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  1. Artikel: Delineating the functional activity of antibodies with cross-reactivity to SARS-CoV-2, SARS-CoV-1 and related sarbecoviruses.

    Ruiz, Felicitas / Foreman, Will / Lilly, Michelle / Baharani, Viren A / Depierreux, Delphine M / Chohan, Vrasha / Taylor, Ashley L / Guenthoer, Jamie / Ralph, Duncan / Matsen, Frederick A / Chu, Helen Y / Bieniasz, Paul D / Côté, Marceline / Starr, Tyler N / Overbaugh, Julie

    bioRxiv : the preprint server for biology

    2024  

    Abstract: The recurring spillover of pathogenic coronaviruses and demonstrated capacity of sarbecoviruses, such SARS-CoV-2, to rapidly evolve in humans underscores the need to better understand immune responses to this virus family. For this purpose, we ... ...

    Abstract The recurring spillover of pathogenic coronaviruses and demonstrated capacity of sarbecoviruses, such SARS-CoV-2, to rapidly evolve in humans underscores the need to better understand immune responses to this virus family. For this purpose, we characterized the functional breadth and potency of antibodies targeting the receptor binding domain (RBD) of the spike glycoprotein that exhibited cross-reactivity against SARS-CoV-2 variants, SARS-CoV-1 and sarbecoviruses from diverse clades and animal origins with spillover potential. One neutralizing antibody, C68.61, showed remarkable neutralization breadth against both SARS-CoV-2 variants and viruses from different sarbecovirus clades. C68.61, which targets a conserved RBD class 5 epitope, did not select for escape variants of SARS-CoV-2 or SARS-CoV-1 in culture nor have predicted escape variants among circulating SARS-CoV-2 strains, suggesting this epitope is functionally constrained. We identified 11 additional SARS-CoV-2/SARS-CoV-1 cross-reactive antibodies that target the more sequence conserved class 4 and class 5 epitopes within RBD that show activity against a subset of diverse sarbecoviruses with one antibody binding every single sarbecovirus RBD tested. A subset of these antibodies exhibited Fc-mediated effector functions as potent as antibodies that impact infection outcome in animal models. Thus, our study identified antibodies targeting conserved regions across SARS-CoV-2 variants and sarbecoviruses that may serve as therapeutics for pandemic preparedness as well as blueprints for the design of immunogens capable of eliciting cross-neutralizing responses.
    Sprache Englisch
    Erscheinungsdatum 2024-04-25
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2024.04.24.590836
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel: Bispecific antibodies with broad neutralization potency against SARS-CoV-2 variants of concern.

    Rubio, Adonis A / Baharani, Viren A / Dadonaite, Bernadeta / Parada, Megan / Abernathy, Morgan E / Wang, Zijun / Lee, Yu E / Eso, Michael R / Phung, Jennie / Ramos, Israel / Chen, Teresia / Nesr, Gina El / Bloom, Jesse D / Bieniasz, Paul D / Nussenzweig, Michel C / Barnes, Christopher O

    bioRxiv : the preprint server for biology

    2024  

    Abstract: The ongoing emergence of SARS-CoV-2 variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized N-terminal ...

    Abstract The ongoing emergence of SARS-CoV-2 variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized N-terminal domain (NTD) and receptor binding domain (RBD)-specific monoclonal antibodies previously isolated from COVID-19 convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo-EM structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596's favorable binding profile, we designed a series of bispecific antibodies (bsAbs) termed CoV2-biRNs, that featured both NTD and RBD specificities. Notably, two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potent
    One sentence summary: Bispecific antibodies with a highly cross-reactive NTD antibody demonstrate resilience to SARS-CoV-2 variants of concern.
    Sprache Englisch
    Erscheinungsdatum 2024-05-06
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2024.05.05.592584
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Epistasis lowers the genetic barrier to SARS-CoV-2 neutralizing antibody escape.

    Witte, Leander / Baharani, Viren A / Schmidt, Fabian / Wang, Zijun / Cho, Alice / Raspe, Raphael / Guzman-Cardozo, Camila / Muecksch, Frauke / Canis, Marie / Park, Debby J / Gaebler, Christian / Caskey, Marina / Nussenzweig, Michel C / Hatziioannou, Theodora / Bieniasz, Paul D

    Nature communications

    2023  Band 14, Heft 1, Seite(n) 302

    Abstract: Waves of SARS-CoV-2 infection have resulted from the emergence of viral variants with neutralizing antibody resistance mutations. Simultaneously, repeated antigen exposure has generated affinity matured B cells, producing broadly neutralizing receptor ... ...

