Engagement of monocytes, NK cells, and CD4⁺ Th1 cells by ALVAC-SIV vaccination results in a decreased risk of SIV_mac251 vaginal acquisition

The recombinant Canarypox ALVAC-HIV/gp120/alum vaccine regimen was the first to significantly decrease the risk of HIV acquisition in humans, with equal effectiveness in both males and females. Similarly, an equivalent SIV-based ALVAC vaccine regimen decreased the risk of virus acquisition in Indian rhesus macaques of both sexes following intrarectal exposure to low doses of SIV_mac251. Here, we demonstrate that the ALVAC-SIV/gp120/ alum vaccine is also efficacious in female Chinese rhesus macaques following intravaginal exposure to low doses of SIV_mac251 and we confirm that CD14⁺ classical monocytes are a strong correlate of decreased risk of virus acquisition. Furthermore, we demonstrate that the frequency of CD14⁺ cells and/or their gene expression correlates with blood Type 1 CD4⁺ T helper cells, α₄β₇ ⁺ plasmablasts, and vaginal cytocidal NKG2A⁺ cells. To better understand the correlate of protection, we contrasted the ALVAC-SIV vaccine with a NYVAC-based SIV/gp120 regimen that used the identical immunogen. We found that NYVAC-SIV induced higher immune activation via CD4⁺Ki67⁺CD38⁺ and CD4⁺Ki67⁺α₄β₇ ⁺ T cells, higher SIV envelope-specific IFN-γ producing cells, equivalent ADCC, and did not decrease the risk of SIV_mac251 acquisition. Using the systems biology approach, we demonstrate that specific expression profiles of plasmablasts, NKG2A⁺ cells, and monocytes elicited by the ALVAC-based regimen correlated with decreased risk of virus acquisition.