Efficient Targeting and Activation of Antigen-Presenting Cells In Vivo after Modified mRNA Vaccine Administration in Rhesus Macaques

mRNA vaccines are rapidly emerging as a powerful platform for infectious diseases because they are well tolerated, immunogenic, and scalable and are built on precise but adaptable antigen design. We show that two immunizations of modified non-replicating mRNA encoding influenza H10 hemagglutinin (HA...

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Bibliographic Details
Published in:	Molecular therapy Vol. 25; no. 12; pp. 2635 - 2647
Main Authors:	Liang, Frank, Lindgren, Gustaf, Lin, Ang, Thompson, Elizabeth A., Ols, Sebastian, Röhss, Josefine, John, Shinu, Hassett, Kimberly, Yuzhakov, Olga, Bahl, Kapil, Brito, Luis A., Salter, Hugh, Ciaramella, Giuseppe, Loré, Karin
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 06-12-2017 Elsevier Limited American Society of Gene & Cell Therapy
Subjects:	Animals Antigen-presenting cells Antigen-Presenting Cells - immunology Antigen-Presenting Cells - metabolism Antigens CD4 antigen CD80 antigen CD86 antigen Cell activation Combined vaccines Conflicts of interest CXCL10 protein Cytokines - metabolism Dendritic cells Deoxyribonucleic acid DNA Gene Expression Hemagglutinins Immunization Immunogenicity Immunophenotyping Infectious diseases Influenza Influenza Vaccines - immunology Injections, Intradermal Innate immunity Interferon Laboratories Leukocytes (neutrophilic) Lymph nodes Lymph Nodes - immunology Lymph Nodes - metabolism Lymphocytes Lymphocytes T Macaca mulatta Manufacturers Medicin och hälsovetenskap Monocytes mRNA mRNA vaccines Nanoparticles nonhuman primates Original Pandemics Phenotype RNA, Messenger - genetics RNA, Messenger - immunology Software Statistical analysis T-Lymphocytes - immunology T-Lymphocytes - metabolism Tumor necrosis factor-TNF Vaccines Vaccines - administration & dosage Vaccines - immunology United States > US mRNA vaccines antigen-presenting cells nonhuman primates
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Summary:	mRNA vaccines are rapidly emerging as a powerful platform for infectious diseases because they are well tolerated, immunogenic, and scalable and are built on precise but adaptable antigen design. We show that two immunizations of modified non-replicating mRNA encoding influenza H10 hemagglutinin (HA) and encapsulated in lipid nanoparticles (LNP) induce protective HA inhibition titers and H10-specific CD4+ T cell responses after intramuscular or intradermal delivery in rhesus macaques. Administration of LNP/mRNA induced rapid and local infiltration of neutrophils, monocytes, and dendritic cells (DCs) to the site of administration and the draining lymph nodes (LNs). While these cells efficiently internalized LNP, mainly monocytes and DCs translated the mRNA and upregulated key co-stimulatory receptors (CD80 and CD86). This coincided with upregulation of type I IFN-inducible genes, including MX1 and CXCL10. The innate immune activation was transient and resulted in priming of H10-specific CD4+ T cells exclusively in the vaccine-draining LNs. Collectively, this demonstrates that mRNA-based vaccines induce type-I IFN-polarized innate immunity and, when combined with antigen production by antigen-presenting cells, lead to generation of potent vaccine-specific responses. mRNA vaccines have been proven to be suitable and efficient against pandemic pathogens. However, the immune processes after mRNA vaccination that lead to robust responses remain elusive. Now in Molecular Therapy, Liang et al. (2017) define the target cells and immune responses at the vaccination sites and in the lymph nodes that result in vaccine immunity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1525-0016 1525-0024 1525-0024
DOI:	10.1016/j.ymthe.2017.08.006