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

Journal Article · · Journal of Experimental Medicine
DOI:https://doi.org/10.1084/jem.20171450· OSTI ID:1505995
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  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)

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.

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
Citation Metrics:
Cited by: 230 works
Citation information provided by
Web of Science

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Genetic programming of macrophages to perform anti-tumor functions using targeted mRNA nanocarriers journal September 2019
The promise of mRNA vaccines: a biotech and industrial perspective journal February 2020
Immunological basis for enhanced immunity of nanoparticle vaccines journal February 2019
Strategies for inducing effective neutralizing antibody responses against HIV-1 journal November 2019
Evaluation of a Single-Dose Nucleoside-Modified Messenger RNA Vaccine Encoding Hendra Virus-Soluble Glycoprotein Against Lethal Nipah virus Challenge in Syrian Hamsters journal November 2019
Nucleoside-modified mRNA encoding HSV-2 glycoproteins C, D, and E prevents clinical and subclinical genital herpes journal September 2019
Nucleoside-modified mRNA vaccination partially overcomes maternal antibody inhibition of de novo immune responses in mice journal January 2020
Assessing the Protective Potential of H1N1 Influenza Virus Hemagglutinin Head and Stalk Antibodies in Humans journal January 2019
Advances in mRNA Vaccines for Infectious Diseases journal March 2019
Protective Efficacy of Nucleic Acid Vaccines Against Transmission of Zika Virus During Pregnancy in Mice journal July 2019
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An mRNA Vaccine Protects Mice against Multiple Tick-Transmitted Flavivirus Infections journal December 2018
Characterization of HIV-1 Nucleoside-Modified mRNA Vaccines in Rabbits and Rhesus Macaques journal April 2019
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Harnessing T Follicular Helper Cell Responses for HIV Vaccine Development journal June 2018
Immunizing the Immune: Can We Overcome Influenza’s Most Formidable Challenge? journal September 2018
Enlisting the mRNA Vaccine Platform to Combat Parasitic Infections journal September 2019