Abstract：
Vaccine-induced protective T cell immunity is necessary for HIV-1 functional cure. We previously reported that rhesus PD1-Gag-based DNA vaccination sustained simian-human immunodeficiency virus (SHIV) suppression by inducing effector-memory CD8+ T cells. Here, we investigated a human PD1-Gag-based DNA vaccine, namely, ICVAX, for clinical translation. PD1-based dendritic cell targeting and mosaic antigenic designs were combined to generate the ICVAX by fusing the human soluble PD1 domain with a bivalent HIV-1 Gag-p41 mosaic antigen. The mosaic antigen was cross-reactive with patients infected with B, CRF07/08_BC, and CRF01_AE variants. In mice, ICVAX elicited stronger, broader, and more polyfunctional T cell responses than mosaic Gag-p41 alone, and suppressed EcoHIV infection more efficiently. In macaques, ICVAX elicited polyfunctional effector-memory T cell responses that targeted multiple nonoverlapping epitopes of the Gag-p41 antigen. Furthermore, ICVAX manufactured following good manufacturing practices proved potent immunogenicity in macaques after biannual homologous vaccination, warranting clinical evaluation of ICVAX as an immunotherapy against HIV-1. IMPORTANCE This study presents that ICVAX, a PD1-based DNA vaccine against HIV-1, could induce broad and polyfunctional T cell responses against different HIV-1 subtypes. ICVAX encodes a recombinant antigen consisting of the human soluble PD1 domain fused with two mosaic Gag-p41 antigens. The mosaic antigens cover more than 500 HIV-1 strains circulating in China including the subtypes B/B\', CRF01_AE, and CRF07/08_BC. In mice, ICVAX elicited stronger, broader, and more polyfunctional T cell responses, with better EcoHIV suppression than the nontargeting mosaic Gag-p41 DNA vaccine. Moreover, both lab-generated and GMP-grade ICVAX also elicited strong polyfunctional effector-memory T cell responses in rhesus macaques with good immunogenicity against multiple nonoverlapping epitopes of the Gag-p41 antigen. This study therefore highlights the great potential to translate the PD1-based DNA vaccine approach into clinical use, and opens up new avenues for alternative HIV-1 vaccine design for HIV-1 preventive and functional cure.
摘要：
疫苗诱导的保护性T细胞免疫是HIV-1功能性治愈所必需的。我们先前报道了基于恒河猴PD1-Gag的DNA疫苗接种通过诱导效应记忆性CD8T细胞来维持猿猴-人类免疫缺陷病毒（SHIV）抑制。这里,我们研究了一种基于人类PD1-Gag的DNA疫苗，即,ICVAX,用于临床翻译。通过将人可溶性PD1结构域与二价HIV-1Gag-p41镶嵌抗原融合,将基于PD1的树突细胞靶向和镶嵌抗原设计组合以产生ICVAX。镶嵌抗原与感染B的患者交叉反应，CRF07/08_BC,和CRF01_AE变体。在老鼠身上,ICVAX引起的更强，更广泛的，和更多的多功能T细胞反应比镶嵌Gag-p41单独，更有效地抑制了EcoHIV感染。在猕猴中，ICVAX引发靶向Gag-p41抗原的多个非重叠表位的多功能效应记忆T细胞应答。此外，根据良好的生产规范生产的ICVAX被证明在一年两次的同源疫苗接种后在猕猴中具有有效的免疫原性。保证ICVAX作为HIV-1免疫疗法的临床评估。重要性这项研究表明，ICVAX，一种基于PD1的针对HIV-1的DNA疫苗，可以诱导针对不同HIV-1亚型的广泛和多功能T细胞应答。ICVAX编码由与两个镶嵌Gag-p41抗原融合的人可溶性PD1结构域组成的重组抗原。镶嵌抗原涵盖了在中国传播的500多种HIV-1毒株，包括B/B亚型，CRF01_AE,和CRF07/08_BC。在老鼠身上,ICVAX引起的更强，更广泛的，和更多功能的T细胞反应，具有比非靶向镶嵌Gag-p41DNA疫苗更好的EcoHIV抑制作用。此外，实验室产生的ICVAX和GMP级ICVAX也在恒河猴中引发了强烈的多功能效应记忆T细胞反应,对Gag-p41抗原的多个非重叠表位具有良好的免疫原性.因此，这项研究强调了将基于PD1的DNA疫苗方法转化为临床用途的巨大潜力，并为HIV-1预防性和功能性治疗的替代HIV-1疫苗设计开辟了新的途径。
