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  1. Article ; Online: A novel mechanism of antibody-mediated enhancement of flavivirus infection.

    Denise Haslwanter / Dieter Blaas / Franz X Heinz / Karin Stiasny

    PLoS Pathogens, Vol 13, Iss 9, p e

    2017  Volume 1006643

    Abstract: Antibody-dependent enhancement of viral infection is a well-described phenomenon that is based on the cellular uptake of infectious virus-antibody complexes following their interaction with Fcγ receptors expressed on myeloid cells. Here we describe a ... ...

    Abstract Antibody-dependent enhancement of viral infection is a well-described phenomenon that is based on the cellular uptake of infectious virus-antibody complexes following their interaction with Fcγ receptors expressed on myeloid cells. Here we describe a novel mechanism of antibody-mediated enhancement of infection by a flavivirus (tick-borne encephalitis virus) in transformed and primary human cells, which is independent of the presence of Fcγ receptors. Using chemical cross-linking and immunoassays, we demonstrate that the monoclonal antibody (mab) A5, recognizing an epitope at the interface of the dimeric envelope protein E, causes dimer dissociation and leads to the exposure of the fusion loop (FL). Under normal conditions of infection, this process is triggered only after virus uptake by the acidic pH in endosomes, resulting in the initiation of membrane fusion through the interaction of the FL with the endosomal membrane. Analysis of virus binding and cellular infection, together with inhibition by the FL-specific mab 4G2, indicated that the FL, exposed after mab A5- induced dimer-dissociation, mediated attachment of the virus to the plasma membrane also at neutral pH, thereby increasing viral infectivity. Since antibody-induced enhancement of binding was not only observed with cells but also with liposomes, it is likely that increased infection was due to FL-lipid interactions and not to interactions with cellular plasma membrane proteins. The novel mechanism of antibody-induced infection enhancement adds a new facet to the complexity of antibody interactions with flaviviruses and may have implications for yet unresolved effects of polyclonal antibody responses on biological properties of these viruses.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2017-09-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: A Powassan virus domain III nanoparticle immunogen elicits neutralizing and protective antibodies in mice.

    Ryan J Malonis / George I Georgiev / Denise Haslwanter / Laura A VanBlargan / Georgia Fallon / Olivia Vergnolle / Sean M Cahill / Richard Harris / David Cowburn / Kartik Chandran / Michael S Diamond / Jonathan R Lai

    PLoS Pathogens, Vol 18, Iss 6, p e

    2022  Volume 1010573

    Abstract: Powassan virus (POWV) is an emerging tick borne flavivirus (TBFV) that causes severe neuroinvasive disease. Currently, there are no approved treatments or vaccines to combat POWV infection. Here, we generated and characterized a nanoparticle immunogen ... ...

    Abstract Powassan virus (POWV) is an emerging tick borne flavivirus (TBFV) that causes severe neuroinvasive disease. Currently, there are no approved treatments or vaccines to combat POWV infection. Here, we generated and characterized a nanoparticle immunogen displaying domain III (EDIII) of the POWV E glycoprotein. Immunization with POWV EDIII presented on nanoparticles resulted in significantly higher serum neutralizing titers against POWV than immunization with monomeric POWV EDIII. Furthermore, passive transfer of EDIII-reactive sera protected against POWV challenge in vivo. We isolated and characterized a panel of EDIII-specific monoclonal antibodies (mAbs) and identified several that potently inhibit POWV infection and engage distinct epitopes within the lateral ridge and C-C' loop of the EDIII. By creating a subunit-based nanoparticle immunogen with vaccine potential that elicits antibodies with protective activity against POWV infection, our findings enhance our understanding of the molecular determinants of antibody-mediated neutralization of TBFVs.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Functional convalescent plasma antibodies and pre-infusion titers shape the early severe COVID-19 immune response

    Jonathan D. Herman / Chuangqi Wang / Carolin Loos / Hyunah Yoon / Johanna Rivera / M. Eugenia Dieterle / Denise Haslwanter / Rohit K. Jangra / Robert H. Bortz / Katharine J. Bar / Boris Julg / Kartik Chandran / Douglas Lauffenburger / Liise-anne Pirofski / Galit Alter

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 11

    Abstract: Convalescent plasma (CP) has been trialed as a therapy for SARS-CoV-2 symptoms, but its heterogenous nature precludes uniform outcomes. Here the authors perform deep profiling of CP, as well as plasma of CP recipients before and after transfer, to find ... ...

