编码猿猴免疫缺陷病毒(SIV)免疫原的腺病毒疫苗载体能够在非人灵长类动物中诱导有效的体液和细胞免疫应答。一些研究已经评估了使用免疫调节剂来进一步增强疫苗诱导的T细胞应答。造血生长因子Flt3L驱动各种骨髓祖细胞群的扩张,和Flt3L的给药被证明可以促进脾脏和血液中树突状细胞群的扩增,它们是沙粒病毒载体的靶标。因此,我们评估了Flt3信号传导增强编码SIV免疫原的沙粒病毒疫苗免疫原性的潜力(SIVSME543Gag,Env,和Pol)在恒河猴中,与恒河猴特异性工程Flt3L-Fc融合蛋白。在健康的动物中,Flt3L-Fc的施用导致1型树突状细胞在给药后7天增加10至100倍,重复给药后无抗药物抗体(ADA)产生。我们观察到,在沙粒病毒疫苗前7天施用Flt3L-Fc融合蛋白增加了先天免疫细胞的频率和激活,并增强了T细胞激活,没有治疗相关的不良事件。Flt3L-Fc给药诱导早期先天免疫激活,导致幅度显著增强,广度,和疫苗诱导的T细胞反应的多功能性。Flt3L-Fc在疫苗免疫原性中的增强与与αCTLA-4的组合相当,并且支持使用Flt3L的安全且有效的变体来增强治疗性疫苗诱导的T细胞应答。重要提示通过治疗性疫苗接种诱导强大的人类免疫缺陷病毒(HIV)特异性CD4和CD8T细胞反应被认为是HIV治愈的必要条件。编码猿猴免疫缺陷病毒(SIV)免疫原的Arenavirus疫苗载体在非人灵长类动物中显示出强的免疫原性和功效。这里,我们证明了编码SIV免疫原的沙粒病毒载体的免疫原性可以通过在接种前7天施用Flt3L-Fc融合蛋白来增强。与单独的疫苗相比,Flt3L-Fc介导的树突状细胞增加导致疫苗诱导的T细胞和B细胞应答的显著改善。Flt3L-Fc给药与任何治疗相关的不良事件无关。重要的是,Flt3L-Fc或αCTLA-4的免疫调节导致疫苗应答的相当增强。这些结果表明,在疫苗施用之前添加Flt3L-Fc融合蛋白可以显著增强疫苗免疫原性。因此,安全有效的Flt3L变异体可用作HIV治愈联合治疗的一部分.
Arenaviral vaccine vectors encoding simian immunodeficiency virus (SIV) immunogens are capable of inducing efficacious humoral and cellular immune responses in nonhuman primates. Several studies have evaluated the use of immune modulators to further enhance vaccine-induced T-cell responses. The hematopoietic growth factor Flt3L drives the expansion of various bone marrow progenitor populations, and administration of Flt3L was shown to promote expansion of dendritic cell populations in spleen and blood, which are targets of arenaviral vectors. Therefore, we evaluated the potential of Flt3 signaling to enhance the immunogenicity of arenaviral vaccines encoding SIV immunogens (SIVSME543 Gag, Env, and Pol) in rhesus macaques, with a rhesus-specific engineered Flt3L-Fc fusion protein. In healthy animals, administration of Flt3L-Fc led to a 10- to 100-fold increase in type 1 dendritic cells 7 days after dosing, with no antidrug antibody (ADA) generation after repeated dosing. We observed that administration of Flt3L-Fc fusion protein 7 days before arenaviral vaccine increased the frequency and activation of innate immune cells and enhanced T-cell activation with no treatment-related adverse events. Flt3L-Fc administration induced early innate immune activation, leading to a significant enhancement in magnitude, breadth, and polyfunctionality of vaccine-induced T-cell responses. The Flt3L-Fc enhancement in vaccine immunogenicity was comparable to a combination with αCTLA-4 and supports the use of safe and effective variants of Flt3L to augment therapeutic vaccine-induced T-cell responses.IMPORTANCEInduction of a robust human immunodeficiency virus (HIV)-specific CD4+ and CD8+ T-cell response through therapeutic vaccination is considered essential for HIV cure. Arenaviral vaccine vectors encoding simian immunodeficiency virus (SIV) immunogens have demonstrated strong immunogenicity and efficacy in nonhuman primates. Here, we demonstrate that the immunogenicity of arenaviral vectors encoding SIV immunogens can be enhanced by administration of Flt3L-Fc fusion protein 7 days before vaccination. Flt3L-Fc-mediated increase in dendritic cells led to robust improvements in vaccine-induced T- and B-cell responses compared with vaccine alone, and Flt3L-Fc dosing was not associated with any treatment-related adverse events. Importantly, immune modulation by either Flt3L-Fc or αCTLA-4 led to comparable enhancement in vaccine response. These results indicate that the addition of Flt3L-Fc fusion protein before vaccine administration can significantly enhance vaccine immunogenicity. Thus, safe and effective Flt3L variants could be utilized as part of a combination therapy for HIV cure.