Arboviral Diseases Branch, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Public Health Service, U.S. Department of Health and Human Service Fort Collins, CO, USA.
Front Immunol. 2012 Nov 8;3:334. doi: 10.3389/fimmu.2012.00334. eCollection 2012.
Dengue viruses (DENV) are the most important mosquito transmitted viral pathogens infecting humans. DENV infection produces a spectrum of disease, most commonly causing a self-limiting flu-like illness known as dengue fever; yet with increased frequency, manifesting as life-threatening dengue hemorrhagic fever (DHF). Waning cross-protective immunity from any of the four dengue serotypes may enhance subsequent infection with another heterologous serotype to increase the probability of DHF. Decades of effort to develop dengue vaccines are reaching the finishing line with multiple candidates in clinical trials. Nevertheless, concerns remain that imbalanced immunity, due to the prolonged prime-boost schedules currently used in clinical trials, could leave some vaccinees temporarily unprotected or with increased susceptibility to enhanced disease. Here we develop a DENV serotype 1 (DENV-1) DNA vaccine with the immunodominant cross-reactive B cell epitopes associated with immune enhancement removed. We compare wild-type (WT) with this cross-reactivity reduced (CRR) vaccine and demonstrate that both vaccines are equally protective against lethal homologous DENV-1 challenge. Under conditions mimicking natural exposure prior to acquiring protective immunity, WT vaccinated mice enhanced a normally sub-lethal heterologous DENV-2 infection resulting in DHF-like disease and 95% mortality in AG129 mice. However, CRR vaccinated mice exhibited redirected serotype-specific and protective immunity, and significantly reduced morbidity and mortality not differing from naїve mice. Thus, we demonstrate in an in vivo DENV disease model, that non-protective vaccine-induced immunity can prime vaccinees for enhanced DHF-like disease and that CRR DNA immunization significantly reduces this potential vaccine safety concern. The sculpting of immune memory by the modified vaccine and resulting redirection of humoral immunity provide insight into DENV vaccine-induced immune responses.
登革热病毒（DENV）是感染人类的最重要的蚊媒传播病毒病原体。DENV 感染会引起一系列疾病，最常见的是自限性流感样疾病，称为登革热；但随着频率的增加，表现为危及生命的登革出血热（DHF）。任何四种登革热血清型的交叉保护免疫力下降，都可能增加随后感染另一种异源血清型的可能性，从而增加 DHF 的可能性。几十年来，人们一直在努力开发登革热疫苗，目前有多个候选疫苗正在临床试验中。然而，人们仍然担心，由于目前临床试验中使用的延长的初级-加强免疫方案，一些疫苗接种者可能会暂时失去保护，或者更容易患上增强型疾病。在这里，我们开发了一种登革热病毒 1 型（DENV-1）DNA 疫苗，该疫苗去除了与免疫增强相关的免疫显性交叉反应 B 细胞表位。我们比较了野生型（WT）和这种交叉反应降低（CRR）疫苗，并证明这两种疫苗在对抗致命同源 DENV-1 挑战时都具有同等的保护作用。在模拟自然暴露之前获得保护性免疫的情况下，WT 接种疫苗的小鼠增强了通常亚致死的异源 DENV-2 感染，导致 AG129 小鼠出现 DHF 样疾病和 95%的死亡率。然而，CRR 接种疫苗的小鼠表现出重新定向的血清型特异性和保护性免疫，发病率和死亡率显著降低，与未接种疫苗的小鼠没有差异。因此，我们在体内 DENV 疾病模型中证明，非保护性疫苗诱导的免疫可以使疫苗接种者更容易患上增强型 DHF 样疾病，而 CRR DNA 免疫接种可显著降低这种潜在的疫苗安全性问题。修饰疫苗对免疫记忆的塑造以及由此产生的体液免疫重定向为登革热疫苗诱导的免疫反应提供了深入了解。
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