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J Exp Med. 2018 Jun 4;215(6):1571-1588. doi: 10.1084/jem.20171450. Epub 2018 May 8.

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

Author information

1
Department of Medicine, University of Pennsylvania, Philadelphia, PA pnorbert@pennmedicine.upenn.edu.
2
Department of Medicine, University of Pennsylvania, Philadelphia, PA.
3
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
4
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
5
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC.
6
Department of Medicinal Chemistry, University of Washington, Seattle, WA.
7
Department of Surgery, Duke University Medical Center, Durham, NC.
8
Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA.
9
Los Alamos National Laboratory, Los Alamos, NM.
10
Acuitas Therapeutics, Vancouver, BC, Canada.
11
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY.
12
BioNTech RNA Pharmaceuticals, Mainz, Germany.
13
Washington National Primate Research Center, University of Washington, Seattle, WA.
14
Bioqual Inc., Rockville, MD.
15
Department of Pharmaceutics, University of Washington, Seattle, WA.
16
Department of Medicine, University of Pennsylvania, Philadelphia, PA dreww@pennmedicine.upenn.edu.

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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