Research, GenVec, Inc., Gaithersburg, Maryland, United States of America.
PLoS One. 2012;7(4):e33920. doi: 10.1371/journal.pone.0033920. Epub 2012 Apr 5.
The development of an effective malaria vaccine is a high global health priority. Vaccine vectors based on adenovirus type 5 are capable of generating robust and protective T cell and antibody responses in animal models and are currently being evaluated in clinical trials for HIV and malaria. They appear to be more effective in terms of inducing antigen-specific immune responses as compared with non-Ad5 serotype vectors. However, the high prevalence of neutralizing antibodies to Ad5 in the human population, particularly in the developing world, has the potential to limit the effectiveness of Ad5-based vaccines. We have generated novel Ad5-based vectors that precisely replace the hexon hypervariable regions with those derived from Ad43, a subgroup D serotype with low prevalence of neutralizing antibody in humans. We have demonstrated that these hexon-modified adenovectors are not neutralized efficiently by Ad5 neutralizing antibodies in vitro using sera from mice, rabbits and human volunteers. We have also generated hexon-modified adenovectors that express a rodent malaria parasite antigen, PyCSP, and demonstrated that they are as immunogenic as an unmodified vector. Furthermore, in contrast to the unmodified vector, the hexon-modified adenovectors induced robust T cell responses in mice with high levels of Ad5 neutralizing antibody. We also show that the hexon-modified vector can be combined with unmodified Ad5 vector in prime-boost regimens to induce protective responses in mice. Our data establish that these hexon-modified vectors are highly immunogenic even in the presence of pre-existing anti-adenovirus antibodies. These hexon-modified adenovectors may have advantages in sub-Saharan Africa where there is a high prevalence of Ad5 neutralizing antibody in the population.
开发有效的疟疾疫苗是全球卫生的当务之急。基于腺病毒 5 型（adenovirus type 5，Ad5）的疫苗载体能够在动物模型中产生强大且具有保护作用的 T 细胞和抗体反应，目前正在针对 HIV 和疟疾进行临床试验评估。与非 Ad5 血清型载体相比，它们在诱导抗原特异性免疫反应方面似乎更有效。然而，在人类中，尤其是在发展中国家，针对 Ad5 的中和抗体的高流行率有可能限制基于 Ad5 的疫苗的有效性。我们已经开发了新型的基于 Ad5 的载体，这些载体精确地用源自 Ad43 的衣壳六邻体超变区取代了衣壳六邻体超变区，Ad43 是一种血清型 D 亚群，在人类中中和抗体的流行率较低。我们已经证明，这些衣壳修饰的腺病毒载体在体外使用来自小鼠、兔子和人类志愿者的血清不能被 Ad5 中和抗体有效地中和。我们还生成了表达啮齿动物疟原虫抗原 PyCSP 的衣壳修饰的腺病毒载体，并证明它们与未修饰的载体一样具有免疫原性。此外，与未修饰的载体相比，衣壳修饰的腺病毒载体在具有高水平 Ad5 中和抗体的小鼠中诱导了强烈的 T 细胞反应。我们还表明，衣壳修饰的载体可以与未修饰的 Ad5 载体联合使用，在小鼠中诱导保护性应答。我们的数据表明，即使存在预先存在的抗腺病毒抗体，这些衣壳修饰的载体也具有高度的免疫原性。在 Ad5 中和抗体流行率较高的撒哈拉以南非洲地区，这些衣壳修饰的腺病毒载体可能具有优势。
