Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses
T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lip...
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| Published in: | The Journal of experimental medicine Vol. 215; no. 6; p. 1571 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
04.06.2018
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| Subjects: | |
| ISSN: | 1540-9538, 1540-9538 |
| Online Access: | Get more information |
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| Abstract | T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional, antigen-specific, CD4
T cell responses and potent neutralizing antibody responses in mice and nonhuman primates. Importantly, the strong antigen-specific Tfh cell response and high numbers of GC B cells and plasma cells were associated with long-lived and high-affinity neutralizing antibodies and durable protection. Comparative studies demonstrated that nucleoside-modified mRNA-LNP vaccines outperformed adjuvanted protein and inactivated virus vaccines and pathogen infection. The incorporation of noninflammatory, modified nucleosides in the mRNA is required for the production of large amounts of antigen and for robust immune responses. |
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| AbstractList | T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional, antigen-specific, CD4
T cell responses and potent neutralizing antibody responses in mice and nonhuman primates. Importantly, the strong antigen-specific Tfh cell response and high numbers of GC B cells and plasma cells were associated with long-lived and high-affinity neutralizing antibodies and durable protection. Comparative studies demonstrated that nucleoside-modified mRNA-LNP vaccines outperformed adjuvanted protein and inactivated virus vaccines and pathogen infection. The incorporation of noninflammatory, modified nucleosides in the mRNA is required for the production of large amounts of antigen and for robust immune responses. T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional, antigen-specific, CD4+ T cell responses and potent neutralizing antibody responses in mice and nonhuman primates. Importantly, the strong antigen-specific Tfh cell response and high numbers of GC B cells and plasma cells were associated with long-lived and high-affinity neutralizing antibodies and durable protection. Comparative studies demonstrated that nucleoside-modified mRNA-LNP vaccines outperformed adjuvanted protein and inactivated virus vaccines and pathogen infection. The incorporation of noninflammatory, modified nucleosides in the mRNA is required for the production of large amounts of antigen and for robust immune responses.T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional, antigen-specific, CD4+ T cell responses and potent neutralizing antibody responses in mice and nonhuman primates. Importantly, the strong antigen-specific Tfh cell response and high numbers of GC B cells and plasma cells were associated with long-lived and high-affinity neutralizing antibodies and durable protection. Comparative studies demonstrated that nucleoside-modified mRNA-LNP vaccines outperformed adjuvanted protein and inactivated virus vaccines and pathogen infection. The incorporation of noninflammatory, modified nucleosides in the mRNA is required for the production of large amounts of antigen and for robust immune responses. |
| Author | Li, Charles Hensley, Scott E Cain, Derek W Lee, Kelly K Krammer, Florian Tombácz, István Hogan, Michael J Haynes, Barton F Madden, Thomas D Cancro, Michael P Eisenlohr, Laurence C Verkerke, Hans P Scearce, Richard M Muramatsu, Hiromi Myles, Arpita LaBranche, Celia C Pardi, Norbert Korber, Bette T Lobby, Jenna L Moody, M Anthony Liao, Hua-Xin Willis, Elinor Saunders, Kevin O Tam, Ying K Hope, Michael J Hraber, Peter T Karikó, Katalin Naradikian, Martin S Lewis, Mark G Sutherland, Laura L Mui, Barbara L Polacino, Patricia Parkhouse, Kaela Weissman, Drew Ni, Houping Balikov, Daniel A Jones, Letitia Montefiori, David C Hu, Shiu-Lok |
| Author_xml | – sequence: 1 givenname: Norbert orcidid: 0000-0003-1008-6242 surname: Pardi fullname: Pardi, Norbert email: pnorbert@pennmedicine.upenn.edu organization: Department of Medicine, University of Pennsylvania, Philadelphia, PA pnorbert@pennmedicine.upenn.edu – sequence: 2 givenname: Michael J surname: Hogan fullname: Hogan, Michael J organization: Department of Medicine, University of Pennsylvania, Philadelphia, PA – sequence: 3 givenname: Martin S surname: Naradikian fullname: Naradikian, Martin S organization: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA – sequence: 4 givenname: Kaela orcidid: 0000-0001-7608-4464 surname: Parkhouse fullname: Parkhouse, Kaela organization: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA – sequence: 5 givenname: Derek W surname: Cain fullname: Cain, Derek W organization: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC – sequence: 6 givenname: Letitia orcidid: 0000-0002-1889-5629 surname: Jones fullname: Jones, Letitia organization: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC – sequence: 7 givenname: M Anthony orcidid: 0000-0002-3890-5855 surname: Moody fullname: Moody, M Anthony organization: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC – sequence: 8 givenname: Hans P surname: Verkerke fullname: Verkerke, Hans P organization: Department of Medicinal Chemistry, University of Washington, Seattle, WA – sequence: 9 givenname: Arpita surname: Myles fullname: Myles, Arpita organization: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA – sequence: 10 givenname: