Engagement of monocytes, NK cells, and CD4+ Th1 cells by ALVAC-SIV vaccination results in a decreased risk of SIVmac251 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 SIVmac251. 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 SIVmac251 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 SIVmac251 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.

重组鸡痘病毒ALVAC-HIV/gp120/铝佐剂疫苗方案，是全球首个可显著降低人类免疫缺陷病毒（HIV, Human Immunodeficiency Virus）感染风险的疫苗策略，且在男女群体中均展现出同等保护效力。与之类似，基于猴免疫缺陷病毒（SIV, Simian Immunodeficiency Virus）的同源ALVAC疫苗方案，在印度恒河猴经直肠暴露于低剂量SIVmac251后，同样可降低病毒感染风险。本研究证实，ALVAC-SIV/gp120/铝佐剂疫苗在雌性中国恒河猴经阴道暴露于低剂量SIVmac251后，同样具备保护效力；同时我们确认，CD14+经典单核细胞是病毒感染风险降低的强相关免疫标志物。此外，本研究发现，CD14+细胞的丰度及其基因表达水平，与血液中1型CD4+辅助性T细胞、α4β7+浆母细胞以及阴道杀细胞性NKG2A+细胞显著相关。为深入解析疫苗保护作用的相关标志物，本研究将ALVAC-SIV疫苗与采用相同免疫原的、基于牛痘病毒载体NYVAC的SIV/gp120疫苗方案进行了对照研究。研究结果显示，NYVAC-SIV可通过CD4+Ki67+CD38+及CD4+Ki67+α4β7+ T细胞诱导更强的免疫激活，产生更多SIV包膜特异性γ干扰素（IFN-γ）分泌细胞，其抗体依赖细胞介导的细胞毒性作用（ADCC, Antibody-Dependent Cell-mediated Cytotoxicity）水平与ALVAC组相当，但无法降低SIVmac251的感染风险。本研究采用系统生物学方法，证实ALVAC载体疫苗方案诱导的浆母细胞、NKG2A+细胞以及单核细胞的特异性表达谱，与病毒感染风险降低显著相关。