HIV vaccine candidate ΔV1gp120 formulated in ALFQA adjuvant augments mucosal immunity in female macaques

Simian or Human immunodeficiency virus (SIV or HIV) vaccines based on V1-deleted envelope virus-like particles, delivered by the DNA/ALVAC platforms, followed by the ΔV1gp120 boost formulated in Alum, protect 50% and 80% of macaques from mucosal infection with SIV_mac251 or Simian-Human immunodeficiency virus, respectively. Adding the Army Liposome Formulation + QS21 (ALFQ) adjuvant to the ΔV1gp120+Alum boost (ALFQA) may enhance protective immune responses. Here, we show that ALFQA protects 58% of female macaques from infection following eleven exposures to SIV_mac251, achieving 79% vaccine efficacy. The ALFQA vaccine regimen augments mucosal CD73⁺CD163⁺ M2-like macrophages and NKp44⁺ innate lymphoid cells (ILCs), while reducing NKG2A^–NKP44^– cells producing interferon-γ. Antibody-Dependent Cellular Cytotoxicity (ADCC) targeting helical V2, and mucosal tolerogenic dendritic cells-10 (DC-10) and envelope-specific interleukin-17⁺ NKp44⁺ ILCs, correlate with decreased risk of infection. Plasma proteome analysis links vaccine efficacy to lymphotoxin-α, mucosal DC-10, and chemokine (C-C motif) ligand-8, a chemokine produced mainly by M2-macrophages. These data support the role of pro-resolution immunity in protection afforded by the V1-deleted SIV and HIV immunogens. The Combined Long-term Efferocytosis and ADCC Responses (CLEAR) phase I HIV-vaccine trial is designed to test the safety and immunogenicity of the Alum and ALFQA adjuvants in combination with V1-deleted HIV immunogens in humans.