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Article ; Online: Antibody-mediated neutralization of SARS-CoV-2.

Gruell, Henning / Vanshylla, Kanika / Weber, Timm / Barnes, Christopher O / Kreer, Christoph / Klein, Florian

2022 Volume 55, Issue 6, Page(s) 925–944

Abstract: Neutralizing antibodies can block infection, clear pathogens, and are essential to provide long-term immunity. Since the onset of the pandemic, SARS-CoV-2 neutralizing antibodies have been comprehensively investigated and critical information on their ... ...

Abstract	Neutralizing antibodies can block infection, clear pathogens, and are essential to provide long-term immunity. Since the onset of the pandemic, SARS-CoV-2 neutralizing antibodies have been comprehensively investigated and critical information on their development, function, and potential use to prevent and treat COVID-19 have been revealed. With the emergence of SARS-CoV-2 immune escape variants, humoral immunity is being challenged, and a detailed understanding of neutralizing antibodies is essential to guide vaccine design strategies as well as antibody-mediated therapies. In this review, we summarize some of the key findings on SARS-CoV-2 neutralizing antibodies, with a focus on their clinical application.
MeSH term(s)	Antibodies, Neutralizing ; Antibodies, Viral ; COVID-19 ; Humans ; Neutralization Tests ; SARS-CoV-2 ; Vaccination
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral
Language	English
Publishing date	2022-05-13
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2022.05.005
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Book ; Online ; Thesis: N-glycosylation of intrinsic and engineered N-X-S/T motifs by Pichia pastoris can be exploited to ligate the mannose receptor but reveals no gain in immunogenicity per se

Kreer, Christoph [Verfasser]

2016

Author's details	Christoph Kreer
Keywords	Biowissenschaften, Biologie ; Life Science, Biology
Subject code	sg570
Language	English
Publisher	Universitäts- und Landesbibliothek Bonn
Publishing place	Bonn
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: Modeling the Amplification of Immunoglobulins through Machine Learning on Sequence-Specific Features.

Döring, Matthias / Kreer, Christoph / Lehnen, Nathalie / Klein, Florian / Pfeifer, Nico

Scientific reports

2019 Volume 9, Issue 1, Page(s) 10748

Abstract: Successful primer design for polymerase chain reaction (PCR) hinges on the ability to identify primers that efficiently amplify template sequences. Here, we generated a novel Taq PCR data set that reports the amplification status for pairs of primers and ...

Abstract	Successful primer design for polymerase chain reaction (PCR) hinges on the ability to identify primers that efficiently amplify template sequences. Here, we generated a novel Taq PCR data set that reports the amplification status for pairs of primers and templates from a reference set of 47 immunoglobulin heavy chain variable sequences and 20 primers. Using logistic regression, we developed TMM, a model for predicting whether a primer amplifies a template given their nucleotide sequences. The model suggests that the free energy of annealing, ΔG, is the key driver of amplification (p = 7.35e-12) and that 3' mismatches should be considered in dependence on ΔG and the mismatch closest to the 3' terminus (p = 1.67e-05). We validated TMM by comparing its estimates with those from the thermodynamic model of DECIPHER (DE) and a model based solely on the free energy of annealing (FE). TMM outperformed the other approaches in terms of the area under the receiver operating characteristic curve (TMM: 0.953, FE: 0.941, DE: 0.896). TMM can improve primer design and is freely available via openPrimeR ( http://openPrimeR.mpi-inf.mpg.de ).
MeSH term(s)	DNA Primers/genetics ; DNA Primers/metabolism ; Humans ; Immunoglobulins/genetics ; Immunoglobulins/metabolism ; Logistic Models ; Machine Learning ; Models, Statistical ; Nucleic Acid Amplification Techniques/methods ; Polymerase Chain Reaction/methods
Chemical Substances	DNA Primers ; Immunoglobulins
Language	English
Publishing date	2019-07-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-47173-w
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Exploiting B Cell Receptor Analyses to Inform on HIV-1 Vaccination Strategies.

Kreer, Christoph / Gruell, Henning / Mora, Thierry / Walczak, Aleksandra M / Klein, Florian

Vaccines

2020 Volume 8, Issue 1

Abstract: The human antibody repertoire is generated by the recombination of different gene segments as well as by processes of somatic mutation. Together these mechanisms result in a tremendous diversity of antibodies that are able to combat various pathogens ... ...