    Abstract Convalescent plasma (CP) has been trialed as a therapy for SARS-CoV-2 symptoms, but its heterogenous nature precludes uniform outcomes. Here the authors perform deep profiling of CP, as well as plasma of CP recipients before and after transfer, to find CP-mediated, spike/nucleocapsid-focused modulations of humoral responses in the recipient.
    Keywords Science ; Q
    Language English
    Publishing date 2021-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Induction of SARS-CoV-2 neutralizing antibodies by CoronaVac and BNT162b2 vaccines in naïve and previously infected individuals

    Nicolás A. Muena / Tamara García-Salum / Catalina Pardo-Roa / María José Avendaño / Eileen F. Serrano / Jorge Levican / Leonardo I. Almonacid / Gonzalo Valenzuela / Estefany Poblete / Shirin Strohmeier / Erick Salinas / Andres Muñoz / Denise Haslwanter / Maria Eugenia Dieterle / Rohit K. Jangra / Kartik Chandran / Claudia González / Arnoldo Riquelme / Florian Krammer /
    Nicole D. Tischler / Rafael A. Medina

    EBioMedicine, Vol 78, Iss , Pp 103972- (2022)

    2022  

    Abstract: Summary: Background: A major challenge of the SARS-CoV-2 pandemic is to better define “protective thresholds” to guide the global response. We aimed to characterize the longitudinal dynamics of the antibody responses in naturally infected individuals in ... ...

    Abstract Summary: Background: A major challenge of the SARS-CoV-2 pandemic is to better define “protective thresholds” to guide the global response. We aimed to characterize the longitudinal dynamics of the antibody responses in naturally infected individuals in Chile and compared them to humoral responses induced after immunization with CoronaVac-based on an inactivated whole virus -or the BNT162b2- based on mRNA-vaccines. We also contrasted them with the respective effectiveness and efficacy data available for both vaccines. Methods: We determined and compared the longitudinal neutralizing (nAb) and anti-nucleocapsid (anti-N) antibody responses of 74 COVID-19 individuals (37 outpatient and 37 hospitalized) during the acute disease and convalescence. We also assessed the antibody boosting of 36 of these individuals who were immunized after convalescence with either the CoronaVac (n = 30) or the BNT162b2 (n = 6) vaccines. Antibody titres were also measured for 50 naïve individuals immunized with two doses of CoronaVac (n = 35) or BNT162b2 (n = 15) vaccines. The neutralizing level after vaccination was compared to those of convalescent individuals and the predicted efficacy was estimated. Findings: SARS-CoV-2 infection induced robust nAb and anti-N antibody responses lasting >9 months, but showing a rapid nAb decay. After convalescence, nAb titres were significantly boosted by vaccination with CoronaVac or BNT162b2. In naïve individuals, the calculated mean titre induced by two doses of CoronaVac or BNT162b2 was 0·2 times and 5.2 times, respectively, that of convalescent individuals, which has been proposed as threshold of protection. CoronaVac induced no or only modest anti-N antibody responses. Using two proposed logistic models, the predicted efficacy of BNT162b2 was estimated at 97%, in close agreement with phase 3 efficacy studies, while for CoronaVac it was ∼50% corresponding to the lowest range of clinical trials and below the real-life data from Chile (from February 2 through May 1, 2021 during the predominant ...
    Keywords COVID-19 ; Serological response ; Neutralizing antibody persistence ; SARS-CoV-2 vaccines ; Vaccination boost ; Medicine ; R ; Medicine (General) ; R5-920
    Subject code 360
    Language English
    Publishing date 2022-04-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Impact of flavivirus vaccine-induced immunity on primary Zika virus antibody response in humans.

    Stefan Malafa / Iris Medits / Judith H Aberle / Stephan W Aberle / Denise Haslwanter / Georgios Tsouchnikas / Silke Wölfel / Kristina L Huber / Elena Percivalle / Pascal Cherpillod / Melissa Thaler / Lena Roßbacher / Michael Kundi / Franz X Heinz / Karin Stiasny

    PLoS Neglected Tropical Diseases, Vol 14, Iss 2, p e

    2020  Volume 0008034

    Abstract: Background Zika virus has recently spread to South- and Central America, causing congenital birth defects and neurological complications. Many people at risk are flavivirus pre-immune due to prior infections with other flaviviruses (e.g. dengue virus) or ...

