Benjamin J. Read
While nanoparticles have been explored as multivalent delivery vehicles for vaccines for some time, their frequently observed inability to efficiently enter lymph node follicles likely inhibits optimal B cell activation and decreases the immunological benefit associated with immunizing with a multimerized antigen. We evaluated the fates of two different heavily glycosylated HIV antigen nanoparticles, germline-targeting gp120 engineered outer domain fused on lumazine synthase (eOD-60mer) and a stabilized HIV envelope trimer fused on ferritin (MD39-8mer), which seem to break from this paradigm. While monomeric formulations of these antigens appeared diffuse throughout the draining lymph nodes seven days after immunization by confocal microscopy, the nanoparticulate antigens heavily localized to the follicular dendritic cell (FDC) network. Studies in C3- and Cr1/2-deficient mice determined that these complement components are required for trafficking to FDCs to occur, and subsequent studies in mannose-binding lectin (MBL)-deficient mice revealed that the follicular trafficking was dependent on this family of proteins. Trafficking of deglycosylated eOD-60mer in wild-type mice was similarly reduced, indicating that MBL recognition of immunogen glycans facilitates a complement driven pathway that deposits multivalent immunogens on FDCs. Furthermore, follicular trafficking was directly correlated with immune response robustness, suggesting enhanced delivery to follicles can enhance immunogen efficacy. This glycan-dependent trafficking mechanism was found to be independent of the presence of antigen and nanoparticle composition through the evaluation of the trafficking of a variety of synthetically mannosylated nanoparticles. These findings identify a novel innate immune-mediated trafficking pathway for enhancing particulate antigen delivery and promoting antibody responses, with broad implications for humoral immunity and vaccine design.