Bioactive Enhanced Adjuvant Chemokine Oligonucleotide Nanoparticles (BEACON) for Mucosal Vaccination Against Genital Herpes 2307637

Abstract Introduction Genital herpes (caused primarily by herpes simplex virus 2 [HSV-2]) remains highly prevalent with no licensed vaccine, in part because intramuscular vaccines are unable to generate robust induction of vaginal tissue-resident memory T cells (Trm) and mucosal antibodies. Our previous strategy of “Prime and Pull”, namely, priming with a conventional intramuscular vaccine followed by vaginal chemokine application to pull effector T cells, confers protection against disease but not infection. Thus, we developed Bioactive Enhanced Adjuvant Chemokine Oligonucleotide Nanoparticles (BEACON) as a mucosal adjuvant to promote vaginal immunity and reduce viral burden and disease. Methods CXCL9 and CpG DNA were electrostatically assembled into nanoparticles to create BEACON, and assessed in vitro for chemotaxis and innate immune activation. Female mice were primed intramuscularly (i.m.) with HSV glycoprotein D (gD) mRNA-LNPs and boosted i.m. or intravaginally with gD and BEACON. Vaginal inflammation and CpG uptake, Trm, gD-specific serum and vaginal IgG/IgA, viral shedding/dorsal root ganglion (DRG) viral DNA, and survival after lethal genital HSV-2 challenge were quantified. Results Compared with free CpG, BEACON increased CpG uptake by vaginal APCs (∼10-fold) and reduced neutrophil uptake and local inflammation. Intravaginal glycoprotein plus BEACON given to mice previously immunized with mRNA vaccine uniquely expanded vaginal HSV-specific CD8+ Trm and induced high local IgG and IgA. This regimen provided complete protection against lethal disease, accelerated viral shedding control (significant by day 2), and reduced DRG viral genomes (∼80-fold) compared with intramuscular boosting. Conclusion An intramuscular prime followed by BEACON-enabled mucosal boost safely coordinates Trm and mucosal antibody and markedly improves protection against genital HSV-2, supporting a generalizable mucosal boosting strategy for HSV-2 and other sexually transmitted infections. Funding Source HHMI Topic Categories Vaccines and Immunotherapy (VAC)