Butrapet Siritorn, Rabablert Jundee, Angsubhakorn Subhkij, Wiriyarat Witawat, Huang Claire, Kinney Richard, Punyim Sakol, Bhamarapravati Natth
Center for Vaccine Development, Institute of Science and Technology for Research and Development, Mahidol University, Bangkok, Thailand.
Southeast Asian J Trop Med Public Health. 2002 Sep;33(3):589-99.
Chimeric dengue type 2/type 1 (DEN2/1) viruses, which contain the structural genes of the dengue-1 (16007) parental virus and the nonstructural genes of the DEN2-PDK53 virus, have been constructed. These DEN2/1 viruses induce high levels of DEN1 virus-specific neutralizing antibodies in mice. In this study, the DEN2/1 viruses induced DEN1 virus-specific neutralizing antibodies without the development of viremia in cynomolgus monkeys. Dengue virus-specific IgM antibodies were detected in the sera of the immunized animals as early as 3 days post-immunization. After challenge with the DEN1-16007 wild-type virus, only a low level of viremia was detected in chimeric DEN2/1 virus-immunized monkeys. A second challenge, with DEN2-16681 virus, was given while the levels of DEN2-specific neutralizing antibodies were very low: infectious Dengue 2 virus could not be detected in sera of the monkeys. A correlation between the level of neutralizing antibody and the incidence of viremia could not be found. In addition, there was no significant increase in the levels of interferon gamma and soluble interleukin 2 receptor in the sera of the challenged monkeys, which suggests a reduction in immunopathogenesis caused by T-cell activation. Our findings suggest that DEN2/1 viruses may used as a live-attenuated candidate vaccine because of their safety, broad immunogenicity, and lower immunopathogenicity.
嵌合型登革2型/1型（DEN2/1）病毒已构建成功，该病毒含有登革1型（16007）亲本病毒的结构基因和DEN2-PDK53病毒的非结构基因。这些DEN2/1病毒在小鼠体内可诱导产生高水平的登革1型病毒特异性中和抗体。在本研究中，DEN2/1病毒在食蟹猴体内诱导产生登革1型病毒特异性中和抗体，且未出现病毒血症。在免疫动物血清中，早在免疫后3天就检测到了登革病毒特异性IgM抗体。在用登革1型-16007野生型病毒攻击后，在嵌合型DEN2/1病毒免疫的猴子中仅检测到低水平的病毒血症。在登革2型特异性中和抗体水平非常低时，用登革2型-16681病毒进行了第二次攻击：在猴子血清中未检测到感染性登革2型病毒。未发现中和抗体水平与病毒血症发生率之间存在相关性。此外，在受攻击猴子的血清中，干扰素γ和可溶性白细胞介素2受体水平没有显著升高，这表明由T细胞激活引起的免疫病理发生有所减少。我们的研究结果表明，DEN2/1病毒因其安全性、广泛的免疫原性和较低的免疫致病性，可能用作减毒活候选疫苗。
