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Title: Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses

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.

Authors:
ORCiD logo [1];  [1];  [1]; ORCiD logo [2];  [2]; ORCiD logo [2]; ORCiD logo [2];  [3];  [1];  [1]; ORCiD logo [4];  [4];  [1];  [2]; ORCiD logo [2]; ORCiD logo [5]; ORCiD logo [2]; ORCiD logo [2]; ORCiD logo [5];  [1] more »;  [1];  [1]; ORCiD logo [1];  [1];  [6];  [6]; ORCiD logo [7]; ORCiD logo [8];  [3];  [9];  [6];  [6];  [10];  [3];  [3];  [1];  [1]; ORCiD logo [2]; ORCiD logo [1] « less
  1. Univ. of Pennsylvania, Philadelphia, PA (United States)
  2. Duke University School of Medicine, Durham, NC (United States)
  3. Univ. of Washington, Seattle, WA (United States)
  4. Duke University Medical Center, Durham, NC (United States)
  5. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  6. Acuitas Therapeutics, Vancouver, BC (Canada)
  7. Icahn School of Medicine at Mount Sinai, New York, NY (United States)
  8. BioNTech RNA Pharmaceuticals, Mainz (Germany)
  9. The Children’s Hospital of Philadelphia, Philadelphia, PA (United States)
  10. Bioqual Inc., Rockville, MD (United States)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH)
OSTI Identifier:
1505995
Report Number(s):
LA-UR-17-26175
Journal ID: ISSN 0022-1007
Grant/Contract Number:  
89233218CNA000001
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Experimental Medicine
Additional Journal Information:
Journal Volume: 215; Journal Issue: 6; Journal ID: ISSN 0022-1007
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Pardi, Norbert, Hogan, Michael J., Naradikian, Martin S., Parkhouse, Kaela, Cain, Derek W., Jones, Letitia, Moody, M. Anthony, Verkerke, Hans P., Myles, Arpita, Willis, Elinor, LaBranche, Celia C., Montefiori, David C., Lobby, Jenna L., Saunders, Kevin O., Liao, Hua-Xin, Korber, Bette T., Sutherland, Laura L., Scearce, Richard M., Hraber, Peter T., Tombácz, István, Muramatsu, Hiromi, Ni, Houping, Balikov, Daniel A., Li, Charles, Mui, Barbara L., Tam, Ying K., Krammer, Florian, Karikó, Katalin, Polacino, Patricia, Eisenlohr, Laurence C., Madden, Thomas D., Hope, Michael J., Lewis, Mark G., Lee, Kelly K., Hu, Shiu-Lok, Hensley, Scott E., Cancro, Michael P., Haynes, Barton F., and Weissman, Drew. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. United States: N. p., 2018. Web. doi:10.1084/jem.20171450.
Pardi, Norbert, Hogan, Michael J., Naradikian, Martin S., Parkhouse, Kaela, Cain, Derek W., Jones, Letitia, Moody, M. Anthony, Verkerke, Hans P., Myles, Arpita, Willis, Elinor, LaBranche, Celia C., Montefiori, David C., Lobby, Jenna L., Saunders, Kevin O., Liao, Hua-Xin, Korber, Bette T., Sutherland, Laura L., Scearce, Richard M., Hraber, Peter T., Tombácz, István, Muramatsu, Hiromi, Ni, Houping, Balikov, Daniel A., Li, Charles, Mui, Barbara L., Tam, Ying K., Krammer, Florian, Karikó, Katalin, Polacino, Patricia, Eisenlohr, Laurence C., Madden, Thomas D., Hope, Michael J., Lewis, Mark G., Lee, Kelly K., Hu, Shiu-Lok, Hensley, Scott E., Cancro, Michael P., Haynes, Barton F., & Weissman, Drew. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. United States. doi:10.1084/jem.20171450.
Pardi, Norbert, Hogan, Michael J., Naradikian, Martin S., Parkhouse, Kaela, Cain, Derek W., Jones, Letitia, Moody, M. Anthony, Verkerke, Hans P., Myles, Arpita, Willis, Elinor, LaBranche, Celia C., Montefiori, David C., Lobby, Jenna L., Saunders, Kevin O., Liao, Hua-Xin, Korber, Bette T., Sutherland, Laura L., Scearce, Richard M., Hraber, Peter T., Tombácz, István, Muramatsu, Hiromi, Ni, Houping, Balikov, Daniel A., Li, Charles, Mui, Barbara L., Tam, Ying K., Krammer, Florian, Karikó, Katalin, Polacino, Patricia, Eisenlohr, Laurence C., Madden, Thomas D., Hope, Michael J., Lewis, Mark G., Lee, Kelly K., Hu, Shiu-Lok, Hensley, Scott E., Cancro, Michael P., Haynes, Barton F., and Weissman, Drew. Tue . "Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses". United States. doi:10.1084/jem.20171450. https://www.osti.gov/servlets/purl/1505995.
@article{osti_1505995,
title = {Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses},
author = {Pardi, Norbert and Hogan, Michael J. and Naradikian, Martin S. and Parkhouse, Kaela and Cain, Derek W. and Jones, Letitia and Moody, M. Anthony and Verkerke, Hans P. and Myles, Arpita and Willis, Elinor and LaBranche, Celia C. and Montefiori, David C. and Lobby, Jenna L. and Saunders, Kevin O. and Liao, Hua-Xin and Korber, Bette T. and Sutherland, Laura L. and Scearce, Richard M. and Hraber, Peter T. and Tombácz, István and Muramatsu, Hiromi and Ni, Houping and Balikov, Daniel A. and Li, Charles and Mui, Barbara L. and Tam, Ying K. and Krammer, Florian and Karikó, Katalin and Polacino, Patricia and Eisenlohr, Laurence C. and Madden, Thomas D. and Hope, Michael J. and Lewis, Mark G. and Lee, Kelly K. and Hu, Shiu-Lok and Hensley, Scott E. and Cancro, Michael P. and Haynes, Barton F. and Weissman, Drew},
abstractNote = {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.},
doi = {10.1084/jem.20171450},
journal = {Journal of Experimental Medicine},
number = 6,
volume = 215,
place = {United States},
year = {2018},
month = {5}
}

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