Nanoparticle Immunoadjuvant Complexes Augment Germinal Center Responses to Vaccination

ABSTRACT Vaccine approaches capable of eliciting enhanced germinal center (GC) responses would result in improved protective humoral immunity against infectious diseases. Here, we investigate whether a cytokine can be scaffolded onto a self‐assembling nanoparticle immunogen to enhance antigen‐specific GC responses and B cell maturation. To test this approach, we design chimeric nanoparticles bearing eOD‐GT8, a germline‐targeting HIV immunogen, and IL‐21, a canonical GC cytokine. DNA delivery of these nanoparticle immunoadjuvant complexes (GT8‐IL‐21‐NICs) drives improved serum antibody titers and antigen‐specific GC B cell responses in mice. Transcriptomic analysis of eOD‐GT8‐specific GC B cells demonstrates upregulation of selection‐associated gene signatures with GT8‐IL‐21‐NIC immunization. In mice harboring human bnAb precursor heavy and light chain genes, immunization with the GT8‐IL‐21‐NIC leads to increased antibody diversity, clonal expansion, somatic hypermutation, and the acquisition of key antibody mutations. These results highlight IL‐21 as a promising genetic adjuvant and demonstrate that NICs may be a valuable tool to improve antigen‐specific GC responses and vaccine‐induced immunity.