Intranasal Delivery of HIV/SIV Antigens with NE/AS01B Adjuvants Enhances Cellular Immunity and Reduces Viral Loads in SHIV-Challenged Macaques

The primary route of HIV transmission is across mucosal tissues; therefore, developing a protective mucosal vaccine is a top priority. In a pilot study, using a macaque model, we delivered HIV gp140 envelope glycoprotein and SIVmac239 P55 Gag and Nef antigens using heterologous prime/boost via the intranasal route with a soybean oil-based nanoemulsion (NE) adjuvant and through the intramuscular route with the AS01B adjuvant system to generate enhanced cell-mediated immunity. We used a NE adjuvant to promote gut-homing cell-mediated immunity and the AS01B system to enhance humoral immune responses. Following intrarectal challenge with SHIV 4MTF.tHy, vaccinated macaques acquired the virus but experienced lower viral loads in plasma (P=0.003) and CSF (P=0.001), and potent polyfunctional gag-specific (CD107a+, IFN{gamma}, TNF+) responses across diverse lymph nodes. Significant antibody-dependent complement deposition (ADCD) and antibody-dependent cellular phagocytosis (ADCP) responses were induced, and gut-microbiome crosstalk could be modulated and showing reduced SHIV-dysbiosis. Notably, vaccination preserved mucosal all-trans retinoic acid levels (atRA) (p<0.05). However, no significant differences were observed for antibody responses between vaccinated and unvaccinated macaques. In summary, the induced gut-homing properties by the NE adjuvant are effective at generating cell-mediated immunity and reducing viral set points and warrant further investigations as a mucosal adjuvant in HIV vaccine design. ImportanceThree major non-mucosal vaccine trials (RV144, HVTN702, and 706) failed to reduce HIV infection rates. Therefore, new approaches in developing a mucosal vaccine remain an effective strategy to attempt to control HIV infection. Coherent vaccine approaches against HIV were focused on immune correlates related to viral loads, persistent reservoirs, and antibody responses. As a proof-of-principle, we developed a vaccine regimen consisting of AS01B and an adjuvanted oil-in-water NE cleaved HIV clade C gp140 protein and non-cleaved Gag, and nef particles administered through intranasal, subcutaneous, and intramuscular routes, followed by intrarectal challenge with clade C SHIV. This vaccine elicited strong ADCD and ADCP responses, modulated immune-microbiome crosstalk, and reduced susceptibility to SHIV-infection-associated dysbiosis. Additionally, it preserved mucosal all trans retinoic acid (atRA) levels, suggesting a potential role for this approach in HIV vaccine development.