Immunization of rhesus monkeys with a recombinant of modified vaccinia virus Ankara expressing a truncated envelope glycoprotein of dengue type 2 virus induced resistance to dengue type 2 virus challenge.
Immunization of rhesus monkeys with a recombinant of modified vaccinia virus Ankara expressing a truncated envelope glycoprotein of dengue type 2 virus induced resistance to dengue type 2 virus challenge.
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DOI：
10.1016/s0264-410x(00)00121-3
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发表时间：
2000-07
期刊：
影响因子：
5.5
通讯作者：
R. Men;L. Wyatt;I. Tokimatsu;S. Arakaki;G. Shameem;R. Elkins;R. Chanock;B. Moss;C. Lai
中科院分区：
文献类型：
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作者：
R. Men;L. Wyatt;I. Tokimatsu;S. Arakaki;G. Shameem;R. Elkins;R. Chanock;B. Moss;C. Lai
登革热流行在热带和亚热带地区的大多数国家日益构成公共卫生问题。尽管经过数十年的研究，安全有效的登革热病毒活疫苗的开发仍处于实验阶段。为了探索一种替代的疫苗策略，我们采用高度减毒的、复制缺陷型的经修饰的安卡拉牛痘（MVA）作为载体来构建用于表达一种或多种登革病毒血清型的主要包膜糖蛋白的重组体。表达高度免疫原性C-末端截短的2型登革热病毒（DEN 2）或4型登革热病毒（DEN 4）包膜蛋白的MVA重组体（E），约80%的全长，在动物模型中评价其保护性免疫。这些重组体中的每一个在加强接种后在小鼠中引起对DEN 2或DEN 4 E的升高的抗体应答，如通过放射免疫沉淀检测的。重组MVA-DEN 2 80%E，而不是MVA-DEN 4 80%E，诱导中和抗体应答。选择MVA-DEN 2 80%E重组体以进一步评估其在猴中诱导对野生型DEN 2攻击的抗性的能力。用重组MVA-DEN 2 80%E免疫两次的猴产生了低至中度的抗体应答，并部分保护其免受DEN 2攻击，如通过病毒血症模式所确定的。重要的是，随后的研究表明，在三个剂量方案中用重组体免疫的所有四只猴子都产生了增加的抗体水平，并且完全免受DEN 2攻击。重组MVA-DEN 2 80%E保护灵长类动物免受登革热感染的潜在功效表明，可能需要构建和评估表达其他血清型登革热病毒E的MVA重组体用于四价疫苗策略。
Dengue epidemics increasingly pose a public health problem in most countries of the tropical and subtropical areas. Despite decades of research, development of a safe and effective live dengue virus vaccine is still at the experimental stage. To explore an alternative vaccine strategy, we employed the highly attenuated, replication-deficient modified vaccinia Ankara (MVA) as a vector to construct recombinants for expression of the major envelope glycoprotein of one or more dengue virus serotypes. MVA recombinants expressing the highly immunogenic C-terminally truncated dengue type 2 virus (DEN2) or dengue type 4 virus (DEN4) envelope protein (E), approx. 80% of the full-length, were evaluated for their protective immunity in animal models. Each of these recombinants elicited an elevated antibody response to DEN2 or DEN4 E in mice following the booster inoculation, as detected by radio-immunoprecipitation. Recombinant MVA-DEN2 80%E, but not MVA-DEN4 80%E, induced a neutralizing antibody response. The MVA-DEN2 80%E recombinant was chosen to further evaluate its ability to induce resistance to wild type DEN2 challenge in monkeys. Monkeys immunized twice with recombinant MVA-DEN2 80%E developed a low to moderate antibody response and were partially protected against DEN2 challenge, as determined by the viremia pattern. Importantly, the subsequent study showed that all four monkeys immunized with the recombinant in a three dose schedule developed an increased level of antibodies and were completely protected against DEN2 challenge. The potential efficacy of recombinant MVA-DEN2 80%E to protect primates against dengue infection suggests that construction and evaluation of MVA recombinants expressing other serotypes of dengue virus E for use in a tetravalent vaccine strategy might be warranted.