    Abstract Waves of SARS-CoV-2 infection have resulted from the emergence of viral variants with neutralizing antibody resistance mutations. Simultaneously, repeated antigen exposure has generated affinity matured B cells, producing broadly neutralizing receptor binding domain (RBD)-specific antibodies with activity against emergent variants. To determine how SARS-CoV-2 might escape these antibodies, we subjected chimeric viruses encoding spike proteins from ancestral, BA.1 or BA.2 variants to selection by 40 broadly neutralizing antibodies. We identify numerous examples of epistasis, whereby in vitro selected and naturally occurring substitutions in RBD epitopes that do not confer antibody resistance in the Wuhan-Hu-1 spike, do so in BA.1 or BA.2 spikes. As few as 2 or 3 of these substitutions in the BA.5 spike, confer resistance to nearly all of the 40 broadly neutralizing antibodies, and substantial resistance to plasma from most individuals. Thus, epistasis facilitates the acquisition of resistance to antibodies that remained effective against early omicron variants.
    Mesh-Begriff(e) Humans ; Antibodies, Neutralizing ; SARS-CoV-2/genetics ; Broadly Neutralizing Antibodies ; Epistasis, Genetic ; COVID-19 ; Spike Glycoprotein, Coronavirus/genetics ; Antibodies, Viral
    Chemische Substanzen Antibodies, Neutralizing ; Broadly Neutralizing Antibodies ; Spike Glycoprotein, Coronavirus ; Antibodies, Viral ; spike protein, SARS-CoV-2
    Sprache Englisch
    Erscheinungsdatum 2023-01-19
    Erscheinungsland England
    Dokumenttyp 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/s41467-023-35927-0
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Heteromultimeric sarbecovirus receptor binding domain immunogens primarily generate variant-specific neutralizing antibodies.

    Zang, Trinity / Osei Kuffour, Edmund / Baharani, Viren A / Canis, Marie / Schmidt, Fabian / Da Silva, Justin / Lercher, Alexander / Chaudhary, Pooja / Hoffmann, Hans-Heinrich / Gazumyan, Anna / Miranda, Ileana C / MacDonald, Margaret R / Rice, Charles M / Nussenzweig, Michel C / Hatziioannou, Theodora / Bieniasz, Paul D

    Proceedings of the National Academy of Sciences of the United States of America

    2023  Band 120, Heft 51, Seite(n) e2317367120

    Abstract: Vaccination will likely be a key component of strategies to curtail or prevent future sarbecovirus pandemics and to reduce the prevalence of infection and disease by future SARS-CoV-2 variants. A "pan-sarbecovirus" vaccine, that provides maximum possible ...

    Abstract Vaccination will likely be a key component of strategies to curtail or prevent future sarbecovirus pandemics and to reduce the prevalence of infection and disease by future SARS-CoV-2 variants. A "pan-sarbecovirus" vaccine, that provides maximum possible mitigation of human disease, should elicit neutralizing antibodies with maximum possible breadth. By positioning multiple different receptor binding domain (RBD) antigens in close proximity on a single immunogen, it is postulated that cross-reactive B cell receptors might be selectively engaged. Heteromultimeric vaccines could therefore elicit individual antibodies that neutralize a broad range of viral species. Here, we use model systems to investigate the ability of multimeric sarbecovirus RBD immunogens to expand cross-reactive B cells and elicit broadly reactive antibodies. Homomultimeric RBD immunogens generated higher serum neutralizing antibody titers than the equivalent monomeric immunogens, while heteromultimeric RBD immunogens generated neutralizing antibodies recognizing each RBD component. Moreover, RBD heterodimers elicited a greater fraction of cross-reactive germinal center B cells and cross-reactive RBD binding antibodies than did homodimers. However, when serum antibodies from RBD heterodimer-immunized mice were depleted using one RBD component, neutralization activity against the homologous viral pseudotype was removed, but neutralization activity against pseudotypes corresponding to the other RBD component was unaffected. Overall, simply combining divergent RBDs in a single immunogen generates largely separate sets of individual RBD-specific neutralizing serum antibodies that are mostly incapable of neutralizing viruses that diverge from the immunogen components.
    Mesh-Begriff(e) Animals ; Mice ; Humans ; Antibodies, Neutralizing ; Antibodies, Viral ; Neutralization Tests ; Severe acute respiratory syndrome-related coronavirus ; Vaccination ; Spike Glycoprotein, Coronavirus/chemistry
    Chemische Substanzen Antibodies, Neutralizing ; Antibodies, Viral ; Spike Glycoprotein, Coronavirus
    Sprache Englisch
    Erscheinungsdatum 2023-12-14
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2317367120
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1148: Hefte anzeigen Standort:
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  5. Artikel ; Online: Delineating the functional activity of antibodies with cross-reactivity to SARS-CoV-2, SARS-CoV-1 and related sarbecoviruses

