Sustained mucosal delivery of SAMT-247 via an intravaginal ring reduces the risk of SIVmac251 acquisition in vaccinated macaques.

We assess the combined effect of sustained mucosal delivery of the anti-HIV small molecule S-acyl-2-mercaptobenzamide thioester 247 (SAMT-247) via an intravaginal ring (IVR) and ΔV1DNA/ALVAC-SIV/ΔV1gp120/alum (ΔV1-SIV) immunization in female macaques. The combined approach reduces the risk of vaginal SIVmac251 infection by 82.8%, with 58% of animals remaining uninfected following 14 weekly low-dose challenges; about half of the initially protected animals also remain uninfected during a second challenge phase. Compared with a historical vaccine-only cohort, continued IVR use shows a trend toward improved protection. Protection correlates with the expansion of tolerogenic CD73+ dendritic cells, IL-10+ macrophages, IL-17-producing NKp44+ innate lymphoid cells (ILCs), and antibody-mediated natural killer (NK) cytotoxic activity targeting the V2 helical conformation. In vitro studies support ex vivo observations that SAMT-247 enhances gp120-reactive anti-inflammatory mucosal immunity and NK activity. These findings support sustained IVR-based delivery of SAMT-247 combined with V1-deleted immunogens as a promising strategy to prevent vaginal HIV transmission.