrew Goldfarb, Lee Gehrke, Bjӧrn Corleis, Todd M. Allen, Amanda L Tan, Angel Balmaseda, Philomena Eromon, Kimberly García, Irene Bosch, Donald S. Grant, Lisa E. Hensley, Onikepe A. Folarin, and Christian B. Matranga
- Subjects
0303 health sciences ,03 medical and health sciences ,030306 microbiology ,Computer science ,Viral genomes ,Metagenomics ,Scalability ,Genomics ,Computational biology ,Full coverage ,Genome ,030304 developmental biology ,Sequence (medicine) - Abstract
Metagenomic sequencing has the potential to transform microbial detection and characterization, but new tools are needed to improve its sensitivity. We developed CATCH (Compact Aggregation of Targets for Comprehensive Hybridization), a computational method to enhance nucleic acid capture for enrichment of diverse microbial taxa. CATCH designs compact probe sets that achieve full coverage of known sequence diversity and that scale well with this diversity. To illustrate applications of CATCH, we focused on capturing viral genomes. We designed, synthesized, and validated multiple probe sets, including one that targets whole genomes of the 356 viral species known to infect humans. Capture with these probe sets enriched unique viral content on average 18× and allowed us to assemble genomes that we could not otherwise recover, while accurately preserving within-sample diversity. We used this approach to recover genomes from the 2018 Lassa fever outbreak in Nigeria and to improve detection of viral infections in samples with unknown content. Together, this work demonstrates a path toward more sensitive, cost-effective metagenomic sequencing.
- Published
- 2018
49. Development of Prototype Filovirus Recombinant Antigen Immunoassays
- Author
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Megan M. Rowland, Darin Oottamasathien, Kelly R. Pitts, Francis Baimba, Marjan Akdag, Robert F. Garry, S. Humarr Khan, Richard Fonnie, Megan L. Heinrich, Donald S. Grant, Abigail B. Jones, Luis M. Branco, Erica Ollmann Saphire, Matthew L. Boisen, Shun-ichiro Oda, Joan B. Geisbert, Lansana Kanneh, Molly M. Millett, Robert W. Cross, Sadiki Safa, Jessica N. Hartnett, Mohammed Fullah, Augustine Goba, Mambu Momoh, Jeffery G. Shaffer, Dafna M. Abelson, John S. Schieffelin, Peter C. Kulakosky, Marnie L. Fusco, Russell B. Wilson, Michael Gbakie, Diana K. S. Nelson, Thomas W. Geisbert, and Zachary A. Bornholdt
- Subjects
viruses ,Enzyme-Linked Immunosorbent Assay ,Cross Reactions ,Antibodies, Viral ,medicine.disease_cause ,Immunoglobulin G ,Sierra Leone ,Sierra leone ,VP40 ,Marburg virus disease ,medicine ,Animals ,Humans ,Ebola and Marburg Viruses-Research, Outbreak Management, Epidemiology and Ecology ,Immunology and Allergy ,Marburg Virus Disease ,Antigens, Viral ,Immunoassay ,Ebola virus ,biology ,medicine.diagnostic_test ,Hemorrhagic Fever, Ebola ,Ebolavirus ,Filoviridae ,Virology ,Africa, Western ,Infectious Diseases ,Immunoglobulin M ,Marburgvirus ,Polyclonal antibodies ,Immunology ,biology.protein - Abstract
Background. Throughout the 2014–2015 Ebola outbreak in West Africa, major gaps were exposed in the availability of validated rapid diagnostic platforms, protective vaccines, and effective therapeutic agents. These gaps potentiated the development of prototype rapid lateral flow immunodiagnostic (LFI) assays that are true point-of-contact platforms, for the detection of active Ebola infections in small blood samples. Methods. RecombinantEbola and Marburg virus matrixVP40and glycoprotein (GP)antigenswere usedtoderive a panel of monoclonal and polyclonal antibodies. Antibodies were tested using a multivariate approach to identify antibody-antigen combinations suitable for enzyme-linked immunosorbent assay (ELISA) and LFI assay development. Results. Polyclonal antibodies generated in goats were superior reagents for capture and detection of recombinant VP40 in test sample matrices. These antibodies were optimized for use in antigen-capture ELISA and LFI assay platforms. Prototype immunoglobulin M (IgM)/immunoglobulin G (IgG) ELISAs were similarly developed that specifically detect Ebola virus–specific antibodies in the serum of experimentally infected nonhuman primates and in blood samples obtained from patients with Ebola from Sierra Leone. Conclusions. The prototype recombinant Ebola LFI assays developed in these studies have sensitivities that are useful for clinical diagnosis of acute ebolavirus infections. The antigen-capture and IgM/IgG ELISAs provide additional confirmatory assay platforms for detecting VP40 and other ebolavirus-specific immunoglobulins.
- Published
- 2015
50. Current and emerging strategies for the diagnosis, prevention and treatment of Lassa fever
- Author
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Luis M. Branco, Kelly R. Pitts, Robert F. Garry, Sheik Humarr Khan, Matthew L. Boisen, Christian T. Happi, Sahr M. Gevao, Donald S. Grant, Mambu Momoh, Darin Oottamasathien, Debra L Holton, Ashley A. Reyna, Julie A. Rouelle, Abigail B. Jones, Chad E. Mire, Jessica N. Hartnett, James E. Robinson, Ivana J Muncy, Joan B. Geisbert, Chandrika B. Kannadka, Lina M. Moses, Mohammed Fullah, Augustine Goba, Thomas W. Geisbert, Molly M. Millett, and Diana K. S. Nelson
- Subjects
Immunodiagnostics ,medicine.medical_specialty ,business.industry ,Transmission (medicine) ,Public health ,medicine.disease_cause ,medicine.disease ,Virology ,West africa ,Lassa virus ,Epidemiology ,medicine ,Fatal disease ,Lassa fever ,business ,Intensive care medicine - Abstract
Lassa fever (LF) is a potentially fatal disease that affects an estimated 300,000–500,000 people in endemic areas of west Africa each year. Though past studies have identified fatality rates of 5–20% in patients suspected to have contracted Lassa virus (LASV), new studies using more precise clinical diagnoses and modern diagnostic assays show fatalities rates above 60% in acutely ill patients from endemic regions. Currently, there are no approved vaccines or therapeutics, and only one Comformité Européenne (CE) marked rapid immunodiagnostic for acute LASV infection. Therefore, preventing LASV transmission is the primary goal in endemic regions. Development of rapid immunodiagnostics and research into the efficacy of current treatment options continues toward saving lives in west Africa as well as creating a line of defense against the nefarious use of LASV in bioterrorism settings.
- Published
- 2015
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