Editor’s summary
No vaccine currently exists for genital herpes, caused by herpes simplex virus 2 (HSV-2), in part because of the challenge of triggering localized immune responses in the reproductive tract mucosa. Bhagchandani et al. generated an adjuvant called bioactive enhanced adjuvant chemokine oligonucleotide nanoparticles (BEACONs) that combines CpG oligodeoxynucleotides (CpG ODNs) with the CXCL9 chemokine through electrostatic interactions. Mice were primed initially by intramuscular injection with mRNA lipid nanoparticles encoding HSV-2 glycoprotein B (gB) or gD and were boosted intravaginally with the cognate recombinant glycoprotein combined with BEACONs. This combination enhanced protection against HSV-2 challenge by specifically increasing localized resident memory T cells and mucosal antibodies. This study highlights the potential broader application of specialized mucosal adjuvants. —Christiana N. Fogg
Abstract
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 (TRM 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 TRM 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.