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

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

doi:10.1084/jem.20171450

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

Journal Article · 08 May 2018 · Journal of Experimental Medicine

DOI: https://doi.org/10.1084/jem.20171450 · OSTI ID:1505995

^[1]; Hogan, Michael J. ^[1]; Naradikian, Martin S. ^[1];

^[2]; Cain, Derek W. ^[2];

^[2];

^[2]; Verkerke, Hans P. ^[3]; Myles, Arpita ^[1]; Willis, Elinor ^[1];

^[4]; Montefiori, David C. ^[4]; Lobby, Jenna L. ^[1]; Saunders, Kevin O. ^[2];

^[2];

^[5];

^[2];

^[5]; Tombácz, István ^[1] more »

Univ. of Pennsylvania, Philadelphia, PA (United States)
Duke University School of Medicine, Durham, NC (United States)
Univ. of Washington, Seattle, WA (United States)
Duke University Medical Center, Durham, NC (United States)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Acuitas Therapeutics, Vancouver, BC (Canada)
Icahn School of Medicine at Mount Sinai, New York, NY (United States)
BioNTech RNA Pharmaceuticals, Mainz (Germany)
The Children’s Hospital of Philadelphia, Philadelphia, PA (United States)
Bioqual Inc., Rockville, MD (United States)

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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Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: 89233218CNA000001

OSTI ID:: 1505995

Report Number(s):: LA-UR-17-26175

Journal Information:: Journal of Experimental Medicine, Vol. 215, Issue 6; ISSN 0022-1007

Country of Publication:: United States

Language:: English

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Cited by: 276 works

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References (110)

