Bioactive enhanced adjuvant chemokine oligonucleotide nanoparticles (BEACONs) for mucosal vaccination against genital...

Genital herpes, caused by herpes simplex virus 2 (HSV-2), remains a prevalent sexually transmitted infection with no available vaccine. Effective local immunity, mediated in part by tissue-resident memory T cells (T_RM cells) and luminal antibodies, provides immediate viral control. Here, we developed bioactive enhanced adjuvant chemokine oligonucleotide nanoparticles (BEACONs) formed via electrostatic interactions between CpG oligodeoxynucleotides (CpG ODNs) and the chemokine CXCL9. This adjuvant enhances antigen-presenting cell engagement and innate immune signaling, promotes CD8 T cell recruitment, and reduces local neutrophilic inflammation relative to CpG ODNs. After intramuscular priming with HSV-2 glycoprotein-encoding messenger RNA-lipid nanoparticles, vaginal boosting with cognate recombinant glycoprotein and BEACONs improved protection against HSV-2 by increasing local CD8 T_RM cell populations and mucosal antibody responses. Vaccine-mediated protection required local delivery of both antigen and adjuvant and was reduced by CD8 T cell or B cell depletion. These findings support engineered mucosal adjuvants for vaccines targeting genital herpes and other sexually transmitted infections.