Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
J Virol. 2012 Dec;86(23):12605-15. doi: 10.1128/JVI.00246-12. Epub 2012 Sep 12.
Modified vaccinia virus Ankara (MVA) is a safe, attenuated orthopoxvirus that is being developed as a vaccine vector but has demonstrated limited immunogenicity in several early-phase clinical trials. Our objective was to rationally improve the immunogenicity of MVA-based HIV/AIDS vaccines via the targeted deletion of specific poxvirus immune-modulatory genes. Vaccines expressing codon-optimized HIV subtype C consensus Env and Gag antigens were generated from MVA vector backbones that (i) harbor simultaneous deletions of four viral immune-modulatory genes, encoding an interleukin-18 (IL-18) binding protein, an IL-1β receptor, a dominant negative Toll/IL-1 signaling adapter, and CC-chemokine binding protein (MVAΔ4-HIV); (ii) harbor a deletion of an additional (fifth) viral gene, encoding uracil-DNA glycosylase (MVAΔ5-HIV); or (iii) represent the parental MVA backbone as a control (MVA-HIV). We performed head-to-head comparisons of the cellular and humoral immune responses that were elicited by these vectors during homologous prime-boost immunization regimens utilizing either high-dose (2 × 10(8) PFU) or low-dose (1 × 10(7) PFU) intramuscular immunization of rhesus macaques. At all time points, a majority of the HIV-specific T cell responses, elicited by all vectors, were directed against Env, rather than Gag, determinants, as previously observed with other vector systems. Both modified vectors elicited up to 6-fold-higher frequencies of HIV-specific CD8 and CD4 T cell responses and up to 25-fold-higher titers of Env (gp120)-specific binding (nonneutralizing) antibody responses that were relatively transient in nature. While the correlates of protection against HIV infection remain incompletely defined, our results indicate that the rational deletion of specific genes from MVA vectors can positively alter their cellular and humoral immunogenicity profiles in nonhuman primates.
改良安卡拉痘苗病毒（MVA）是一种安全、减毒的正痘病毒，目前正在开发作为疫苗载体，但在几项早期临床试验中表现出有限的免疫原性。我们的目标是通过靶向删除特定的痘病毒免疫调节基因，合理地提高基于 MVA 的 HIV/AIDS 疫苗的免疫原性。从 MVA 载体骨架生成表达密码子优化的 HIV 亚型 C 共识Env 和 gag 抗原的疫苗，这些载体骨架：（i）同时缺失四个病毒免疫调节基因，编码白细胞介素 18（IL-18）结合蛋白、IL-1β 受体、显性负 Toll/IL-1 信号传导接头和 CC-趋化因子结合蛋白（MVAΔ4-HIV）；（ii）缺失另外一个（第五个）病毒基因，编码尿嘧啶-DNA 糖基化酶（MVAΔ5-HIV）；或（iii）作为对照（MVA-HIV）保留亲本 MVA 骨架。我们在恒河猴中进行了头对头比较，这些载体在同源的初次-加强免疫方案中引发的细胞和体液免疫反应，使用高剂量（2×10^8PFU）或低剂量（1×10^7PFU）肌肉内免疫。在所有时间点，所有载体引发的大多数 HIV 特异性 T 细胞反应针对 Env 决定簇，而不是 Gag 决定簇，这与其他载体系统先前观察到的情况相同。两种改良载体引发的 HIV 特异性 CD8 和 CD4 T 细胞反应频率高达 6 倍，Env（gp120）特异性结合（非中和）抗体反应的滴度高达 25 倍，这些反应本质上是短暂的。虽然 HIV 感染保护的相关性仍不完全确定，但我们的结果表明，从 MVA 载体中合理删除特定基因可以积极改变其在非人类灵长类动物中的细胞和体液免疫原性特征。