    Abstract Background Zika virus has recently spread to South- and Central America, causing congenital birth defects and neurological complications. Many people at risk are flavivirus pre-immune due to prior infections with other flaviviruses (e.g. dengue virus) or flavivirus vaccinations. Since pre-existing cross-reactive immunity can potentially modulate antibody responses to Zika virus infection and may affect the outcome of disease, we analyzed fine-specificity as well as virus-neutralizing and infection-enhancing activities of antibodies induced by a primary Zika virus infection in flavivirus-naïve as well as yellow fever- and/or tick-borne encephalitis-vaccinated individuals. Methodology Antibodies in sera from convalescent Zika patients with and without vaccine-induced immunity were assessed by ELISA with respect to Zika virus-specificity and flavivirus cross-reactivity. Functional analyses included virus neutralization and infection-enhancement. The contribution of IgM and cross-reactive antibodies to these properties was determined by depletion experiments. Principal findings Pre-existing flavivirus immunity had a strong influence on the antibody response in primary Zika virus infections, resulting in higher titers of broadly flavivirus cross-reactive antibodies and slightly lower levels of Zika virus-specific IgM. Antibody-dependent enhancement (ADE) of Zika virus was mediated by sub-neutralizing concentrations of specific IgG but not by cross-reactive antibodies. This effect was potently counteracted by the presence of neutralizing IgM. Broadly cross-reactive antibodies were able to both neutralize and enhance infection of dengue virus but not Zika virus, indicating a different exposure of conserved sequence elements in the two viruses. Conclusions Our data point to an important role of flavivirus-specific IgM during the transient early stages of infection, by contributing substantially to neutralization and by counteracting ADE. In addition, our results highlight structural differences between strains of Zika ...
    Keywords Arctic medicine. Tropical medicine ; RC955-962 ; Public aspects of medicine ; RA1-1270
    Subject code 570
    Language English
    Publishing date 2020-02-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Longitudinally monitored immune biomarkers predict the timing of COVID-19 outcomes.

    Gorka Lasso / Saad Khan / Stephanie A Allen / Margarette Mariano / Catalina Florez / Erika P Orner / Jose A Quiroz / Gregory Quevedo / Aldo Massimi / Aditi Hegde / Ariel S Wirchnianski / Robert H Bortz / Ryan J Malonis / George I Georgiev / Karen Tong / Natalia G Herrera / Nicholas C Morano / Scott J Garforth / Avinash Malaviya /
    Ahmed Khokhar / Ethan Laudermilch / M Eugenia Dieterle / J Maximilian Fels / Denise Haslwanter / Rohit K Jangra / Jason Barnhill / Steven C Almo / Kartik Chandran / Jonathan R Lai / Libusha Kelly / Johanna P Daily / Olivia Vergnolle

    PLoS Computational Biology, Vol 18, Iss 1, p e

    2022  Volume 1009778

    Abstract: The clinical outcome of SARS-CoV-2 infection varies widely between individuals. Machine learning models can support decision making in healthcare by assessing fatality risk in patients that do not yet show severe signs of COVID-19. Most predictive models ...

    Abstract The clinical outcome of SARS-CoV-2 infection varies widely between individuals. Machine learning models can support decision making in healthcare by assessing fatality risk in patients that do not yet show severe signs of COVID-19. Most predictive models rely on static demographic features and clinical values obtained upon hospitalization. However, time-dependent biomarkers associated with COVID-19 severity, such as antibody titers, can substantially contribute to the development of more accurate outcome models. Here we show that models trained on immune biomarkers, longitudinally monitored throughout hospitalization, predicted mortality and were more accurate than models based on demographic and clinical data upon hospital admission. Our best-performing predictive models were based on the temporal analysis of anti-SARS-CoV-2 Spike IgG titers, white blood cell (WBC), neutrophil and lymphocyte counts. These biomarkers, together with C-reactive protein and blood urea nitrogen levels, were found to correlate with severity of disease and mortality in a time-dependent manner. Shapley additive explanations of our model revealed the higher predictive value of day post-symptom onset (PSO) as hospitalization progresses and showed how immune biomarkers contribute to predict mortality. In sum, we demonstrate that the kinetics of immune biomarkers can inform clinical models to serve as a powerful monitoring tool for predicting fatality risk in hospitalized COVID-19 patients, underscoring the importance of contextualizing clinical parameters according to their time post-symptom onset.
    Keywords Biology (General) ; QH301-705.5
    Subject code 310
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Characterization of the SARS-CoV‑2 S Protein

