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  1. Article ; Online: Invasion of the germinal centers.

    Maurer, Daniel P / Schmidt, Aaron G

    Cell

    2023  Volume 186, Issue 1, Page(s) 12–14

    Abstract: After vaccination or infection, long-lived germinal centers can produce antibodies with high affinity and specificity against pathogens. In this issue of Cell, de Carvalho et al. and Hägglöf et al. show that naive B cells can invade germinal centers, ... ...

    Abstract After vaccination or infection, long-lived germinal centers can produce antibodies with high affinity and specificity against pathogens. In this issue of Cell, de Carvalho et al. and Hägglöf et al. show that naive B cells can invade germinal centers, replacing B cells that entered early and changing features of antibody production. These findings have implications for vaccine design.
    MeSH term(s) Germinal Center ; B-Lymphocytes ; Antibody Formation ; Vaccination
    Language English
    Publishing date 2023-01-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Comment
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2022.12.023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1167: Show issues Location:
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  2. Article: Antigenic drift expands viral escape pathways from imprinted host humoral immunity.

    Maurer, Daniel P / Vu, Mya / Schmidt, Aaron G

    bioRxiv : the preprint server for biology

    2024  

    Abstract: An initial virus exposure can imprint antibodies such that future responses to antigenically drifted strains are dependent on the identity of the imprinting strain. Subsequent exposure to antigenically distinct strains followed by affinity maturation can ...

    Abstract An initial virus exposure can imprint antibodies such that future responses to antigenically drifted strains are dependent on the identity of the imprinting strain. Subsequent exposure to antigenically distinct strains followed by affinity maturation can guide immune responses toward generation of cross-reactive antibodies. How viruses evolve in turn to escape these imprinted broad antibody responses is unclear. Here, we used clonal antibody lineages from two human donors recognizing conserved influenza virus hemagglutinin (HA) epitopes to assess viral escape potential using deep mutational scanning. We show that even though antibody affinity maturation does restrict the number of potential escape routes in the imprinting strain through repositioning the antibody variable domains, escape is still readily observed in drifted strains and attributed to epistatic networks within HA. These data explain how influenza virus continues to evolve in the human population by escaping even broad antibody responses.
    Language English
    Publishing date 2024-03-23
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.03.20.585891
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Protein engineering strategies for rational immunogen design.

    Caradonna, Timothy M / Schmidt, Aaron G

    NPJ vaccines

    2021  Volume 6, Issue 1, Page(s) 154

    Abstract: Antibody immunodominance refers to the preferential and asymmetric elicitation of antibodies against specific epitopes on a complex protein antigen. Traditional vaccination approaches for rapidly evolving pathogens have had limited success in part ... ...

    Abstract Antibody immunodominance refers to the preferential and asymmetric elicitation of antibodies against specific epitopes on a complex protein antigen. Traditional vaccination approaches for rapidly evolving pathogens have had limited success in part because of this phenomenon, as elicited antibodies preferentially target highly variable regions of antigens, and thus do not confer long lasting protection. While antibodies targeting functionally conserved epitopes have the potential to be broadly protective, they often make up a minority of the overall repertoire. Here, we discuss recent protein engineering strategies used to favorably alter patterns of immunodominance, and selectively focus antibody responses toward broadly protective epitopes in the pursuit of next-generation vaccines for rapidly evolving pathogens.
    Language English
    Publishing date 2021-12-17
    Publishing country England
    Document type Journal Article ; Review
    ISSN 2059-0105
    ISSN (online) 2059-0105
    DOI 10.1038/s41541-021-00417-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Repeated vaccination with homologous influenza hemagglutinin broadens human antibody responses to unmatched flu viruses.

    Deng, Yixiang / Tang, Melbourne / Ross, Ted M / Schmidt, Aaron G / Chakraborty, Arup K / Lingwood, Daniel

    medRxiv : the preprint server for health sciences

    2024  

    Abstract: The on-going diversification of influenza virus necessicates annual vaccine updating. The vaccine antigen, the viral spike protein hemagglutinin (HA), tends to elicit strain-specific neutralizing activity, predicting that sequential immunization with the ...