Abstract	The human antibody repertoire is generated by the recombination of different gene segments as well as by processes of somatic mutation. Together these mechanisms result in a tremendous diversity of antibodies that are able to combat various pathogens including viruses and bacteria, or malignant cells. In this review, we summarize the opportunities and challenges that are associated with the analyses of the B cell receptor repertoire and the antigen-specific B cell response. We will discuss how recent advances have increased our understanding of the antibody response and how repertoire analyses can be exploited to inform on vaccine strategies, particularly against HIV-1.
Keywords	covid19
Language	English
Publishing date	2020-01-01
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines8010013
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Article ; Online: Probabilities of developing HIV-1 bNAb sequence features in uninfected and chronically infected individuals.

Kreer, Christoph / Lupo, Cosimo / Ercanoglu, Meryem S / Gieselmann, Lutz / Spisak, Natanael / Grossbach, Jan / Schlotz, Maike / Schommers, Philipp / Gruell, Henning / Dold, Leona / Beyer, Andreas / Nourmohammad, Armita / Mora, Thierry / Walczak, Aleksandra M / Klein, Florian

Nature communications

2023 Volume 14, Issue 1, Page(s) 7137

Abstract: HIV-1 broadly neutralizing antibodies (bNAbs) are able to suppress viremia and prevent infection. Their induction by vaccination is therefore a major goal. However, in contrast to antibodies that neutralize other pathogens, HIV-1-specific bNAbs ... ...

Abstract	HIV-1 broadly neutralizing antibodies (bNAbs) are able to suppress viremia and prevent infection. Their induction by vaccination is therefore a major goal. However, in contrast to antibodies that neutralize other pathogens, HIV-1-specific bNAbs frequently carry uncommon molecular characteristics that might prevent their induction. Here, we perform unbiased sequence analyses of B cell receptor repertoires from 57 uninfected and 46 chronically HIV-1- or HCV-infected individuals and learn probabilistic models to predict the likelihood of bNAb development. We formally show that lower probabilities for bNAbs are predictive of higher HIV-1 neutralization activity. Moreover, ranking bNAbs by their probabilities allows to identify highly potent antibodies with superior generation probabilities as preferential targets for vaccination approaches. Importantly, we find equal bNAb probabilities across infected and uninfected individuals. This implies that chronic infection is not a prerequisite for the generation of bNAbs, fostering the hope that HIV-1 vaccines can induce bNAb development in uninfected people.
MeSH term(s)	Humans ; Broadly Neutralizing Antibodies ; HIV Infections ; HIV Antibodies ; HIV-1 ; Antibodies, Neutralizing ; AIDS Vaccines
Chemical Substances	Broadly Neutralizing Antibodies ; HIV Antibodies ; Antibodies, Neutralizing ; AIDS Vaccines
Language	English
Publishing date	2023-11-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-42906-y
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Article ; Online: Enhanced SARS-CoV-2 humoral immunity following breakthrough infection builds upon the preexisting memory B cell pool.

Weber, Timm / Dähling, Sabrina / Rose, Svea / Affeldt, Patrick / Vanshylla, Kanika / Ullrich, Leon / Gieselmann, Lutz / Teipel, Finn / Gruell, Henning / Di Cristanziano, Veronica / Kim, Dae Sung / Georgiou, George / Koch, Manuel / Kreer, Christoph / Klein, Florian

Science immunology

2023 Volume 8, Issue 89, Page(s) eadk5845

Abstract: The human immune response must continuously adapt to newly emerging SARS-CoV-2 variants. To investigate how B cells respond to repeated SARS-CoV-2 antigen exposure by Wu01 booster vaccination and Omicron breakthrough infection, we performed a molecular ... ...

