Circumventing Antivector Immunity by Using Adenovirus-Infected Blood Cells for Repeated Application of Adenovirus-Vectored Vaccines: Proof of Concept in Rhesus Macaques
Circumventing Antivector Immunity by Using Adenovirus-Infected Blood Cells for Repeated Application of Adenovirus-Vectored Vaccines: Proof of Concept in Rhesus Macaques
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通过使用腺病毒感染的血细胞重复应用腺病毒载体疫苗来规避抗载体免疫：在恒河猴中的概念证明
DOI：
10.1128/jvi.00783-12
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发表时间：
2012-10-01
影响因子：
5.4
通讯作者：
Chen, Ling
中科院分区：
文献类型：
--
作者：
Sun, Caijun;Feng, Liqiang;Chen, Ling
摘要腺病毒已被广泛用作递送疫苗的载体平台。然而，预先存在的抗腺病毒免疫是应用腺病毒载体疫苗的主要绊脚石。在这项研究中，我们发现，新鲜分离的外周血单核细胞（PBMC），主要是CD 14+细胞，从腺病毒血清型5（Ad 5）-血清阳性灵长类动物（人类和恒河猴）可以有效地感染Ad 5在体外。在此观察的基础上，探索了一种基于腺病毒载体感染的PBMC（AVIP）免疫的新策略以规避抗载体免疫。自体输注Ad 5-SIVgag感染的PBMC引起了强烈的Gag特异性细胞免疫应答，但在Ad 5血清阴性猕猴中诱导的Ad 5中和抗体（NAb）比肌肉注射Ad 5-SIVgag的猕猴弱。此外，接受Ad 5-SIVenv、Ad 5-SIVgag和Ad 5-SIVpol疫苗的多次AVIP免疫的Ad 5血清阳性猕猴在每次免疫后引起增强的Env-、Gag-和Pol-特异性免疫应答，其显著大于肌肉内注射这些Ad 5-SIV疫苗的猕猴中的那些。在用高致病性SIVmac 239病毒进行静脉内攻击后，与没有Ad 5-SIV疫苗的猕猴相比，接受AVIP免疫的猕猴在峰值时间和设定点期间表现出病毒载量的显著降低。我们的研究保证了AVIP免疫作为腺病毒载体疫苗重复应用的平台的进一步研究和开发。
ABSTRACT Adenovirus has been extensively exploited as a vector platform for delivering vaccines. However, preexisting antiadenovirus immunity is the major stumbling block for application of adenovirus-vectored vaccines. In this study, we found that freshly isolated peripheral blood mononuclear cells (PBMCs), mostly CD14+ cells, from adenovirus serotype 5 (Ad5)-seropositive primates (humans and rhesus macaques) can be efficiently infected with Ad5 in vitro. On the basis of this observation, a novel strategy based on adenoviral vector-infected PBMC (AVIP) immunization was explored to circumvent antivector immunity. Autologous infusion of Ad5-SIVgag-infected PBMCs elicited a strong Gag-specific cellular immune response but induced weaker Ad5-neutralizing antibody (NAb) in Ad5-seronegative macaques than in macaques intramuscularly injected with Ad5-SIVgag. Moreover, Ad5-seropositive macaques receiving multiple AVIP immunizations with Ad5-SIVenv, Ad5-SIVgag, and Ad5-SIVpol vaccines elicited escalated Env-, Gag-, and Pol-specific immune responses after each immunization that were significantly greater than those in macaques intramuscularly injected with these Ad5-SIV vaccines. After challenged intravenously with a highly pathogenic SIVmac239 virus, macaques receiving AVIP immunization demonstrated a significant reduction in viral load at both the peak time and set-point period compared with macaques without Ad5-SIV vaccines. Our study warranted further research and development of the AVIP immunization as a platform for repeated applications of adenovirus-vectored vaccines.