Elinor surname: Willis fullname: Willis, Elinor organization: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA – sequence: 11 givenname: Celia C orcidid: 0000-0002-6653-6655 surname: LaBranche fullname: LaBranche, Celia C organization: Department of Surgery, Duke University Medical Center, Durham, NC – sequence: 12 givenname: David C surname: Montefiori fullname: Montefiori, David C organization: Department of Surgery, Duke University Medical Center, Durham, NC – sequence: 13 givenname: Jenna L surname: Lobby fullname: Lobby, Jenna L organization: Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA – sequence: 14 givenname: Kevin O surname: Saunders fullname: Saunders, Kevin O organization: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC – sequence: 15 givenname: Hua-Xin orcidid: 0000-0002-7871-1334 surname: Liao fullname: Liao, Hua-Xin organization: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC – sequence: 16 givenname: Bette T orcidid: 0000-0002-2026-5757 surname: Korber fullname: Korber, Bette T organization: Los Alamos National Laboratory, Los Alamos, NM – sequence: 17 givenname: Laura L orcidid: 0000-0003-4119-3884 surname: Sutherland fullname: Sutherland, Laura L organization: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC – sequence: 18 givenname: Richard M orcidid: 0000-0002-6361-3758 surname: Scearce fullname: Scearce, Richard M organization: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC – sequence: 19 givenname: Peter T orcidid: 0000-0002-2920-4897 surname: Hraber fullname: Hraber, Peter T organization: Los Alamos National Laboratory, Los Alamos, NM – sequence: 20 givenname: István surname: Tombácz fullname: Tombácz, István organization: Department of Medicine, University of Pennsylvania, Philadelphia, PA – sequence: 21 givenname: Hiromi surname: Muramatsu fullname: Muramatsu, Hiromi organization: Department of Medicine, University of Pennsylvania, Philadelphia, PA – sequence: 22 givenname: Houping surname: Ni fullname: Ni, Houping organization: Department of Medicine, University of Pennsylvania, Philadelphia, PA – sequence: 23 givenname: Daniel A orcidid: 0000-0003-0392-5087 surname: Balikov fullname: Balikov, Daniel A organization: Department of Medicine, University of Pennsylvania, Philadelphia, PA – sequence: 24 givenname: Charles surname: Li fullname: Li, Charles organization: Department of Medicine, University of Pennsylvania, Philadelphia, PA – sequence: 25 givenname: Barbara L surname: Mui fullname: Mui, Barbara L organization: Acuitas Therapeutics, Vancouver, BC, Canada – sequence: 26 givenname: Ying K surname: Tam fullname: Tam, Ying K organization: Acuitas Therapeutics, Vancouver, BC, Canada – sequence: 27 givenname: Florian orcidid: 0000-0003-4121-776X surname: Krammer fullname: Krammer, Florian organization: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY – sequence: 28 givenname: Katalin orcidid: 0000-0002-1864-3851 surname: Karikó fullname: Karikó, Katalin organization: BioNTech RNA Pharmaceuticals, Mainz, Germany – sequence: 29 givenname: Patricia surname: Polacino fullname: Polacino, Patricia organization: Washington National Primate Research Center, University of Washington, Seattle, WA – sequence: 30 givenname: Laurence C surname: Eisenlohr fullname: Eisenlohr, Laurence C organization: Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA – sequence: 31 givenname: Thomas D surname: Madden fullname: Madden, Thomas D organization: Acuitas Therapeutics, Vancouver, BC, Canada – sequence: 32 givenname: Michael J surname: Hope fullname: Hope, Michael J organization: Acuitas Therapeutics, Vancouver, BC, Canada – sequence: 33 givenname: Mark G surname: Lewis fullname: Lewis, Mark G organization: Bioqual Inc., Rockville, MD – sequence: 34 givenname: Kelly K surname: Lee fullname: Lee, Kelly K organization: Department of Medicinal Chemistry, University of Washington, Seattle, WA – sequence: 35 givenname: Shiu-Lok surname: Hu fullname: Hu, Shiu-Lok organization: Department of Pharmaceutics, University of Washington, Seattle, WA – sequence: 36 givenname: Scott E surname: Hensley fullname: Hensley, Scott E organization: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA – sequence: 37 givenname: Michael P surname: Cancro fullname: Cancro, Michael P organization: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA – sequence: 38 givenname: Barton F orcidid: 0000-0002-7643-9023 surname: Haynes fullname: Haynes, Barton F organization: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC – sequence: 39 givenname: Drew orcidid: 0000-0002-1501-6510 surname: Weissman fullname: Weissman, Drew email: dreww@pennmedicine.upenn.edu organization: Department of Medicine, University of Pennsylvania, Philadelphia, PA dreww@pennmedicine.upenn.edu |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29739835$$D View this record in MEDLINE/PubMed |
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| Snippet | T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and... |
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| SubjectTerms | Adjuvants, Immunologic - pharmacology Animals Antibodies, Neutralizing - immunology Antibody Formation - immunology Antigens - metabolism B-Lymphocytes - immunology Germinal Center - cytology Lipids - chemistry Macaca mulatta Nanoparticles - chemistry Nucleosides - metabolism Protein Subunits - metabolism RNA, Messenger - metabolism T-Lymphocytes, Helper-Inducer - immunology Time Factors Vaccination Vaccines, Subunit - immunology |
| Title | Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses |
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