Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents preexisting immunity to adenovirus in mice
Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents preexisting immunity to adenovirus in mice
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DOI：
10.1172/jci39812
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发表时间：
2010-10-01
影响因子：
15.9
通讯作者：
Tsuji, Moriya
中科院分区：
文献类型：
--
作者：
Shiratsuchi, Takayuki;Rai, Urvashi;Tsuji, Moriya
尽管腺病毒（Ad）被认为是一种优秀的疫苗载体，但使用该平台存在2个主要缺点：（a）基于Ad的疫苗诱导针对编码的转基因的相对弱的体液应答，和（B）对Ad的预先存在的免疫在一般人群中高度流行。为了克服这些障碍，我们通过将源自约氏疟原虫环子孢子（CS）蛋白的B细胞表位（称为PyCS-B表位）插入WT/CS-GFP（表达约氏疟原虫CS蛋白和GFP作为其转基因的重组Ad）的衣壳蛋白中，构建了基于Ad的疟疾疫苗。与未修饰的WT/CS-GFP相比，用captain修饰的Ad多次接种在小鼠中诱导了针对随后的疟疾攻击的显著增加的保护水平。增加的保护与针对衣壳中表达的PyCS-B表位的增强的抗体应答相关。此外，替换的高变区1（HVR 1）的Ad衣壳蛋白与PyCS-B表位规避中和的修饰的广告通过预先存在的广告特异性抗体，在体内和体外。重要的是，HVR 1和约氏疟原虫CS转基因中含有Ad的PyCS-B表位的免疫原性得以维持。总的来说，该研究表明HVR 1修饰的Ad大大改善了Ad作为有希望的疟疾疫苗平台候选物。
Although adenovirus (Ad) has been regarded as an excellent vaccine vector, there are 2 major drawbacks to using this platform: (a) Ad-based vaccines induce a relatively weak humoral response against encoded transgenes, and (b) preexisting immunity to Ad is highly prevalent among the general population. To overcome these obstacles, we constructed an Ad-based malaria vaccine by inserting a B cell epitope derived from a Plasmodium yoelii circumsporozoite (CS) protein (referred to as the PyCS-B epitope) into the capsid proteins of WT/CS-GFP, a recombinant Ad expressing P. yoelii CS protein and GFP as its transgene. Multiple vaccinations with the capsid-modified Ad induced a substantially increased level of protection against subsequent malaria challenge in mice when compared with that of unmodified WT/CS-GFP. Increased protection correlated with augmented antibody responses against the PyCS-B epitope expressed in the capsid. Furthermore, replacement of hypervariable region 1 (HVR1) of the Ad capsid proteins with the PyCS-B epitope circumvented neutralization of the modified Ad by preexisting Ad-specific antibody, both in vivo and in vitro. Importantly, the irnrnunogenicity of the Ad-containing PyCS-B epitope in the HVR1 and a P. yoelii CS transgene was maintained. Overall, this study demonstrates that the HVR1-modifed Ad vastly improves upon Ad as a promising malaria vaccine platform candidate.