最近中科院廣州生物醫(yī)藥與健康研究院特聘研究員陳凌博士帶領(lǐng)其研究組成員孫彩軍博士,、馮立強(qiáng)博士等研發(fā)了一種可克服體內(nèi)腺病毒中和抗體的新技術(shù)AVIP，并在恒河猴模型中利用腺病毒載體艾滋病疫苗進(jìn)行了概念驗(yàn)證,。相關(guān)成果發(fā)表于國(guó)際病毒學(xué)權(quán)威期刊《病毒學(xué)雜志》（J Virol. 2012,86(20):11031-42.）。
腺病毒（Adenovirus）,，尤其是人5型腺病毒（Ad5）已被廣泛作為重組基因治療和疫苗載體,，最新的數(shù)據(jù)表明全球約有1/4的基因治療和疫苗載體的臨床試驗(yàn)應(yīng)用了Ad5載體。然而人群中普遍存在腺病毒中和抗體,，例如陳凌研究組在去年發(fā)現(xiàn)華南人群中約有77%呈Ad5抗體陽性（發(fā)表于國(guó)際疫苗學(xué)期刊Vaccine,，2011,29(22):3837-3841）。即使是Ad5抗體陰性的人在使用過一次Ad5載體產(chǎn)品后也會(huì)轉(zhuǎn)變成Ad5抗體陽性,。這些腺病毒中和抗體很大程度抑制了腺病毒載體相關(guān)產(chǎn)品的重復(fù)使用效率,。
為了避免體內(nèi)腺病毒中和抗體的這種負(fù)面影響，該研究首先將外周血單核細(xì)胞PBMC從腺病毒中和抗體陽性的個(gè)體中分離出來,，然后用腺病毒載體疫苗在體外感染PBMC細(xì)胞,，接著將其靜脈回輸至自體。由于在分離純化PBMC時(shí)已去除了血液中的中和抗體等其他可能影響腺病毒感染效率的因素,，此外體內(nèi)血液中的中和抗體無法識(shí)別那些已進(jìn)入細(xì)胞內(nèi)的腺病毒載體疫苗,，因此這些疫苗可在體內(nèi)更有效地發(fā)揮特定的生物學(xué)功能。AVIP的特征還在于整個(gè)感染過程是發(fā)生在體外,，這樣就可更有好地控制腺病毒載體產(chǎn)品對(duì)靶細(xì)胞的感染效率,。本研究為提升腺病毒載體的使用效率和使用范圍提出了一種新思路。該成果有望被應(yīng)用于臨床研究和實(shí)踐,，對(duì)加快HIV/艾滋病疫苗,、其他疫苗以及基因治療技術(shù)的研發(fā)具有重要意義。（生物谷Bioon.com）
doi: 10.1128/JVI.00783-12
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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.
