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.

包括登革热病毒（DENV 1 - 4）在内的蚊媒黄病毒是全球公共卫生的主要威胁 这需要多学科的控制方法。减毒活CYD-TDV（Dengvaxia®）是第一种登革热病毒， 美国FDA于2019年批准的疫苗，是控制地方性登革热疾病的重要新工具。 国家然而，CYD-TDV是一种不完美的疫苗，具有显着的局限性。随机化，安慰剂- 对照试验发现，该疫苗仅在给予预先存在DENV免疫力的受试者时具有保护性， 而接种DENV初治受试者更有可能因后续DENV而住院。因此 FDA只批准了9 - 16岁的个体使用该疫苗，这些个体先前被实验室证实感染过DENV， 阻碍了疫苗在控制DENV方面的作用，并强调了持续疫苗的必要性。 发展和改进。目前还不清楚为什么这种疫苗在DENV免疫中更具免疫原性， 与DENV naïve个体相比。虽然现有的MBC预计将推动更广泛的交叉- 反应性抗体应答，可能是疫苗病毒通过预先存在的循环抗体增强 免疫细胞也是引发有效免疫应答所必需的。在这种假设下，免疫 增强，就像在严重的登革热疾病中看到的那样，由抗体与疫苗病毒的复合物驱动， DENV交叉反应性CD8+细胞驱动疫苗后先天免疫应答，以产生更广泛和更有效的免疫应答。 有效的抗体反应。这一假设至今仍基本上未被探索。因此，为了解决知识 我们将利用CYD-TDV在波多黎各免疫前接种人群中的推广， 表征疫苗接种前和接种后的抗体、白细胞和炎症途径。从这些 预计研究将精确确定导致疫苗在某些群体中有效的机制， 为未来疫苗的改进和部署提出新的方法。将实现两个目标。目标1 我们表征了疫苗接种前后DENV类型特异性和交叉反应性血清抗体， 在DENV免疫前接种者中的DENV群体和DENV特异性MBC频率。我们检验了一个假设， 预先存在的DENV MBC将以独特和可预测的方式指导CYD-TDV抗体应答。 具体地说，我们预测预先存在的DENV1免疫力将导致显著更高的DENV1类型特异性。 接种后的抗体滴度与接种前分布的DENV 2 - 4交叉反应性抗体应答 DENV MBC特定方式。在目的2中，我们评估了CYD-1后的急性先天性和适应性免疫应答。 TDV疫苗接种。在这里，我们测试的假设，有一个急性后， 增强的疫苗接种炎性标志物以及疫苗接种后DENV的效力和广度 抗体的具体来说，我们将测试后， 疫苗接种病毒载量、炎性细胞因子水平、自然杀伤细胞、单核细胞和中性粒细胞活化，以及 接种后DENV特异性抗体的T细胞活化、特异性和效力。