    Ruiz, Felicitas / Foreman, Will / Lilly, Michelle / Baharani, Viren A. / Depierreux, Delphine M. / Chohan, Vrasha / Taylor, Ashley L. / Guenthoer, Jamie / Ralph, Duncan / Matsen, Frederick A. / Chu, Helen Y. / Bieniasz, Paul D. / Côté, Marceline / Starr, Tyler N. / Overbaugh, Julie

    bioRxiv

    Abstract: The recurring spillover of pathogenic coronaviruses and demonstrated capacity of sarbecoviruses, such SARS-CoV-2, to rapidly evolve in humans underscores the need to better understand immune responses to this virus family. For this purpose, we ... ...

    Abstract The recurring spillover of pathogenic coronaviruses and demonstrated capacity of sarbecoviruses, such SARS-CoV-2, to rapidly evolve in humans underscores the need to better understand immune responses to this virus family. For this purpose, we characterized the functional breadth and potency of antibodies targeting the receptor binding domain (RBD) of the spike glycoprotein that exhibited cross-reactivity against SARS-CoV-2 variants, SARS-CoV-1 and sarbecoviruses from diverse clades and animal origins with spillover potential. One neutralizing antibody, C68.61, showed remarkable neutralization breadth against both SARS-CoV-2 variants and viruses from different sarbecovirus clades. C68.61, which targets a conserved RBD class 5 epitope, did not select for escape variants of SARS-CoV-2 or SARS-CoV-1 in culture nor have predicted escape variants among circulating SARS-CoV-2 strains, suggesting this epitope is functionally constrained. We identified 11 additional SARS-CoV-2/SARS-CoV-1 cross-reactive antibodies that target the more sequence conserved class 4 and class 5 epitopes within RBD that show activity against a subset of diverse sarbecoviruses with one antibody binding every single sarbecovirus RBD tested. A subset of these antibodies exhibited Fc-mediated effector functions as potent as antibodies that impact infection outcome in animal models. Thus, our study identified antibodies targeting conserved regions across SARS-CoV-2 variants and sarbecoviruses that may serve as therapeutics for pandemic preparedness as well as blueprints for the design of immunogens capable of eliciting cross-neutralizing responses.
    Schlagwörter covid19
    Sprache Englisch
    Erscheinungsdatum 2024-04-25
    Verlag Cold Spring Harbor Laboratory
    Dokumenttyp Artikel ; Online
    DOI 10.1101/2024.04.24.590836
    Datenquelle COVID19

    Volltext online

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  6. Artikel ; Online: Bispecific antibodies with broad neutralization potency against SARS-CoV-2 variants of concern

    Rubio, Adonis A. / Baharani, Viren A. / Dadonaite, Bernadeta / Parada, Megan / Abernathy, Morgan E. / Wang, Zijun / Lee, Yu E. / Eso, Michael R. / Phung, Jennie / Ramos, Israel / Chen, Teresia / Nesr, Gina El / Bloom, Jesse D. / Bieniasz, Paul D. / Nussenzweig, Michel C. / Barnes, Christopher O.

    bioRxiv

    Abstract: The ongoing emergence of SARS-CoV-2 variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized N-terminal ...

    Abstract The ongoing emergence of SARS-CoV-2 variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized N-terminal domain (NTD) and receptor binding domain (RBD)-specific monoclonal antibodies previously isolated from COVID-19 convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo-EM structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596′s favorable binding profile, we designed a series of bispecific antibodies (bsAbs) termed CoV2-biRNs, that featured both NTD and RBD specificities. Notably, two of the C1596-inclusive bsAbs, CoV2 biRN5 and CoV2-biRN7, retained potent in vitro neutralization activity against all Omicron variants tested, including XBB.1.5, EG.5.1, and BA.2.86, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 significantly reduced the viral load within the lungs of K18-hACE2 mice following challenge with SARS-CoV-2 XBB.1.5. In conclusion, our NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs.
    Schlagwörter covid19
    Sprache Englisch
    Erscheinungsdatum 2024-05-06
    Verlag Cold Spring Harbor Laboratory
    Dokumenttyp Artikel ; Online
    DOI 10.1101/2024.05.05.592584
    Datenquelle COVID19

    Volltext online

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  7. Artikel ; Online: Memory B cell development elicited by mRNA booster vaccinations in the elderly.

