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.

蚊媒黄病毒，包括登革热病毒 (DENV1-4)，是全球主要的公共卫生威胁 需要多学科控制方法的减毒活 CYD-TDV (Dengvaxia®) 是第一种登革热。 疫苗于2019年获得美国FDA批准，是控制地方性登革热疾病的重要新工具 然而，CYD-TDV 是一种不完善的疫苗，具有显着的局限性。 对照试验发现，该疫苗只有在给予预先存在 DENV 免疫力的受试者时才具有保护作用， 而未接触过 DENV 的受试者更有可能因随后的 DENV 而住院。 FDA 仅批准该疫苗用于实验室确认既往感染过 DENV 的 9-16 岁个体， 阻碍了疫苗在控制登革热病毒方面发挥的作用，并强调了持续开发疫苗的必要性 目前尚不清楚为什么该疫苗在 DENV 免疫中更具免疫原性。 与 DENV 幼稚个体相比，而预先存在的 MBC 预计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 根据这一假设，免疫细胞也需要引发有效的免疫反应。 增强，就像在严重登革热疾病中看到的那样，由疫苗病毒和抗体复合物驱动 DENV 交叉反应 CD8+ 细胞，驱动疫苗后先天免疫反应，产生更广泛和更广泛的免疫反应。 迄今为止，这一假设在很大程度上尚未得到探索。 差距，我们将利用 CYD-TDV 在波多黎各免疫前疫苗接种人群中的推广，前瞻性地 表征疫苗接种前和疫苗后的抗体、白细胞和炎症途径的结果。 预计调查将准确确定导致疫苗在某些群体中发挥功效的机制 目标 1 将实施未来疫苗完善和部署的新提案方法。 我们表征了接种前和接种后 DENV 类型特异性和交叉反应性血清抗体 我们检验了以下假设： 预先存在的 DENV MBC 将以独特且可预测的方式指导 CYD-TDV 抗体反应。 具体来说，我们预测预先存在的 DENV1 免疫力将导致显着更高的 DENV1 类型特异性 接种后抗体滴度与接种前分布的 DENV2-4 交叉反应抗体反应 在目标 2 中，我们评估了 CYD-后的急性先天性和适应性免疫反应。 在这里，我们检验了急性后遗症之间存在剂量反应关系的假设。 疫苗接种炎症标志物的增强以及疫苗接种后 DENV 的效力和广度 具体来说，我们将测试后抗体之间关系的强度、方向和显着性。 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 疫苗接种后 DENV 特异性抗体的 T 细胞激活、特异性和效力。