    Abstract The on-going diversification of influenza virus necessicates annual vaccine updating. The vaccine antigen, the viral spike protein hemagglutinin (HA), tends to elicit strain-specific neutralizing activity, predicting that sequential immunization with the same HA strain will boost antibodies with narrow coverage. However, repeated vaccination with homologous SARS-CoV-2 vaccine eventually elicits neutralizing activity against highly unmatched variants, questioning this immunological premise. We evaluated a longitudinal influenza vaccine cohort, where each year the subjects received the same, novel H1N1 2009 pandemic vaccine strain. Repeated vaccination gradually enhanced receptor-blocking antibodies (HAI) to highly unmatched H1N1 strains within individuals with no initial memory recall against these historical viruses. An
    Language English
    Publishing date 2024-03-29
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.03.27.24303943
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  5. Article ; Online: Mechanisms that promote the evolution of cross-reactive antibodies upon vaccination with designed influenza immunogens.

    Yang, Leerang / Caradonna, Timothy M / Schmidt, Aaron G / Chakraborty, Arup K

    Cell reports

    2023  Volume 42, Issue 3, Page(s) 112160

    Abstract: Immunogens that elicit broadly neutralizing antibodies targeting the conserved receptor-binding site (RBS) on influenza hemagglutinin may serve as candidates for a universal influenza vaccine. Here, we develop a computational model to interrogate ... ...

    Abstract Immunogens that elicit broadly neutralizing antibodies targeting the conserved receptor-binding site (RBS) on influenza hemagglutinin may serve as candidates for a universal influenza vaccine. Here, we develop a computational model to interrogate antibody evolution by affinity maturation after immunization with two types of immunogens: a heterotrimeric "chimera" hemagglutinin that is enriched for the RBS epitope relative to other B cell epitopes and a cocktail composed of three non-epitope-enriched homotrimers of the monomers that comprise the chimera. Experiments in mice find that the chimera outperforms the cocktail for eliciting RBS-directed antibodies. We show that this result follows from an interplay between how B cells engage these antigens and interact with diverse helper T cells and requires T cell-mediated selection of germinal center B cells to be a stringent constraint. Our results shed light on antibody evolution and highlight how immunogen design and T cells modulate vaccination outcomes.
    MeSH term(s) Animals ; Mice ; Humans ; Influenza, Human ; Influenza Vaccines ; Antibodies, Viral ; Antibodies, Neutralizing ; Hemagglutinins ; Hemagglutinin Glycoproteins, Influenza Virus ; Vaccination
    Chemical Substances Influenza Vaccines ; Antibodies, Viral ; Antibodies, Neutralizing ; Hemagglutinins ; Hemagglutinin Glycoproteins, Influenza Virus
    Language English
    Publishing date 2023-03-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2023.112160
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Hierarchical sequence-affinity landscapes shape the evolution of breadth in an anti-influenza receptor binding site antibody.

    Phillips, Angela M / Maurer, Daniel P / Brooks, Caelan / Dupic, Thomas / Schmidt, Aaron G / Desai, Michael M

    eLife

    2023  Volume 12

    Abstract: Broadly neutralizing antibodies (bnAbs) that neutralize diverse variants of a particular virus are of considerable therapeutic interest. Recent advances have enabled us to isolate and engineer these antibodies as therapeutics, but eliciting them through ... ...

    Abstract Broadly neutralizing antibodies (bnAbs) that neutralize diverse variants of a particular virus are of considerable therapeutic interest. Recent advances have enabled us to isolate and engineer these antibodies as therapeutics, but eliciting them through vaccination remains challenging, in part due to our limited understanding of how antibodies evolve breadth. Here, we analyze the landscape by which an anti-influenza receptor binding site (RBS) bnAb, CH65, evolved broad affinity to diverse H1 influenza strains. We do this by generating an antibody library of all possible evolutionary intermediates between the unmutated common ancestor (UCA) and the affinity-matured CH65 antibody and measure the affinity of each intermediate to three distinct H1 antigens. We find that affinity to each antigen requires a specific set of mutations - distributed across the variable light and heavy chains - that interact non-additively (i.e., epistatically). These sets of mutations form a hierarchical pattern across the antigens, with increasingly divergent antigens requiring additional epistatic mutations beyond those required to bind less divergent antigens. We investigate the underlying biochemical and structural basis for these hierarchical sets of epistatic mutations and find that epistasis between heavy chain mutations and a mutation in the light chain at the V
    MeSH term(s) Humans ; Antibodies, Neutralizing ; Influenza, Human ; Binding Sites ; Protein Binding ; Antibodies, Viral ; Hemagglutinin Glycoproteins, Influenza Virus
    Chemical Substances Antibodies, Neutralizing ; Antibodies, Viral ; Hemagglutinin Glycoproteins, Influenza Virus
    Language English
    Publishing date 2023-01-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.83628
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  7. Article: Lupus-associated innate receptors drive extrafollicular evolution of autoreactive B cells.