    Wang, Zijun / Muecksch, Frauke / Raspe, Raphael / Johannsen, Frederik / Turroja, Martina / Canis, Marie / ElTanbouly, Mohamed A / Santos, Gabriela S Silva / Johnson, Brianna / Baharani, Viren A / Patejak, Rachel / Yao, Kai-Hui / Chirco, Bennett J / Millard, Katrina G / Shimeliovich, Irina / Gazumyan, Anna / Oliveira, Thiago Y / Bieniasz, Paul D / Hatziioannou, Theodora /
    Caskey, Marina / Nussenzweig, Michel C

    The Journal of experimental medicine

    2023  Band 220, Heft 9

    Abstract: Despite mRNA vaccination, elderly individuals remain especially vulnerable to severe consequences of SARS-CoV-2 infection. Here, we compare the memory B cell responses in a cohort of elderly and younger individuals who received mRNA booster vaccinations. ...

    Abstract Despite mRNA vaccination, elderly individuals remain especially vulnerable to severe consequences of SARS-CoV-2 infection. Here, we compare the memory B cell responses in a cohort of elderly and younger individuals who received mRNA booster vaccinations. Plasma neutralizing potency and breadth were similar between the two groups. By contrast, the absolute number of SARS-CoV-2-specific memory B cells was lower in the elderly. Antibody sequencing revealed that the SARS-CoV-2-specific elderly memory compartments were more clonal and less diverse. Notably, memory antibodies from the elderly preferentially targeted the ACE2-binding site on the RBD, while those from younger individuals targeted less accessible but more conserved epitopes. Nevertheless, individual memory antibodies elicited by booster vaccines in the elderly and younger individuals showed similar levels of neutralizing activity and breadth against SARS-CoV-2 variants. Thus, the relatively diminished protective effects of vaccination against serious disease in the elderly are associated with a smaller number of antigen-specific memory B cells that express altered antibody repertoires.
    Mesh-Begriff(e) Aged ; Humans ; Memory B Cells ; COVID-19/prevention & control ; SARS-CoV-2 ; Vaccination ; Antibodies ; RNA, Messenger/genetics ; Antibodies, Neutralizing ; Antibodies, Viral
    Chemische Substanzen Antibodies ; RNA, Messenger ; Antibodies, Neutralizing ; Antibodies, Viral
    Sprache Englisch
    Erscheinungsdatum 2023-06-27
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20230668
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Verfügbar in ZB MED Köln/Königswinter

    Ua VI Zs.107: Hefte anzeigen Standort:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 45: Hefte anzeigen

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  8. Artikel ; Online: Pan-sarbecovirus prophylaxis with human anti-ACE2 monoclonal antibodies.

    Zhang, Fengwen / Jenkins, Jesse / de Carvalho, Renan V H / Nakandakari-Higa, Sandra / Chen, Teresia / Abernathy, Morgan E / Baharani, Viren A / Nyakatura, Elisabeth K / Andrew, David / Lebedeva, Irina V / Lorenz, Ivo C / Hoffmann, H-Heinrich / Rice, Charles M / Victora, Gabriel D / Barnes, Christopher O / Hatziioannou, Theodora / Bieniasz, Paul D

    Nature microbiology

    2023  Band 8, Heft 6, Seite(n) 1051–1063

    Abstract: Human monoclonal antibodies (mAbs) that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have been isolated from convalescent individuals and developed into therapeutics for SARS-CoV-2 infection. However, therapeutic ... ...

    Abstract Human monoclonal antibodies (mAbs) that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have been isolated from convalescent individuals and developed into therapeutics for SARS-CoV-2 infection. However, therapeutic mAbs for SARS-CoV-2 have been rendered obsolete by the emergence of mAb-resistant virus variants. Here we report the generation of a set of six human mAbs that bind the human angiotensin-converting enzyme-2 (hACE2) receptor, rather than the SARS-CoV-2 spike protein. We show that these antibodies block infection by all hACE2 binding sarbecoviruses tested, including SARS-CoV-2 ancestral, Delta and Omicron variants at concentrations of ~7-100 ng ml
    Mesh-Begriff(e) Humans ; Animals ; Mice ; Severe acute respiratory syndrome-related coronavirus ; SARS-CoV-2 ; COVID-19/prevention & control ; Antibodies, Monoclonal/pharmacology
    Chemische Substanzen spike protein, SARS-CoV-2 ; Antibodies, Monoclonal
    Sprache Englisch
    Erscheinungsdatum 2023-05-15
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ISSN 2058-5276
    ISSN (online) 2058-5276
    DOI 10.1038/s41564-023-01389-9
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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