Resurfaced ZIKV EDIII nanoparticle immunogens elicit neutralizing and protective responses in vivo
Copyright © 2022 Elsevier Ltd. All rights reserved..
Zika virus (ZIKV) is a flavivirus that can cause severe disease, but there are no approved treatments or vaccines. A complication for flavivirus vaccine development is the potential of immunogens to enhance infection via antibody-dependent enhancement (ADE), a process mediated by poorly neutralizing and cross-reactive antibodies. Thus, there is a great need to develop immunogens that minimize the potential to elicit enhancing antibodies. Here we utilized structure-based protein engineering to develop "resurfaced" (rs) ZIKV immunogens based on E glycoprotein domain III (ZDIIIs), in which epitopes bound by variably neutralizing antibodies were masked by combinatorial mutagenesis. We identified one resurfaced ZDIII immunogen (rsZDIII-2.39) that elicited a protective but immune-focused response. Compared to wild type ZDIII, immunization with resurfaced rsZDIII-2.39 protein nanoparticles produced fewer numbers of ZIKV EDIII antigen-reactive B cells and elicited serum that had a lower magnitude of induced ADE against dengue virus serotype 1 (DENV1) Our findings enhance our understanding of the structural and functional determinants of antibody protection against ZIKV.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:29 |
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| Enthalten in: |
Cell chemical biology - 29(2022), 5 vom: 19. Mai, Seite 811-823.e7 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Georgiev, George I [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.05.2022 Date Revised 20.05.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.chembiol.2022.02.004 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM337627061 |
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| 100 | 1 | |a Georgiev, George I |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Resurfaced ZIKV EDIII nanoparticle immunogens elicit neutralizing and protective responses in vivo |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Revised 20.05.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 Elsevier Ltd. All rights reserved. | ||
| 520 | |a Zika virus (ZIKV) is a flavivirus that can cause severe disease, but there are no approved treatments or vaccines. A complication for flavivirus vaccine development is the potential of immunogens to enhance infection via antibody-dependent enhancement (ADE), a process mediated by poorly neutralizing and cross-reactive antibodies. Thus, there is a great need to develop immunogens that minimize the potential to elicit enhancing antibodies. Here we utilized structure-based protein engineering to develop "resurfaced" (rs) ZIKV immunogens based on E glycoprotein domain III (ZDIIIs), in which epitopes bound by variably neutralizing antibodies were masked by combinatorial mutagenesis. We identified one resurfaced ZDIII immunogen (rsZDIII-2.39) that elicited a protective but immune-focused response. Compared to wild type ZDIII, immunization with resurfaced rsZDIII-2.39 protein nanoparticles produced fewer numbers of ZIKV EDIII antigen-reactive B cells and elicited serum that had a lower magnitude of induced ADE against dengue virus serotype 1 (DENV1) Our findings enhance our understanding of the structural and functional determinants of antibody protection against ZIKV | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a DENV | |
| 650 | 4 | |a ZIKV | |
| 650 | 4 | |a combinatorial mutagenesis | |
| 650 | 4 | |a flavivirus | |
| 650 | 4 | |a immune focusing | |
| 650 | 4 | |a immunogen resurfacing | |
| 650 | 4 | |a nanoparticle | |
| 650 | 4 | |a phage display | |
| 650 | 4 | |a protein engineering | |
| 650 | 4 | |a vaccine | |
| 650 | 7 | |a Antibodies, Neutralizing |2 NLM | |
| 650 | 7 | |a Antibodies, Viral |2 NLM | |
| 650 | 7 | |a Viral Envelope Proteins |2 NLM | |
| 700 | 1 | |a Malonis, Ryan J |e verfasserin |4 aut | |
| 700 | 1 | |a Wirchnianski, Ariel S |e verfasserin |4 aut | |
| 700 | 1 | |a Wessel, Alex W |e verfasserin |4 aut | |
| 700 | 1 | |a Jung, Helen S |e verfasserin |4 aut | |
| 700 | 1 | |a Cahill, Sean M |e verfasserin |4 aut | |
| 700 | 1 | |a Nyakatura, Elisabeth K |e verfasserin |4 aut | |
| 700 | 1 | |a Vergnolle, Olivia |e verfasserin |4 aut | |
| 700 | 1 | |a Dowd, Kimberly A |e verfasserin |4 aut | |
| 700 | 1 | |a Cowburn, David |e verfasserin |4 aut | |
| 700 | 1 | |a Pierson, Theodore C |e verfasserin |4 aut | |
| 700 | 1 | |a Diamond, Michael S |e verfasserin |4 aut | |
| 700 | 1 | |a Lai, Jonathan R |e verfasserin |4 aut | |
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