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Induction of virus-specific cytotoxic T lymphocytesin vivo by liposome-entrapped mRNA Martinon, Frédéric; Krishnan, Sivadasan; Lenzen, Gerlinde European Journal of Immunology, Vol. 23, Issue 7 https://doi.org/10.1002/eji.1830230749	journal	July 1993
Designing therapeutic cancer vaccines by mimicking viral infections Sultan, Hussein; Fesenkova, Valentyna I.; Addis, Diane Cancer Immunology, Immunotherapy, Vol. 66, Issue 2 https://doi.org/10.1007/s00262-016-1834-5	journal	April 2016
The use of self-adjuvanting nanofiber vaccines to elicit high-affinity B cell responses to peptide antigens without inflammation Chen, Jianjun; Pompano, Rebecca R.; Santiago, Felix W. Biomaterials, Vol. 34, Issue 34 https://doi.org/10.1016/j.biomaterials.2013.07.063	journal	November 2013
Germinal Center Selection and the Antibody Response to Influenza Victora, Gabriel D.; Wilson, Patrick C. Cell, Vol. 163, Issue 3 https://doi.org/10.1016/j.cell.2015.10.004	journal	October 2015
Modified mRNA Vaccines Protect against Zika Virus Infection Richner, Justin M.; Himansu, Sunny; Dowd, Kimberly A. Cell, Vol. 168, Issue 6 https://doi.org/10.1016/j.cell.2017.02.017	journal	March 2017
Novel universal influenza virus vaccine approaches Krammer, Florian Current Opinion in Virology, Vol. 17 https://doi.org/10.1016/j.coviro.2016.02.002	journal	April 2016
Type I Interferon Signaling in Dendritic Cells Stimulates the Development of Lymph-Node-Resident T Follicular Helper Cells Cucak, Helena; Yrlid, Ulf; Reizis, Boris Immunity, Vol. 31, Issue 3 https://doi.org/10.1016/j.immuni.2009.07.005	journal	September 2009
Human Antibodies that Neutralize HIV-1: Identification, Structures, and B Cell Ontogenies Kwong, Peter D.; Mascola, John R. Immunity, Vol. 37, Issue 3 https://doi.org/10.1016/j.immuni.2012.08.012	journal	September 2012
T Follicular Helper Cell Differentiation, Function, and Roles in Disease Crotty, Shane Immunity, Vol. 41, Issue 4 https://doi.org/10.1016/j.immuni.2014.10.004	journal	October 2014
Skin dendritic cells induce follicular helper T cells and protective humoral immune responses Yao, Chen; Zurawski, Sandra M.; Jarrett, Elizabeth S. Journal of Allergy and Clinical Immunology, Vol. 136, Issue 5 https://doi.org/10.1016/j.jaci.2015.04.001	journal	November 2015
N1-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice Andries, Oliwia; Mc Cafferty, Séan; De Smedt, Stefaan C. Journal of Controlled Release, Vol. 217 https://doi.org/10.1016/j.jconrel.2015.08.051	journal	November 2015
Purification of recombinant vaccinia virus-expressed monomeric HIV-1 gp120 to apparent homogeneity Guo, Wenjin; Cleveland, Brad; Davenport, Thaddeus M. Protein Expression and Purification, Vol. 90, Issue 1 https://doi.org/10.1016/j.pep.2013.04.009	journal	July 2013
Lymphatic-targeted cationic liposomes: A robust vaccine adjuvant for promoting long-term immunological memory Wang, Ce; Liu, Peng; Zhuang, Yan Vaccine, Vol. 32, Issue 42 https://doi.org/10.1016/j.vaccine.2014.07.081	journal	September 2014
Characterization of a thymus-tropic HIV-1 isolate from a rapid progressor: role of the envelope Meissner, Eric G.; Duus, Karen M.; Gao, Feng Virology, Vol. 328, Issue 1 https://doi.org/10.1016/j.virol.2004.07.019	journal	October 2004
Cross-reactive monoclonal antibodies to multiple HIV-1 subtype and SIVcpz envelope glycoproteins Gao, Feng; Scearce, Richard M.; Alam, S. Munir Virology, Vol. 394, Issue 1 https://doi.org/10.1016/j.virol.2009.07.041	journal	November 2009
Immunogenicity and protective efficacy of influenza vaccination Hannoun, Claude; Megas, Francoise; Piercy, James Virus Research, Vol. 103, Issue 1-2 https://doi.org/10.1016/j.virusres.2004.02.025	journal	July 2004
Preclinical and Clinical Demonstration of Immunogenicity by mRNA Vaccines against H10N8 and H7N9 Influenza Viruses Bahl, Kapil; Senn, Joe J.; Yuzhakov, Olga Molecular Therapy, Vol. 25, Issue 6 https://doi.org/10.1016/j.ymthe.2017.03.035	journal	June 2017
Efficient Targeting and Activation of Antigen-Presenting Cells In Vivo after Modified mRNA Vaccine Administration in Rhesus Macaques Liang, Frank; Lindgren, Gustaf; Lin, Ang Molecular Therapy, Vol. 25, Issue 12 https://doi.org/10.1016/j.ymthe.2017.08.006	journal	December 2017
Is there a future for mRNAs as viral vaccines? Warrell, Mary The Lancet, Vol. 390, Issue 10101 https://doi.org/10.1016/s0140-6736(17)31964-5	journal	September 2017
Incorporation of Pseudouridine Into mRNA Yields Superior Nonimmunogenic Vector With Increased Translational Capacity and Biological Stability Karikó, Katalin; Muramatsu, Hiromi; Welsh, Frank A. Molecular Therapy, Vol. 16, Issue 11 https://doi.org/10.1038/mt.2008.200	journal	November 2008
Biodegradable Lipids Enabling Rapidly Eliminated Lipid Nanoparticles for Systemic Delivery of RNAi Therapeutics Maier, Martin A.; Jayaraman, Muthusamy; Matsuda, Shigeo Molecular Therapy, Vol. 21, Issue 8 https://doi.org/10.1038/mt.2013.124	journal	August 2013
Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination Pardi, Norbert; Hogan, Michael J.; Pelc, Rebecca S. Nature, Vol. 543, Issue 7644 https://doi.org/10.1038/nature21428	journal	February 2017
Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs Morrissey, David V.; Lockridge, Jennifer A.; Shaw, Lucinda Nature Biotechnology, Vol. 23, Issue 8 https://doi.org/10.1038/nbt1122	journal	July 2005
Activin A programs the differentiation of human TFH cells Locci, Michela; Wu, Jennifer E.; Arumemi, Fortuna Nature Immunology, Vol. 17, Issue 8 https://doi.org/10.1038/ni.3494	journal	July 2016
mRNA vaccines — a new era in vaccinology Pardi, Norbert; Hogan, Michael J.; Porter, Frederick W. Nature Reviews Drug Discovery, Vol. 17, Issue 4 https://doi.org/10.1038/nrd.2017.243	journal	January 2018
Broadly neutralizing antibodies and the search for an HIV-1 vaccine: the end of the beginning Kwong, Peter D.; Mascola, John R.; Nabel, Gary J. Nature Reviews Immunology, Vol. 13, Issue 9 https://doi.org/10.1038/nri3516	journal	August 2013
Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines Lutz, Johannes; Lazzaro, Sandra; Habbeddine, Mohamed npj Vaccines, Vol. 2, Issue 1 https://doi.org/10.1038/s41541-017-0032-6	journal	October 2017
Affinity maturation in an HIV broadly neutralizing B-cell lineage through reorientation of variable domains Fera, D.; Schmidt, A. G.; Haynes, B. F. Proceedings of the National Academy of Sciences, Vol. 111, Issue 28 https://doi.org/10.1073/pnas.1409954111	journal	June 2014
Sustained antigen availability during germinal center initiation enhances antibody responses to vaccination Tam, Hok Hei; Melo, Mariane B.; Kang, Myungsun Proceedings of the National Academy of Sciences, Vol. 113, Issue 43 https://doi.org/10.1073/pnas.1606050113	journal	October 2016
Progress in developing virus-like particle influenza vaccines Quan, Fu-Shi; Lee, Young-Tae; Kim, Ki-Hye Expert Review of Vaccines, Vol. 15, Issue 10 https://doi.org/10.1080/14760584.2016.1175942	journal	May 2016
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