Gil Lázaro, Lazo Laura, Valdés Iris, Suzarte Edith, Yen Phuong, Ramírez Rosa, Álvarez Mayling, Dung Le T, Cobas Karem, Marcos Ernesto, Pérez Yusleidi, Guzmán María G, D Hien Ngyen, Guillén Gerardo, Hermida Lisset
Division of Vaccine, Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba.
The Center for Research and Production of Vaccines and Biological (POLYVAC), Hanoi, Vietnam.
Clin Transl Immunology. 2017 Jun 23;6(6):e148. doi: 10.1038/cti.2017.24. eCollection 2017 Jun.
Tetra DIIIC is a vaccine candidate against dengue virus (DENV) composed by four chimeric proteins that fuse the domain III of the envelope protein of each virus to the corresponding capsid protein. Containing B- and T-cell epitopes, these proteins form aggregates after the incubation with an immunostimulatory oligodeoxynucleotide, and their tetravalent formulation induces neutralizing antibodies and cellular immune response in mice and monkeys. Also, Tetra DIIIC protects mice after challenge with each DENV, and the monovalent formulation obtained from DENV-2 protects monkeys upon homologous viral challenge. However, in the last years, new evidences have arisen regarding domain III of DENV envelope protein as irrelevant target for neutralizing antibodies in humans. Nevertheless, vaccination with domain III induces a neutralizing antibody response that confers protection against re-infection. In addition, it has been demonstrated that the induction of a cellular immune response is essential to protect during the infection. This response can also avoid severe manifestations of dengue disease, associated to the antibody-dependent enhancement of the infection. In this study, we observed that Tetra DIIIC was able to boost the antiviral and neutralizing antibody responses previously generated in monkeys during an experimental DENV infection, demonstrating that domain III is targeted by B cells during the viral infection. Additionally, Tetra DIIIC successfully boosted the cellular immune response generated by the viruses, probably against T-cells epitopes in the capsid proteins. These results highlight the functionality of Tetra DIIIC as a vaccine candidate against DENV.
四价DIIIC是一种针对登革病毒（DENV）的候选疫苗，由四种嵌合蛋白组成，这些嵌合蛋白将每种病毒包膜蛋白的结构域III与相应的衣壳蛋白融合。这些蛋白含有B细胞和T细胞表位，与免疫刺激寡脱氧核苷酸孵育后形成聚集体，其四价制剂可在小鼠和猴子体内诱导中和抗体和细胞免疫反应。此外，四价DIIIC在用每种DENV攻击小鼠后可起到保护作用，从DENV-2获得的单价制剂在同源病毒攻击时可保护猴子。然而，在过去几年中，出现了关于DENV包膜蛋白结构域III并非人类中和抗体相关靶点的新证据。尽管如此，用结构域III进行疫苗接种可诱导中和抗体反应，从而提供针对再次感染的保护。此外，已经证明诱导细胞免疫反应对于感染期间的保护至关重要。这种反应还可以避免与抗体依赖性感染增强相关的登革热疾病的严重表现。在本研究中，我们观察到四价DIIIC能够增强在实验性DENV感染期间猴子先前产生的抗病毒和中和抗体反应，表明在病毒感染期间B细胞靶向结构域III。此外，四价DIIIC成功增强了病毒产生的细胞免疫反应，可能针对衣壳蛋白中的T细胞表位。这些结果突出了四价DIIIC作为抗DENV候选疫苗的功能。