Abstract	The human immune response must continuously adapt to newly emerging SARS-CoV-2 variants. To investigate how B cells respond to repeated SARS-CoV-2 antigen exposure by Wu01 booster vaccination and Omicron breakthrough infection, we performed a molecular longitudinal analysis of the memory B cell pool. We demonstrate that a subsequent breakthrough infection substantially increases the frequency of B cells encoding SARS-CoV-2-neutralizing antibodies. However, this is not primarily attributable to maturation, but to selection of preexisting B cell clones. Moreover, broadly reactive memory B cells arose early and even neutralized highly mutated variants like XBB.1.5 that the individuals had not encountered. Together, our data show that SARS-CoV-2 immunity is largely imprinted on Wu01 over the course of multiple antigen contacts but can respond to new variants through preexisting diversity.
MeSH term(s)	Humans ; Memory B Cells ; Immunity, Humoral ; Breakthrough Infections ; SARS-CoV-2 ; COVID-19 ; Antibodies, Viral
Chemical Substances	Antibodies, Viral
Language	English
Publishing date	2023-11-17
Publishing country	United States
Document type	Journal Article
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.adk5845
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Article ; Online: Somatic hypermutation introduces bystander mutations that prepare SARS-CoV-2 antibodies for emerging variants.

Korenkov, Michael / Zehner, Matthias / Cohen-Dvashi, Hadas / Borenstein-Katz, Aliza / Kottege, Lisa / Janicki, Hanna / Vanshylla, Kanika / Weber, Timm / Gruell, Henning / Koch, Manuel / Diskin, Ron / Kreer, Christoph / Klein, Florian

Immunity

2023 Volume 56, Issue 12, Page(s) 2803–2815.e6

Abstract: Somatic hypermutation (SHM) drives affinity maturation and continues over months in SARS-CoV-2-neutralizing antibodies (nAbs). However, several potent SARS-CoV-2 antibodies carry no or only a few mutations, leaving the question of how ongoing SHM affects ...

Abstract	Somatic hypermutation (SHM) drives affinity maturation and continues over months in SARS-CoV-2-neutralizing antibodies (nAbs). However, several potent SARS-CoV-2 antibodies carry no or only a few mutations, leaving the question of how ongoing SHM affects neutralization unclear. Here, we reverted variable region mutations of 92 antibodies and tested their impact on SARS-CoV-2 binding and neutralization. Reverting higher numbers of mutations correlated with decreasing antibody functionality. However, for some antibodies, including antibodies of the public clonotype VH1-58, neutralization of Wu01 remained unaffected. Although mutations were dispensable for Wu01-induced VH1-58 antibodies to neutralize Alpha, Beta, and Delta variants, they were critical for Omicron BA.1/BA.2 neutralization. We exploited this knowledge to convert the clinical antibody tixagevimab into a BA.1/BA.2 neutralizer. These findings broaden our understanding of SHM as a mechanism that not only improves antibody responses during affinity maturation but also contributes to antibody diversification, thus increasing the chances of neutralizing viral escape variants.
MeSH term(s)	Humans ; SARS-CoV-2 ; COVID-19/genetics ; Antibodies, Viral ; Mutation/genetics ; Antibodies, Neutralizing
Chemical Substances	Antibodies, Viral ; Antibodies, Neutralizing
Language	English
Publishing date	2023-11-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2023.11.004
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Article ; Online: Effective high-throughput isolation of fully human antibodies targeting infectious pathogens.

Gieselmann, Lutz / Kreer, Christoph / Ercanoglu, Meryem Seda / Lehnen, Nathalie / Zehner, Matthias / Schommers, Philipp / Potthoff, Julian / Gruell, Henning / Klein, Florian

Nature protocols

2021 Volume 16, Issue 7, Page(s) 3639–3671

Abstract: As exemplified by the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, there is a strong demand for rapid high-throughput isolation pipelines to identify potent neutralizing antibodies for prevention and therapy of ... ...

