Broadly neutralizing DNA vaccine with specific mutation alters the antigenicity and sugar-binding activities of influenza hemagglutinin
Broadly neutralizing DNA vaccine with specific mutation alters the antigenicity and sugar-binding activities of influenza hemagglutinin
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DOI：
10.1073/pnas.1019744108
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发表时间：
2011-03-01
影响因子：
11.1
通讯作者：
Wong, Chi-Huey
中科院分区：
文献类型：
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作者：
Chen, Ming-Wei;Liao, Hsin-Yu;Wong, Chi-Huey
流感病毒血凝素的快速遗传漂变是疫苗效力的障碍。此前，我们发现公认的血凝素DNA疫苗(PCHA5)只能诱导出对H5N1分支2.1和分支2.3病毒的中等中和活性。因此，采取了两种方法来提高CHA5的保护广度。第一个是包括某些具有分支2.3病毒特征的表面氨基酸，以改善保护性。当我们用具有个别突变的CHA5免疫小鼠时，含有P157S的CHA5所激发的抗体对分支2.3病毒具有更高的中和活性。同样，含有157S血凝素的假型病毒变得更容易中和。第二种方法是用更新的H5N1毒株更新共识序列，产生第二代DNA疫苗pCHA5II。我们发现pCHA5II对所有H5N1病毒都有较高的交叉中和活性。比较CHA5和CHA5II的中和谱，以及动物攻击研究，发现CHA5II诱导了最广泛的保护谱。我们的结论是，CHA5II结合电穿孔传递是一种有希望的策略，可以诱导出针对不同H5N1流感病毒的具有广泛交叉反应的抗体。
The rapid genetic drift of influenza virus hemagglutinin is an obstacle to vaccine efficacy. Previously, we found that the consensus hemagglutinin DNA vaccine (pCHA5) can only elicit moderate neutralization activities toward the H5N1 clade 2.1 and clade 2.3 viruses. Two approaches were thus taken to improve the protection broadness of CHA5. The first one was to include certain surface amino acids that are characteristic of clade 2.3 viruses to improve the protection profiles. When we immunized mice with CHA5 harboring individual mutations, the antibodies elicited by CHA5 containing P157S elicited higher neutralizing activity against the clade 2.3 viruses. Likewise, the viruses pseudotyped with hemagglutinin containing 157S became more susceptible to neutralization. The second approach was to update the consensus sequence with more recent H5N1 strains, generating a second-generation DNA vaccine pCHA5II. We showed that pCHA5II was able to elicit higher cross-neutralization activities against all H5N1 viruses. Comparison of the neutralization profiles of CHA5 and CHA5II, and the animal challenge studies, revealed that CHA5II induced the broadest protection profile. We concluded that CHA5II combined with electroporation delivery is a promising strategy to induce antibodies with broad cross-reactivities against divergent H5N1 influenza viruses.