Nanoparticle immunoadjuvant complexes augment antigen-specific germinal center responses and enhance humoral immunity

An alluring strategy for improving protective humoral immunity against infectious diseases would be to directly target the germinal center (GC). There remains a critical need for next generation vaccine approaches to elicit more potent GC responses and durable humoral immunity. Here, we investigated whether cytokines could be scaffolded on nanoparticles to further enhance antigen-specific GC responses. We designed a chimeric nanoparticle using the GT8-60mer, a germline-targeting HIV immunogen, as a model to scaffold IL-21. Nanoparticle immunoadjuvant complexes (NICs) scaffolding GT8 and IL-21 (GT8-IL-21-NIC) drove improved serum antibody titers, antigen-specific GC B cells, and functional Tfh cell responses relative to antigen-only nanoparticles and to co-delivery of IL-21 monomer. Single-cell RNA sequencing of antigen-specific GC B cells from GT8-IL-21-NIC immunized mice demonstrated upregulation of LZ and selection-associated gene signatures. The NIC platform was versatile and could support changes to both the antigen and cytokine domains utilizing numerous GC-associated cytokines. Thus, NICs may provide value as a tool to improve antigen-specific vaccine-induced immunity. Overall design: Single Cell RNA-Seq of antigen-specific germinal center B cells sorted from lymph nodes of mice immunized with a DNA-launched nanoparticle vaccine or DNA-launched nanoparticle immunoadjvuant complex (NIC)