Department of Virology 1, National Institute of Infectious Diseases, Tokyo, Japan.
Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.
Virol J. 2018 Mar 27;15(1):51. doi: 10.1186/s12985-018-0967-x.
A vaccine against all four dengue virus (DENV) serotypes includes the formulation of one genotype of each serotype. Although genetic similarities among genotypes within a serotype are higher as compared to those among serotypes, differences in the immunogenicity of the included genotypes would be a critical issue in maximizing successful dengue vaccine development. Thus, we determined the neutralizing antibody responses against three genotypes of dengue virus serotype 2 (DENV-2), namely Cosmopolitan, Asian I, and Asian/American, after primary and secondary inoculation with DENV-2 in a dengue animal model, the common marmoset (Callithrix jacchus).
A total of fifty-four plasma samples were obtained from thirty-four marmosets that were inoculated with clinically-isolated DENV strains or DENV candidate vaccines, were used in this study. Plasma samples were obtained from marmosets after primary inoculation with DENV-2 infection, secondary inoculation with homologous or heterologous genotypes, and tertiary inoculation with heterologous DENV. Neutralizing antibody titers against DENV-2 (Cosmopolitan, Asian I, and Asian/American genotypes) and DENV-1 were determined using a conventional plaque reduction neutralization assay.
In marmosets that were inoculated with the Cosmopolitan genotype in primary infection, neutralizing antibody neutralized 3 genotypes, and the titers to Asian I genotype were significantly higher than those to homologous Cosmopolitan genotype. After secondary DENV-2 infection with heterologous genotype (Asian I in primary and Asian/American in secondary), neutralizing antibody titers to Asian/American genotype was significantly higher than those against Cosmopolitan and Asian I genotypes. Following tertiary infection with DENV-1 following DENV-2 Asian I and Cosmopolitan genotypes, neutralizing antibody titers to Asian/American were also significantly higher than those against Cosmopolitan and Asian I genotypes.
The present study demonstrated that different levels of neutralizing antibodies were induced against variable DENV-2 genotypes after primary, secondary and tertiary infections, and that neutralizing antibody titers to some heterologous genotypes were higher than those to homologous genotypes within a serotype. The results indicate that heterogeneity and homogeneity of infecting genotypes influence the levels and cross-reactivity of neutralizing antibodies induced in following infections. The results also suggest that certain genotypes may possess advantage in terms of breakthrough infections against vaccination.
针对所有四种登革热病毒（DENV）血清型的疫苗包含每种血清型的一个基因型的制剂。尽管同一血清型内各基因型之间的遗传相似性高于不同血清型之间的相似性，但包含基因型的免疫原性差异将是最大程度成功开发登革热疫苗的关键问题。因此，我们在登革热动物模型（普通狨猴（Callithrix jacchus））中用 DENV-2 进行初次和二次接种后，确定了针对登革热病毒血清型 2（DENV-2）的三种基因型（世界性，亚洲 I 型和亚洲/美洲型）的中和抗体反应。
从接种了临床分离的 DENV 株或 DENV 候选疫苗的 34 只狨猴中获得了总共 54 个血浆样本，用于本研究。在 DENV-2 感染的初次接种后，同源或异源基因型的二次接种以及异源 DENV 的三次接种后，从狨猴中获得了血浆样本。使用常规蚀斑减少中和试验测定针对 DENV-2（世界性，亚洲 I 型和亚洲/美洲基因型）和 DENV-1 的中和抗体滴度。
在初次感染中接种世界性基因型的狨猴中，中和抗体中和了 3 种基因型，并且对亚洲 I 型的滴度明显高于同源世界性基因型。在二次感染异源基因型（初次感染亚洲 I 型，二次感染亚洲/美洲型）的 DENV-2 后，对亚洲/美洲基因型的中和抗体滴度明显高于对世界性和亚洲 I 型的滴度。在 DENV-2 亚洲 I 型和世界性基因型之后感染 DENV-1 之后，对亚洲/美洲型的中和抗体滴度也明显高于对世界性和亚洲 I 型的滴度。
本研究表明，初次，二次和三次感染后，针对不同的 DENV-2 基因型诱导了不同水平的中和抗体，并且同种血清型内某些异源基因型的中和抗体滴度高于同源基因型。结果表明，感染基因型的异质性和同质性会影响后续感染中诱导的中和抗体的水平和交叉反应性。结果还表明，某些基因型在针对疫苗接种的突破性感染方面可能具有优势。