Abstract	As exemplified by the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, there is a strong demand for rapid high-throughput isolation pipelines to identify potent neutralizing antibodies for prevention and therapy of infectious diseases. However, despite substantial progress and extensive efforts, the identification and production of antigen-specific antibodies remains labor- and cost-intensive. We have advanced existing concepts to develop a highly efficient high-throughput protocol with proven application for the isolation of potent antigen-specific antibodies against human immunodeficiency virus 1, hepatitis C virus, human cytomegalovirus, Middle East respiratory syndrome coronavirus, SARS-CoV-2 and Ebola virus. It is based on computationally optimized multiplex primer sets (openPrimeR), which guarantee high coverage of even highly mutated immunoglobulin gene segments as well as on optimized antibody cloning and production strategies. Here, we provide the detailed protocol, which covers all critical steps from sample collection to antibody production within 12-14 d.
MeSH term(s)	Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/pharmacology ; Antibodies, Neutralizing/immunology ; Antibodies, Neutralizing/isolation & purification ; Antibodies, Neutralizing/pharmacology ; Antibodies, Viral/immunology ; Antibodies, Viral/isolation & purification ; COVID-19/immunology ; Communicable Diseases ; High-Throughput Screening Assays/methods ; Humans ; Immunoglobulin G/immunology ; Pandemics ; SARS-CoV-2/immunology
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Neutralizing ; Antibodies, Viral ; Immunoglobulin G
Language	English
Publishing date	2021-05-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2244966-8
ISSN	1750-2799 ; 1754-2189
ISSN (online)	1750-2799
ISSN	1754-2189
DOI	10.1038/s41596-021-00554-w
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Article ; Online: Modeling the Amplification of Immunoglobulins through Machine Learning on Sequence-Specific Features

Matthias Döring / Christoph Kreer / Nathalie Lehnen / Florian Klein / Nico Pfeifer

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 11

Abstract: Abstract Successful primer design for polymerase chain reaction (PCR) hinges on the ability to identify primers that efficiently amplify template sequences. Here, we generated a novel Taq PCR data set that reports the amplification status for pairs of ... ...

Abstract	Abstract Successful primer design for polymerase chain reaction (PCR) hinges on the ability to identify primers that efficiently amplify template sequences. Here, we generated a novel Taq PCR data set that reports the amplification status for pairs of primers and templates from a reference set of 47 immunoglobulin heavy chain variable sequences and 20 primers. Using logistic regression, we developed TMM, a model for predicting whether a primer amplifies a template given their nucleotide sequences. The model suggests that the free energy of annealing, ΔG, is the key driver of amplification (p = 7.35e-12) and that 3′ mismatches should be considered in dependence on ΔG and the mismatch closest to the 3′ terminus (p = 1.67e-05). We validated TMM by comparing its estimates with those from the thermodynamic model of DECIPHER (DE) and a model based solely on the free energy of annealing (FE). TMM outperformed the other approaches in terms of the area under the receiver operating characteristic curve (TMM: 0.953, FE: 0.941, DE: 0.896). TMM can improve primer design and is freely available via openPrimeR (http://openPrimeR.mpi-inf.mpg.de).
Keywords	Medicine ; R ; Science ; Q
Subject code	612
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Probabilities of developing HIV-1 bNAb sequence features in uninfected and chronically infected individuals

Christoph Kreer / Cosimo Lupo / Meryem S. Ercanoglu / Lutz Gieselmann / Natanael Spisak / Jan Grossbach / Maike Schlotz / Philipp Schommers / Henning Gruell / Leona Dold / Andreas Beyer / Armita Nourmohammad / Thierry Mora / Aleksandra M. Walczak / Florian Klein

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 14

Abstract: Abstract HIV-1 broadly neutralizing antibodies (bNAbs) are able to suppress viremia and prevent infection. Their induction by vaccination is therefore a major goal. However, in contrast to antibodies that neutralize other pathogens, HIV-1-specific bNAbs ... ...

Abstract	Abstract HIV-1 broadly neutralizing antibodies (bNAbs) are able to suppress viremia and prevent infection. Their induction by vaccination is therefore a major goal. However, in contrast to antibodies that neutralize other pathogens, HIV-1-specific bNAbs frequently carry uncommon molecular characteristics that might prevent their induction. Here, we perform unbiased sequence analyses of B cell receptor repertoires from 57 uninfected and 46 chronically HIV-1- or HCV-infected individuals and learn probabilistic models to predict the likelihood of bNAb development. We formally show that lower probabilities for bNAbs are predictive of higher HIV-1 neutralization activity. Moreover, ranking bNAbs by their probabilities allows to identify highly potent antibodies with superior generation probabilities as preferential targets for vaccination approaches. Importantly, we find equal bNAb probabilities across infected and uninfected individuals. This implies that chronic infection is not a prerequisite for the generation of bNAbs, fostering the hope that HIV-1 vaccines can induce bNAb development in uninfected people.
Keywords	Science ; Q
Subject code	005
Language	English
Publishing date	2023-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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