Bioactive Enhanced Adjuvant Chemokine Oligonucleotide Nanoparticles (BEACONs) for Mucosal Vaccination Against Genital Herpes

Genital herpes, caused primarily by herpes simplex virus-2 (HSV-2), remains a highly prevalent sexually transmitted infection with no available vaccine. Previous intramuscular vaccination strategies have failed to protect against HSV-2 infections due to their inability to induce robust local immunity and activate resident memory T cells (Trm cells). The approach known as "prime and pull", whereby host animals are primed with vaccines intramuscularly followed by vaginal delivery of specific chemokines to facilitate the recruitment of effector T cells (i.e., "pull"), confers partial protection against genital HSV-2 disease. However, this strategy fails to prevent infection or establish B cell-mediated immunity. Here, we introduce Bioactive Enhanced Adjuvant Chemokine Oligonucleotide Nanoparticles (BEACONs) formed via electrostatic interactions between CpG DNA and the chemokine CXCL9. This dual-function adjuvant promotes CD8+ T cell recruitment and enhances innate immune activation while reducing non-specific local inflammation. When co-administered vaginally with HSV-2 glycoproteins following intramuscular priming, BEACONs significantly improved protection against HSV by increasing local CD8+ Trm populations and augmenting mucosal IgG and IgA responses. Optimal immune protection required delivery of both local antigen and adjuvant delivery, as neither intramuscular boosting nor introduction of the vaginal adjuvant alone conferred comparable efficacy. Moreover, CD8+ T cell or B cell depletion led to a significant reduction in immune protection conferred by the BEACON-based "pull" strategy. Collectively, these findings highlight the potential of engineered mucosal adjuvants as a means to coordinate local T and B cell responses and offer a promising approach for vaccines targeting genital herpes and other sexually transmitted infections.