The use of dengue virus (DENV) vaccines has been hindered by the complexities of antibody dependent enhancement (ADE). Current late-stage vaccine candidates utilize attenuated and chimeric DENVs that produce particles of varying maturities. Antibodies that are elicited by preferentially exposed epitopes on immature virions have been linked to increased ADE. We aimed to further understand the humoral immunity promoted by DENV particles of varying maturities in an AG129 mouse model using a chimeric insect specific vaccine candidate, bDENV-2. We immunized mice with mature, partially mature, and immature bDENV-2 and found that immunization with partially mature bDENV-2 produced more robust and cross-neutralizing immune responses than immunization with immature or mature bDENV-2. Upon challenge with mouse adapted DENV-2 (D220), we observed 80% protection for mature bDENV-2 vaccinated mice and 100% for immature and partially mature vaccinated mice, suggesting that protection to homotypic challenge is not dependent on maturation. Finally, we found reduced in vitro ADE at subneutralising serum concentrations for mice immunized with mature bDENV-2. These results suggest that both immature and mature DENV particles play a role in homotypic protection; however, the increased risk of in vitro ADE from immature particles indicates potential safety benefits from mature DENV-based vaccines.

中文翻译：

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登革热病毒成熟对小鼠疫苗诱导体液免疫的影响

抗体依赖性增强 (ADE) 的复杂性阻碍了登革热病毒 (DENV) 疫苗的使用。目前的后期候选疫苗利用减毒和嵌合 DENV，产生不同成熟度的颗粒。由未成熟病毒粒子上优先暴露的表位引发的抗体与 ADE 增加有关。我们旨在使用嵌合昆虫特异性候选疫苗 bDENV-2 进一步了解 AG129 小鼠模型中不同成熟度的 DENV 颗粒促进的体液免疫。我们用成熟、部分成熟和未成熟的 bDENV-2 免疫小鼠，发现用部分成熟的 bDENV-2 免疫比用未成熟或成熟的 bDENV-2 免疫产生更强大和交叉中和的免疫反应。在用小鼠适应的 DENV-2 (D220) 挑战后，我们观察到成熟 bDENV-2 疫苗接种小鼠的保护率为 80%，未成熟和部分成熟的疫苗接种小鼠为 100%，这表明对同型攻击的保护不依赖于成熟。最后，我们发现用成熟 bDENV-2 免疫的小鼠在亚中和血清浓度下体外 ADE 降低。这些结果表明，未成熟和成熟的 DENV 颗粒都在同型保护中起作用。然而，来自未成熟颗粒的体外 ADE 风险增加表明成熟的基于 DENV 的疫苗具有潜在的安全优势。我们发现用成熟 bDENV-2 免疫的小鼠在亚中和血清浓度下体外 ADE 降低。这些结果表明，未成熟和成熟的 DENV 颗粒都在同型保护中起作用。然而，来自未成熟颗粒的体外 ADE 风险增加表明成熟的基于 DENV 的疫苗具有潜在的安全优势。我们发现用成熟 bDENV-2 免疫的小鼠在亚中和血清浓度下体外 ADE 降低。这些结果表明，未成熟和成熟的 DENV 颗粒都在同型保护中起作用。然而，来自未成熟颗粒的体外 ADE 风险增加表明成熟的基于 DENV 的疫苗具有潜在的安全优势。