    Natalia G. Herrera / Nicholas C. Morano / Alev Celikgil / George I. Georgiev / Ryan J. Malonis / James H. Lee / Karen Tong / Olivia Vergnolle / Aldo B. Massimi / Laura Y. Yen / Alex J. Noble / Mykhailo Kopylov / Jeffrey B. Bonanno / Sarah C. Garrett-Thomson / David B. Hayes / Robert H. Bortz / Ariel S. Wirchnianski / Catalina Florez / Ethan Laudermilch /
    Denise Haslwanter / J. Maximilian Fels / M. Eugenia Dieterle / Rohit K. Jangra / Jason Barnhill / Amanda Mengotto / Duncan Kimmel / Johanna P. Daily / Liise-anne Pirofski / Kartik Chandran / Michael Brenowitz / Scott J. Garforth / Edward T. Eng / Jonathan R. Lai / Steven C. Almo

    ACS Omega, Vol 6, Iss 1, Pp 85-

    Biophysical, Biochemical, Structural, and Antigenic Analysis

    2020  Volume 102

    Keywords Chemistry ; QD1-999
    Language English
    Publishing date 2020-12-01T00:00:00Z
    Publisher American Chemical Society
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Treatment of severe COVID-19 with convalescent plasma in Bronx, NYC

    Hyun ah Yoon / Rachel Bartash / Inessa Gendlina / Johanna Rivera / Antonio Nakouzi / Robert H. Bortz III / Ariel S. Wirchnianski / Monika Paroder / Karen Fehn / Leana Serrano-Rahman / Rachelle Babb / Uzma N. Sarwar / Denise Haslwanter / Ethan Laudermilch / Catalina Florez / M. Eugenia Dieterle / Rohit K. Jangra / J. Maximilian Fels / Karen Tong /
    Margarette C. Mariano / Olivia Vergnolle / George I. Georgiev / Natalia G. Herrera / Ryan J. Malonis / Jose A. Quiroz / Nicholas C. Morano / Gregory J. Krause / Joseph M. Sweeney / Kelsie Cowman / Stephanie Allen / Jayabhargav Annam / Ariella Applebaum / Daniel Barboto / Ahmed Khokhar / Brianna J. Lally / Audrey Lee / Max Lee / Avinash Malaviya / Reise Sample / Xiuyi A. Yang / Yang Li / Rafael Ruiz / Raja Thota / Jason Barnhill / Doctor Y. Goldstein / Joan Uehlinger / Scott J. Garforth / Steven C. Almo / Jonathan R. Lai / Morayma Reyes Gil / Amy S. Fox / Kartik Chandran / Tao Wang / Johanna P. Daily / Liise-anne Pirofski

    JCI Insight, Vol 6, Iss

    2021  Volume 4

    Abstract: Convalescent plasma with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) antibodies (CCP) may hold promise as a treatment for coronavirus disease 2019 (COVID-19). We compared the mortality and clinical outcome of patients with COVID-19 who ... ...

    Abstract Convalescent plasma with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) antibodies (CCP) may hold promise as a treatment for coronavirus disease 2019 (COVID-19). We compared the mortality and clinical outcome of patients with COVID-19 who received 200 mL of CCP with a spike protein IgG titer ≥ 1:2430 (median 1:47,385) within 72 hours of admission with propensity score–matched controls cared for at a medical center in the Bronx, between April 13 and May 4, 2020. Matching criteria for controls were age, sex, body mass index, race, ethnicity, comorbidities, week of admission, oxygen requirement, D-dimer, lymphocyte counts, corticosteroid use, and anticoagulation use. There was no difference in mortality or oxygenation between CCP recipients and controls at day 28. When stratified by age, compared with matched controls, CCP recipients less than 65 years had 4-fold lower risk of mortality and 4-fold lower risk of deterioration in oxygenation or mortality at day 28. For CCP recipients, pretransfusion spike protein IgG, IgM, and IgA titers were associated with mortality at day 28 in univariate analyses. No adverse effects of CCP were observed. Our results suggest CCP may be beneficial for hospitalized patients less than 65 years, but data from controlled trials are needed to validate this finding and establish the effect of aging on CCP efficacy.
    Keywords COVID-19 ; Infectious disease ; Medicine ; R
    Subject code 610
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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