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.
