Immune response genes at the mRNA vaccine delivery sites and draining lymph nodes of rhesus macaques. Macaca mulatta

mRNA vaccines are emerging as a powerful vaccine platform as they are well-tolerated and scalable. Modified non-replicating mRNA encoding Influenza hemagglutinin and encapsulated in lipid nanoparticles (LNP) induced robust antibody and CD4 T cell responses after intramuscular or intradermal delivery in rhesus macaques. We investigated the local innate immune responses modulating such vaccine-induced immunity at the sites of immunization (skeletal muscle and skin) and their draining lymph nodes (LNs). Rapid mobilization of antigen presenting cells was found at the LNP/mRNA-injection sites and LNs. Dendritic cells efficiently internalized the LNPs, translated the mRNA cargo and upregulated co-stimulatory molecules. In addition, several type I interferon-inducible genes were expressed at the immunization sites and draining LNs. The innate immune activation was transient and resulted in priming of antigen-specific CD4+ T cells exclusively in the vaccine-draining LNs. Collectively, mRNA-based vaccines induce type I interferon-polarized innate immunity and antigen production by antigen presenting cells, which resulted potent vaccine-specific responses. Overall design: Two groups of rhesus macaques (n=4/group) receiving either intramuscular (I.M.) or intradermal (I.D.) injection of lipid nanoparticle (LNP)-encapsulated mRNA vaccine plus a saline control injection given at a different site on the same animal. Injection site biopsies and draining lymph nodes from I.M. and I.D. group were collected for gene expression analysis.