    Zhu, Danni Yi-Dan / Maurer, Daniel P / Castrillon, Carlos / Deng, Yixiang / Mohamed, Faez Amokrane Nait / Ma, Minghe / Schmidt, Aaron G / Lingwood, Daniel / Carroll, Michael C

    bioRxiv : the preprint server for biology

    2024  

    Abstract: In systemic lupus erythematosus, recent findings highlight the extrafollicular (EF) pathway as prominent origin of autoantibody-secreting cells (ASCs). ... ...

    Abstract In systemic lupus erythematosus, recent findings highlight the extrafollicular (EF) pathway as prominent origin of autoantibody-secreting cells (ASCs). CD21
    Language English
    Publishing date 2024-01-09
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.01.09.574739
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  8. Article ; Online: Heterologous Sarbecovirus Receptor Binding Domains as Scaffolds for SARS-CoV-2 Receptor Binding Motif Presentation.

    Hauser, Blake M / Sangesland, Maya / Lam, Evan C / St Denis, Kerri J / Sheehan, Maegan L / Vu, Mya L / Cheng, Agnes H / Sordilla, Sophia / Lamson, Dana Thornlow / Almawi, Ahmad W / Balazs, Alejandro B / Lingwood, Daniel / Schmidt, Aaron G

    ACS infectious diseases

    2024  Volume 10, Issue 2, Page(s) 553–561

    Abstract: Structure-guided rational immunogen design can generate optimized immunogens that elicit a desired humoral response. Design strategies often center on targeting conserved sites on viral glycoproteins that will ultimately confer potent neutralization. For ...

    Abstract Structure-guided rational immunogen design can generate optimized immunogens that elicit a desired humoral response. Design strategies often center on targeting conserved sites on viral glycoproteins that will ultimately confer potent neutralization. For SARS-CoV-2 (SARS-2), the surface-exposed spike glycoprotein includes a broadly conserved portion, the receptor binding motif (RBM), that is required to engage the host cellular receptor, ACE2. Expanding humoral responses to this site may result in a more potent neutralizing antibody response against diverse sarbecoviruses. Here, we used a "resurfacing" approach and iterative design cycles to graft the SARS-2 RBM onto heterologous sarbecovirus scaffolds. The scaffolds were selected to vary the antigenic distance relative to SARS-2 to potentially focus responses to RBM. Multimerized versions of these immunogens elicited broad neutralization against sarbecoviruses in the context of preexisting SARS-2 immunity. These validated engineering approaches can help inform future immunogen design efforts for sarbecoviruses and are generally applicable to other viruses.
    MeSH term(s) Humans ; SARS-CoV-2 ; Severe acute respiratory syndrome-related coronavirus ; COVID-19 ; Antibodies, Neutralizing
    Chemical Substances Antibodies, Neutralizing
    Language English
    Publishing date 2024-01-28
    Publishing country United States
    Document type Journal Article
    ISSN 2373-8227
    ISSN (online) 2373-8227
    DOI 10.1021/acsinfecdis.3c00483
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  9. Article ; Online: Humoral responses to the SARS-CoV-2 spike and receptor binding domain in context of pre-existing immunity confer broad sarbecovirus neutralization.

