Cell reports. Medicine · 2026
Sustained mucosal delivery of SAMT-247 via an intravaginal ring reduces the risk of SIVmac251 acquisition in vaccinated macaques.
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Rahman Mohammad Arif, Woode Emmanuel K, Moss John A, Bissa Massimiliano, Gunawardana Manjula, Gutowska Anna, Schifanella Luca, Silva de Castro Isabela, Brown Sophia, Stamos James D, Sarkis Sarkis, Robello Marco, Castonguay Amalia E, Butkyavichene Irina, Pise-Masison Cynthia A, Choo-Wosoba Hyoyoung, Doster Melvin, Alilin Aian Neil, Killoran Kristin Elizabeth, Kramer Joshua, Breed Matthew W, Cardozo Timothy, Appella Daniel H, Baum Marc M, Franchini Genoveffa
Аннотация
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.