Malaria vaccine evaluation in a novel infant NHP challenge model

新型婴儿 NHP 攻击模型中的疟疾疫苗评估

• 批准号: 10592678
• 负责人: Melanie Janet Shears
• 金额: $ 35.3万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-04 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10592678
• 关键词: Acceleration; Adjuvant; Adult; Age; Animals; Antibodies; Antibody titer measurement; Attenuated; Autopsy; B-Lymphocytes; Blood; Cell physiology; Cells; Cessation of life; Characteristics; Child; Childhood; Clinical Trials; Clinical assessments; Communicable Diseases; Cytotoxic T-Lymphocytes; Data; Development; Disease; Dose; Enrollment; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunization; Immunological Models; Immunologics; Individual; Infant; Infection; Intravenous; Licensing; Liver; Longevity; Macaca mulatta; Malaria; Malaria Vaccines; Modeling; Morbidity - disease rate; Nature; Parasites; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Plasma; Plasmodium; Plasmodium falciparum vaccine; Plasmodium knowlesi; Population; Research; Research Design; Reverse Transcriptase Polymerase Chain Reaction; Rhesus; Ribosomal RNA; Route; Sampling; Schedule; Shapes; Sporozoite vaccine; Sporozoites; Subunit Vaccines; Symptoms; System; Systems Development; T cell response; T-Lymphocyte; Target Populations; Testing; Tissues; Vaccination; Vaccine Clinical Trial; Vaccines; age effect; age group; age related; cell killing; cohort; diagnostic assay; human model; immunogenicity; infant infection; liver biopsy; malaria infection; malaria transmission; mature animal; mortality; nonhuman primate; novel; peripheral blood; preclinical study; response; transmission process; trend; vaccination outcome; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vaccine immunogenicity; vaccine response; vaccine strategy; vaccine trial; young adult

PROJECT SUMMARY The objective of this proposal is to develop a novel infant rhesus malaria challenge model and use this model to determine how age impacts immune responses to malaria vaccination and protection at challenge. Malaria, caused by Plasmodium parasites, is responsible for 225 million infections and 400,000 deaths per year. Malaria burden is unevenly distributed by age, with infants and children suffering most. There is currently no licensed malaria vaccine that can provide high level efficacy and reduce transmission in these populations. The most advanced vaccine candidates target the malaria sporozoite and liver stages, which precede the symptomatic blood stage of infection. These include the subunit vaccines RTS,S, R21, and ME-TRAP, and the live-attenuated sporozoite vaccine PfSPZ. These vaccines confer protection by inducing anti-sporozoite antibodies or cytotoxic T cells that kill infected cells in the liver. While these candidates have shown promising vaccine efficacy in adults, age de-escalation trials have revealed vaccine immunogenicity and efficacy vary with age, with a trend for poorer vaccine efficacy in younger infants. This has been attributed to the inherently tolerogenic nature of the infant immune system, which gradually changes as the individual ages and becomes more immunologically mature. Non-human primates (NHPs) are excellent models of the human immune system and pre-clinical studies in adult rhesus macaques have directly informed malaria vaccine clinical trials. For vaccines that induce liver-specific T cell responses, NHPs have been particularly valuable for identifying tissue correlates of protection since the liver is typically inaccessible in vaccine clinical trials. Yet, despite infants and children being the target population for malaria vaccines, there is currently no infant NHP challenge model for malaria vaccine evaluation. This proposal will address this critical gap by establishing a novel infant rhesus malaria challenge model and using it to define the effect of age on immune responses to malaria vaccination and protection at challenge. This model will use the NHP-adapted Plasmodium knowlesi (Pk) malaria parasite and the well-characterized PkSPZ live-attenuated sporozoite vaccine, which is equivalent to the PfSPZ vaccine recently tested in human infants. This vaccine strategy is ideal as it is known to induce antibodies and T cell responses in both the periphery and liver and confer substantial protection in adult rhesus macaques. The study design will age de-escalate and enroll one cohort young adult animals and another of 5-12 month old infants. The hypothesis is that age-dependent differences in peripheral and liver-specific immune responses to vaccination will result in decreased vaccine efficacy in the infants. As it is infeasible to study vaccine-induced T cell responses in the liver of human infants, this study will be the first to assess how the inherent characteristics of the developing infant immune system impact liver T cell responses in a translationally relevant model. These studies aim to launch this novel infant NHP research model and accelerate the development of a highly effective malaria vaccine for human infants.

项目摘要 本提案的目的是开发一种新的婴儿恒河猴疟疾攻击模型，并使用该模型来 确定年龄如何影响对疟疾疫苗接种的免疫反应和挑战时的保护。疟疾， 由疟原虫寄生虫引起的疟疾每年造成2.25亿人感染和40万人死亡。疟疾 负担按年龄分布不均，婴儿和儿童受害最重。目前没有许可的 疟疾疫苗，可以提供高水平的效力，并减少在这些人群中的传播。最 先进的候选疫苗针对疟疾子孢子和肝脏阶段，这是症状出现之前的阶段。 血液感染阶段。这些包括亚单位疫苗RTS、S、R21和ME-TRAP，以及减毒活疫苗。 子孢子疫苗PfSPZ。这些疫苗通过诱导抗子孢子抗体或细胞毒性抗体来提供保护。 杀死肝脏中受感染细胞的T细胞。虽然这些候选疫苗在成人中显示出有希望的疫苗功效， 年龄递减试验显示，疫苗免疫原性和有效性随年龄而变化， 疫苗对年幼婴儿的效果。这归因于婴儿固有的致耐受性 免疫系统，随着个体年龄的增长而逐渐变化，变得更加免疫成熟。 非人灵长类动物（NHP）是研究人类免疫系统和成人临床前研究的理想模型 恒河猴直接为疟疾疫苗临床试验提供了信息。对于诱导肝脏特异性T细胞的疫苗， 细胞反应，NHP对于鉴定保护的组织相关性特别有价值，因为肝脏 在疫苗临床试验中通常无法获得。然而，尽管婴儿和儿童是 虽然目前还没有婴儿NHP攻毒模型用于疟疾疫苗的评估，这项建议 将通过建立一个新的婴儿恒河猴疟疾挑战模型来解决这一关键差距，并利用它来定义 年龄对疟疾疫苗免疫应答和攻毒保护的影响。该模型将使用 NHP适应的诺氏疟原虫（Pk）疟疾寄生虫和充分表征的PkSPZ减毒活 子孢子疫苗，其等同于最近在人类婴儿中测试的PfSPZ疫苗。这种疫苗 该策略是理想的，因为已知其在外周和肝脏中诱导抗体和T细胞应答， 在成年恒河猴中提供实质性保护。研究设计将年龄递减并招募一名 一组年轻的成年动物和另一组5-12个月大的婴儿。假设是年龄依赖的 对疫苗接种的外周和肝脏特异性免疫应答的差异将导致疫苗接种率降低， 对婴儿的功效。由于在人类婴儿的肝脏中研究疫苗诱导的T细胞应答是不可行的， 这项研究将是第一个评估婴儿免疫系统发育的内在特征 影响免疫相关模型中的肝T细胞应答。这些研究旨在推出这种新颖的婴儿 NHP研究模型，并加速为人类婴儿开发高效疟疾疫苗。