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

登革热疫苗 CYD-TDV 在登革热病毒血清型 1 免疫群体中的免疫原性

• 批准号: 10728086
• 负责人: William Messer
• 金额: $ 24.74万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-21 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728086
• 关键词: Acute; Address; Antibodies; Antibody Response; Antibody Specificity; Antibody titer measurement; Area; Attenuated; CD8-Positive T-Lymphocytes; Cells; Collaborations; Complex; Country; Dengue; Dengue Infection; Dengue Vaccine; Dengue Virus; Dengvaxia; Disease; Disease Outbreaks; Dose; Evaluation; Exposure to; Flavivirus; Fostering; Founder Generation; Frequencies; Future; Genes; Genome; Health Sciences; Hospitalization; Immune; Immune response; Immunity; Individual; Inflammatory; Innate Immune Response; Investigation; Knowledge; Laboratories; Leukocytes; Membrane; Memory B-Lymphocyte; Mission; Natural Killer Cells; Neutrophil Activation; Pathway interactions; Phase; Play; Population; Public Health; Puerto Rican; Puerto Rico; Research; Risk; Role; Serotyping; Serum; Shapes; Specificity; Study of serum; T-Cell Activation; Testing; United States National Institutes of Health; Universities; Vaccinated; Vaccination; Vaccinee; Vaccines; Viral Load result; Viremia; Virus; Yellow Fever; Yellow Fever Vaccine; adaptive immune response; aged; burden of illness; cross reactivity; cytokine; immunogenic; immunogenicity; improved; inflammatory marker; innovation; monocyte; mosquito-borne; multidisciplinary; neutralizing antibody; novel strategies; preclinical study; prospective; randomized placebo controlled trial; response; severe dengue; tool; vaccine development; vaccine efficacy

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.

蚊子传播的黄病毒，包括邓古病毒（DENV1-4），是全球主要的公共卫生威胁 这需要多学科控制方法。实时侵蚀的CYD-TDV（Dengvaxia®）是第一个登革热 美国FDA在2019年批准的疫苗，这是控制登革热疾病的重要新工具 国家。但是，CYD-TDV是一种不完善的疫苗，具有显着局限性。随机，安慰剂 - 对照试验发现，只有在接受先前存在的DENV免疫的受试者时，该疫苗才受到保护， 虽然接种疫苗的DENV幼稚受试者更有可能在随后的DENV住院。就是这样 FDA仅批准了9-16岁实验室的个人的疫苗，证实了先前的DENV感染， 阻碍疫苗可以控制DENV并突出疫苗的需求 发展和改进。尚不清楚为什么这种疫苗在DENV免疫中更具免疫原性 与denv幼稚的个体相比。虽然预计先前存在的MBC将推动更广泛的交叉 反应性抗体反应，疫苗病毒可能通过预先存在的循环抗体增强 还需要免疫细胞引发有效的免疫响应。在这个假设下，免疫 像在严重风扇中看到的那样，由疫苗病毒和 DENV交叉反应性CD8+细胞，驱动疫苗的先天免疫响应产生更宽和更宽的 潜在的抗体反应。迄今为止，这个假设在很大程度上仍然是出乎意料的。这是为了解决知识 差距，我们将利用波多黎各的免疫疫苗人口中的CYD-TDV推出 表征前后疫苗发生后抗体，白细胞和炎症途径。这些结果 预计调查将准确确定导致某些组疫苗效率的机制，以及 提案的新方法，用于未来的疫苗改进和部署。将执行两个目标。在目标1中 我们表征了疫苗发生前后DENV类型特异性和交叉反应性血清抗体 DENV免疫前疫苗的种群和DENV特异性MBC频率。我们检验了以下假设 现有的DENV MBC将以独特且可预测的方式指导CYD-TDV抗体反应。 具体而言，我们预测现有的DENV1免疫学将导致更高的DENV1特异性 抗体滴度在疫苗接种后用DENV2-4交叉反应抗体反应分布在预疫苗中 DENV MBC特定方式。在AIM 2中，我们评估了CYD-之后的急性先天和适应性免疫回报 TDV疫苗接种。在这里，我们检验了以下假设：急性后急性响应关系 增强的疫苗炎症标志物以及疫苗后DENV的效力和广度 抗体。特别是，我们将测试后的强度，方向和意义 疫苗接种病毒负荷，炎性细胞因子水平，天然杀伤细胞，单核细胞和中性粒细胞活化，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。