Delivering HIV-1 Envelope trimers through the targeting of Langerin induces early and broad immunogenicity

Despite the conduct of several phase 2b/3 studies of various HIV vaccines, a protective HIV vaccine is still lacking. One challenge is the development of innovative delivery strategies of adapted immunogens. We developed an Antibody-Mediated Vaccine (AMV) platform targeting HIV antigens to Langerhans cells (LCs) using an anti-Langerin mAb fused to either trimeric Env constructs (LC3.Env3) or BG505 SOSIP.664 (LC3.SOSIP), and demonstrated herein, that targeting antigen presenting cells, particularly LCs in the skin, offer promise. We showed that intra-dermal LC3.Env3 immunizations in mice enhanced Env-specific GC B cell expansion, increased IgG avidity, structured GC formation, and long-lasting immunity as compared to non-targeted Env antigens. LC3.Env3 and LC3.SOSIP, without adjuvant, led to robust Env-specific IgG and neutralizing antibody (NeutAb) production. These findings highlight LC-mediated delivery as a powerful tool to enhance humoral immunity, presenting a promising direction for advancing HIV vaccines through targeted skin-based immunization strategies.