Immunogenicity of the dengue vaccine CYD-TDV in a dengue virus serotype 1 immune population

蚊媒黄病毒，包括登革热病毒(DENV1-4)，是全球公共卫生的主要威胁 这需要多学科的控制方法。登革热减毒活病毒是我国首例登革热病毒 2019年美国FDA批准疫苗和控制登革热流行的重要新工具 国家。然而，CyD-TDV是一种不完美的疫苗，具有显著的局限性。随机的，安慰剂- 对照试验发现，该疫苗只有在接种给已有DENV免疫力的受试者时才具有保护性。 接种DENV疫苗时，幼稚的受试者更有可能因随后的DENV而住院。因此， FDA只批准了9-16岁实验室确认之前感染过DENV的人接种疫苗， 阻碍疫苗在控制DENV方面发挥的作用，并突出了正在进行的疫苗的必要性 发展完善。目前尚不清楚为什么这种疫苗在DENV免疫中具有更强的免疫原性 与天真无邪的人相比。虽然现有的MBC预计将推动更广泛的交叉- 反应性抗体反应，有可能通过预先存在的循环抗体来增强疫苗病毒 免疫细胞也需要激发有效的免疫反应。在这个假设下，免疫 像在严重的登革热疾病中看到的那样，增强是由疫苗病毒和 DENV交叉反应CD8细胞，驱动疫苗后先天免疫反应产生更广泛和 强大的抗体反应。到目前为止，这一假设在很大程度上仍未得到探索。因此，要解决这一知识 GAP，我们将利用在波多黎各免疫前接种疫苗人群中推出的CyD-TDV来前瞻性地 描述疫苗接种前后的抗体、白细胞和炎症途径。来自这些的结果 预计调查将准确地确定导致某些群体和 为未来疫苗的改进和部署提出新的方法。将实现两个目标。在目标1中 我们对接种前和接种后的DENV型特异性和交叉反应血清抗体进行了表征 DENV免疫前疫苗接种者的人群和DENV特异性MBC频率。我们检验了这一假设 现有的DENV MBC将以一种独特和可预测的方式指导CyD-TDV抗体反应。 具体地说，我们预测预先存在的DENV1免疫将导致显著更高的DENV1类型特异性 接种前分布的DENV2-4交叉反应抗体反应在接种后的抗体滴度 DENV MBC特定的方式。在目标2中，我们评估了CyD-2后的急性先天和获得性免疫反应。 TDV疫苗接种。在这里，我们检验了这样的假设，即急性后遗症之间存在剂量-反应关系。 加强免疫的炎性标志物与接种后DENV的效力和广度 抗体。具体地说，我们将检验后两国关系的力度、方向和意义。 疫苗接种病毒载量、炎症细胞因子水平、自然杀伤细胞、单核细胞和中性粒细胞激活，以及 疫苗接种后DENV特异性抗体的T细胞激活、特异性和效力。

Mosquito-borne flaviviruses, including the dengue viruses (DENV1-4), are a major global public health threats that require multidisciplinary control approaches. The live-attenuated CYD-TDV (Dengvaxia®), is the first dengue vaccine approved by the US FDA in 2019 and an important new tool for controlling dengue illness in endemic countries. However, CYD-TDV is an imperfect vaccine with significant limitations. Randomized, placebo- controlled trials found the vaccine was only protective when given to subjects with pre-existing DENV immunity, while vaccinated DENV naïve subjects were more likely to be hospitalized with subsequent DENV. Thus the FDA only approved the vaccine for individuals aged 9-16 years with laboratory confirmed prior DENV infection, hampering the role the vaccine can play in controlling DENV and highlighting the need for ongoing vaccine development and improvement. It remains unclear why this vaccine is more immunogenic in DENV immune compared to DENV naïve individuals. While pre-existing MBCs are expected to drive the more broadly cross- reactive antibody response, it is possible that vaccine virus enhancement via pre-existing circulating antibodies and immune cells also are required to elicit an effective immune response. Under this hypothesis, immune enhancement, like that seen in severe dengue disease, driven by antibody complexes with vaccine virus and DENV cross-reactive CD8+ cells, drives post-vaccine innate immune response to generate a more broad and potent antibody response. This hypothesis to date remains largely unexplored. Thus, to address the knowledge gap, we will leverage the CYD-TDV rollout in the pre-immune vaccinee population in Puerto Rico to prospectively characterize pre- and post-vaccination antibodies, leukocytes, and inflammatory pathways. Results from these investigations are expected to precisely identify the mechanisms leading to vaccine efficacy in some groups and propose novel approaches for future vaccine refinement and deployment. Two Aims will be carried out. In Aim 1 we Characterize the pre- and post-vaccination DENV type-specific and cross-reactive serum antibody populations and DENV-specific MBC frequencies in DENV pre-immune vaccinees. We test the hypothesis that pre-existing DENV MBCs will direct the CYD-TDV antibody response in a unique and predictable manner. Specifically, we predict that pre-existing DENV1 immunity will lead to significantly higher DENV1 type-specific antibody titers post vaccination with a DENV2-4 cross-reactive antibody response distributed in a pre-vaccination DENV MBC-specific manner. In Aim 2 we evaluate acute innate and adaptive immune responses following CYD- TDV vaccination. Here we test the hypothesis that there is a dose-response relationship between acute post- vaccination inflammatory markers of enhancement and the potency and breadth of post-vaccination DENV antibodies. Specifically, we will test the strength, direction, and significance of the relationship between post- vaccination viral load, inflammatory cytokine levels, natural killer cell, monocyte, and neutrophil activation, and T-cell activation, specificity, and potency of DENV-specific antibodies post-vaccination.