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J Virol.:中科院广州生物院在腺病毒载体疫苗领域取得新成果

来源:中科院广州生物院 2012-11-02 11:17

最近中科院广州生物医药与健康研究院特聘研究员陈凌博士带领其研究组成员孙彩军博士、冯立强博士等研发了一种可克服体内腺病毒中和抗体的新技术AVIP,并在恒河猴模型中利用腺病毒载体艾滋病疫苗进行了概念验证。相关成果发表于国际病毒学权威期刊《病毒学杂志》(J Virol. 2012,86(20):11031-42.)。

腺病毒(Adenovirus),尤其是人5型腺病毒(Ad5)已被广泛作为重组基因治疗和疫苗载体,最新的数据表明全球约有1/4的基因治疗和疫苗载体的临床试验应用了Ad5载体。然而人群中普遍存在腺病毒中和抗体,例如陈凌研究组在去年发现华南人群中约有77%呈Ad5抗体阳性(发表于国际疫苗学期刊Vaccine,2011,29(22):3837-3841)。即使是Ad5抗体阴性的人在使用过一次Ad5载体产品后也会转变成Ad5抗体阳性。这些腺病毒中和抗体很大程度抑制了腺病毒载体相关产品的重复使用效率。

为了避免体内腺病毒中和抗体的这种负面影响,该研究首先将外周血单核细胞PBMC从腺病毒中和抗体阳性的个体中分离出来,然后用腺病毒载体疫苗在体外感染PBMC细胞,接着将其静脉回输至自体。由于在分离纯化PBMC时已去除了血液中的中和抗体等其他可能影响腺病毒感染效率的因素,此外体内血液中的中和抗体无法识别那些已进入细胞内的腺病毒载体疫苗,因此这些疫苗可在体内更有效地发挥特定的生物学功能。AVIP的特征还在于整个感染过程是发生在体外,这样就可更有好地控制腺病毒载体产品对靶细胞的感染效率。本研究为提升腺病毒载体的使用效率和使用范围提出了一种新思路。该成果有望被应用于临床研究和实践,对加快HIV/艾滋病疫苗、其他疫苗以及基因治疗技术的研发具有重要意义。(生物谷Bioon.com)

Circumventing antivector immunity by using adenovirus-infected blood cells for repeated application of adenovirus-vectored vaccines: proof of concept in rhesus macaques

Sun C, Feng L, Zhang Y, Xiao L, Pan W, Li C, Zhang L, Chen L.

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.

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