Center for Vaccines and Immunology, University of Georgia, Athens, Georgia, USA.
Center for Vaccines and Immunology, University of Georgia, Athens, Georgia, USA
J Virol. 2021 Jan 28;95(4). doi: 10.1128/JVI.00658-20.
Any potential dengue virus (DENV) vaccine needs to elicit protective immunity against strains from all four serotypes to avoid potential antibody-dependent enhancement (ADE). In this study, four independent DENV envelope (E) glycoproteins were generated using wild-type E sequences from viruses isolated between 1943 and 2006 using computationally optimized broadly reactive antigen (COBRA) methodology. COBRA and wild-type E antigens were expressed on the surface of subvirion viral particles (SVPs). Four separate wild-type E antigens were used for each serotype. Mice vaccinated with wild-type DENV SVPs had anti-E IgG antibodies that neutralized serotype-specific viruses. COBRA DENV SVPs elicited a broader breadth of antibodies that neutralized strains across all four serotypes. Two COBRA DENV vaccine candidates that elicited the broadest breadth of neutralizing antibodies in mice were used to vaccinate rhesus macaques () that either were immunologically naive to any DENV serotype or had preexisting antibodies to DENV. Antibodies elicited by COBRA DENV E immunogens neutralized all 12 strains of DENV , which was comparable to antibodies elicited by a tetravalent wild-type E SVP vaccination mixture. Therefore, using a single DENV COBRA E protein can elicit neutralizing antibodies against strains representing all four serotypes of DENV in both naive and dengue virus-preimmune populations. Dengue virus infects millions of people living in tropical areas of the world. Dengue virus-induced diseases can range from mild to severe with death. An effective vaccine will need to neutralize viruses from all four serotypes of dengue virus without inducing enhanced disease. A dengue virus E vaccine candidate generated by computationally optimized broadly reactive antigen algorithms elicits broadly neutralizing protection for currently circulating strains from all four serotypes regardless of immune status. Most dengue vaccines in development formulate four separate components based on prM-E from a wild-type strain representing each serotype. Designing a monovalent vaccine that elicits protective immunity against all four serotypes is an effective and economical strategy.
任何潜在的登革热病毒 (DENV) 疫苗都需要针对所有四个血清型产生保护性免疫，以避免潜在的抗体依赖性增强 (ADE)。在这项研究中，使用从 1943 年至 2006 年分离的病毒的野生型 E 序列，通过计算优化的广泛反应性抗原 (COBRA) 方法生成了四个独立的 DENV 包膜 (E) 糖蛋白。COBRA 和野生型 E 抗原在亚病毒颗粒 (SVP) 的表面表达。每个血清型使用四种不同的野生型 E 抗原。用野生型 DENV SVP 接种的小鼠产生的抗 E IgG 抗体可中和血清型特异性病毒。COBRA DENV SVP 诱导出更广泛的抗体谱，可中和所有四个血清型的病毒株。在小鼠中诱导出最广泛中和抗体谱的两种 COBRA DENV 疫苗候选物被用于接种恒河猴（），这些猴子对任何 DENV 血清型均无免疫，或对 DENV 具有预先存在的抗体。由 COBRA DENV E 免疫原诱导的抗体中和了所有 12 株 DENV，与四价野生型 E SVP 疫苗混合物诱导的抗体相当。因此，使用单个 DENV COBRA E 蛋白可以在无预先存在的 DENV 抗体的情况下，在初免和已免疫人群中针对所有四个血清型的 DENV 株诱导出中和抗体。登革热病毒感染了世界热带地区数以百万计的人。登革热病毒引起的疾病从轻微到严重，甚至导致死亡。有效的疫苗将需要中和所有四个血清型的登革热病毒，而不会引起疾病加重。一种通过计算优化的广泛反应性抗原算法生成的登革热病毒 E 疫苗候选物，针对目前流行的所有四个血清型的病毒株产生广泛中和保护作用，无论免疫状态如何。目前开发的大多数登革热疫苗都是基于来自每个血清型的野生型毒株的 prM-E 设计的四种单独成分。设计一种针对所有四个血清型产生保护性免疫的单价疫苗是一种有效且经济的策略。
