Antibody-dependent enhancement (ADE) is an important safety concern for vaccine development against dengue virus (DENV) and its antigenically related Zika virus (ZIKV) because vaccine may prime deleterious antibodies to enhance natural infections. Cross-reactive antibodies targeting the conserved fusion loop epitope (FLE) are known as the main sources of ADE. We design ZIKV immunogens engineered to change the FLE conformation but preserve neutralizing epitopes. Single vaccination conferred sterilizing immunity against ZIKV without ADE of DENV-serotype 1–4 infections and abrogated maternal–neonatal transmission in mice. Unlike the wild-type-based vaccine inducing predominately cross-reactive ADE-prone antibodies, B cell profiling revealed that the engineered vaccines switched immunodominance to dispersed patterns without DENV enhancement. The crystal structure of the engineered immunogen showed the dimeric conformation of the envelope protein with FLE disruption. We provide vaccine candidates that will prevent both ZIKV infection and infection-/vaccination-induced DENV ADE.

抗体依赖性增强 (ADE) 是针对登革热病毒 (DENV) 及其抗原相关寨卡病毒 (ZIKV) 疫苗开发的一个重要安全问题，因为疫苗可能引发有害抗体以增强自然感染。靶向保守融合环表位 (FLE) 的交叉反应性抗体被认为是 ADE 的主要来源。我们设计了 ZIKV 免疫原，旨在改变 FLE 构象但保留中和表位。在没有 ADE 的 DENV 血清型 1-4 感染的情况下，单次疫苗接种赋予了对 ZIKV 的灭菌免疫力，并消除了小鼠的母婴传播。与基于野生型的疫苗主要诱导具有交叉反应性 ADE 倾向的抗体不同，B 细胞分析显示，工程化疫苗将免疫优势转变为分散模式，而没有 DENV 增强。工程化免疫原的晶体结构显示包膜蛋白的二聚体构象与 FLE 破坏。我们提供可预防 ZIKV 感染和感染/疫苗接种诱导的 DENV ADE 的候选疫苗。