    Hauser, Blake M / Sangesland, Maya / Lam, Evan C / Feldman, Jared / Balazs, Alejandro B / Lingwood, Daniel / Schmidt, Aaron G

    Frontiers in immunology

    2022  Volume 13, Page(s) 902260

    Abstract: Since the emergence of SARS-CoV-2 (SARS-2), multiple vaccine candidates were developed and studied both preclinically and clinically. Nearly all are based on the SARS-2 spike glycoprotein or its receptor binding domain (RBD). Studies of these vaccine ... ...

    Abstract Since the emergence of SARS-CoV-2 (SARS-2), multiple vaccine candidates were developed and studied both preclinically and clinically. Nearly all are based on the SARS-2 spike glycoprotein or its receptor binding domain (RBD). Studies of these vaccine candidates have largely been in a SARS-2 naïve context. However, pre-existing immunity to SARS-2 acquired through infection or vaccination continues to increase. Evaluating future vaccine candidates in context of this pre-existing immunity is necessary to understand how immune responses are subsequently influenced. Here, we evaluated the serum and IgG
    MeSH term(s) Antibodies, Viral ; COVID-19/prevention & control ; Epitopes ; Humans ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus
    Chemical Substances Antibodies, Viral ; Epitopes ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
    Language English
    Publishing date 2022-08-04
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2022.902260
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  10. Article ; Online: Rotavirus VP4 Epitope of a Broadly Neutralizing Human Antibody Defined by Its Structure Bound with an Attenuated-Strain Virion.

    Jenni, Simon / Li, Zongli / Wang, Yuhuan / Bessey, Theresa / Salgado, Eric N / Schmidt, Aaron G / Greenberg, Harry B / Jiang, Baoming / Harrison, Stephen C

    Journal of virology

    2022  Volume 96, Issue 16, Page(s) e0062722

    Abstract: Rotavirus live-attenuated vaccines, both mono- and pentavalent, generate broadly heterotypic protection. B-cells isolated from adults encode neutralizing antibodies, some with affinity for VP5*, that afford broad protection in mice. We have mapped the ... ...

    Abstract Rotavirus live-attenuated vaccines, both mono- and pentavalent, generate broadly heterotypic protection. B-cells isolated from adults encode neutralizing antibodies, some with affinity for VP5*, that afford broad protection in mice. We have mapped the epitope of one such antibody by determining the high-resolution cryo-EM structure of its antigen-binding fragment (Fab) bound to the virion of a candidate vaccine strain, CDC-9. The Fab contacts both the distal end of a VP5* β-barrel domain and the two VP8* lectin-like domains at the tip of a projecting spike. Its interactions with VP8* do not impinge on the likely receptor-binding site, suggesting that the mechanism of neutralization is at a step subsequent to initial attachment. We also examined structures of CDC-9 virions from two different stages of serial passaging. Nearly all the VP4 (cleaved to VP8*/VP5*) spikes on particles from the earlier passage (wild-type isolate) had transitioned from the "upright" conformation present on fully infectious virions to the "reversed" conformation that is probably the end state of membrane insertion, unable to mediate penetration, consistent with the very low
    MeSH term(s) Animals ; Broadly Neutralizing Antibodies/immunology ; Broadly Neutralizing Antibodies/ultrastructure ; Capsid Proteins/chemistry ; Capsid Proteins/immunology ; Capsid Proteins/ultrastructure ; Cryoelectron Microscopy ; Epitopes, B-Lymphocyte/immunology ; Epitopes, B-Lymphocyte/ultrastructure ; Humans ; Immunoglobulin Fab Fragments/immunology ; Immunoglobulin Fab Fragments/ultrastructure ; Mice ; Protein Conformation ; Rats ; Rotavirus/chemistry ; Rotavirus/classification ; Rotavirus/immunology ; Rotavirus/physiology ; Serial Passage ; Vaccines, Attenuated/chemistry ; Vaccines, Attenuated/immunology ; Vaccines, Attenuated/metabolism ; Virion/immunology ; Virion/metabolism ; Virion/ultrastructure
    Chemical Substances Broadly Neutralizing Antibodies ; Capsid Proteins ; Epitopes, B-Lymphocyte ; Immunoglobulin Fab Fragments ; VP4 protein, Rotavirus ; Vaccines, Attenuated
    Language English
    Publishing date 2022-08-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/jvi.00627-22
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 609: Show issues Location:
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