A novel tetrameric gp350 1-470 as a potential Epstein-Barr virus vaccine.
A novel tetrameric gp350 1-470 as a potential Epstein-Barr virus vaccine.
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DOI：
10.1016/j.vaccine.2013.04.071
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发表时间：
2013-06-26
期刊：
影响因子：
5.5
通讯作者：
Snapper, Clifford M.
中科院分区：
文献类型：
--
作者：
Cui, Xinle;Cao, Zhouhong;Sen, Goutam;Chattopadhyay, Gouri;Fuller, Deborah H.;Fuller, James T.;Snapper, Dustin M.;Snow, Andrew L.;Mond, James J.;Snapper, Clifford M.
传染性单核细胞增多症和B细胞对EB病毒感染的反应依赖于B细胞上EBV包膜糖蛋白gp350与CD21的结合。Gp350特异性抗体包括感染患者血清中大部分EBV中和活性，使该蛋白成为预防性EBV疫苗的有希望的靶抗原。我们描述了一种新型的、基于四聚体gp350的疫苗，与其单体疫苗相比，它的免疫原性显著增强。构建了质粒DNA，用于在转基因CHO细胞内合成截短的四聚体(A.A.1-470)gp350蛋白(gp3501-470)。四聚体gp3501-470在最高剂量下诱导gp3501-470特异性免疫球蛋白的血清滴度增加约20倍，中和滴度增加19倍，单位重量的免疫原性比单体gp3501-470高25倍。此外，用编码gp3501-470四聚体的质粒DNA进行表皮免疫，可以诱导出比单体高8倍的gp3501-470特异性免疫球蛋白。在单位重量基础上，四聚体gp3501-470与人CD21结合的效率是单体的24倍，但四聚体和单体都不能介导多克隆人B细胞的激活。最后，将强大的、通用的破伤风类毒素(TT)特异性CD4+T细胞表位引入四聚体gp3501-470中，对幼稚小鼠的gp3501-470特异性免疫球蛋白反应没有影响，并导致tt免疫小鼠的gp3501-470特异性免疫球蛋白反应受到抑制。总而言之，这些数据表明，四聚体gp3501-470是作为预防性EBV疫苗测试的一个潜在的有希望的候选者，并且使用这里描述的方法的蛋白质多聚体可能在临床上与增强其他疫苗相关蛋白质的免疫原性有关。
Infectious mononucleosis and B-cell transformation in response to infection with Epstein-Barr virus (EBV) is dependent upon binding of the EBV envelope glycoprotein gp350 to CD21 on B-cells. Gp350-specific antibody comprises most of the EBV neutralizing activity in the serum of infected patients, making this protein a promising target antigen for a prophylactic EBV vaccine. We describe a novel, tetrameric gp350-based vaccine that exhibits markedly enhanced immunogenicity relative to its monomeric counterpart. Plasmid DNA was constructed for synthesis, within transfected CHO cells, of a tetrameric, truncated (a.a. 1-470) gp350 protein (gp3501-470). Tetrameric gp3501-470 induced ~20-fold higher serum titers of gp3501-470-specific IgG and >19-fold enhancements in neutralizing titers at the highest dose, and was >25-fold more immunogenic on a per-weight basis than monomeric gp3501-470. Further, epidermal immunization with plasmid DNA encoding gp3501-470 tetramer induced 8-fold higher serum titers of gp3501-470-specific IgG relative to monomer. Tetrameric gp3501-470 binding to human CD21 was >24-fold more efficient on a per-weight basis than monomer, but neither tetramer nor monomer mediated polyclonal human B-cell activation. Finally, the introduction of strong, universal tetanus toxoid (TT)-specific CD4+ T-cell epitopes into the tetrameric gp3501-470 had no effect on the gp3501-470-specific IgG response in naïve mice, and resulted in suppressed gp3501-470-specific IgG responses in TT-primed mice. Collectively, these data suggest that tetrameric gp3501-470 is a potentially promising candidate for testing as a prophylactic EBV vaccine, and that protein multimerization, using the approach described herein, is likely to be clinically relevant for enhancing the immunogenicity of other proteins of vaccine interest.
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