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 该提案的目的是开发一个新型婴儿恒河猴挑战模型，并使用该模型来 确定年龄在挑战下对疟疾疫苗接种和保护的免疫反应如何影响。疟疾， 由疟原虫寄生虫引起的，每年导致2.25亿感染和40万人死亡。疟疾 负担按年龄分配不均，婴儿和儿童遭受最大的痛苦。目前没有许可 可以提供高水平功效并降低这些人群的传播的疟疾疫苗。最多 先进的候选疫苗候选者针对疟疾孢子虫和肝脏阶段，该阶段是有症状的 感染的血液阶段。其中包括亚基疫苗RTS，S，R21和ME-TRAP，以及活体侵蚀的 Sporozoite疫苗PFSPZ。这些疫苗通过诱导抗孢子虫抗体或细胞毒性赋予保护 T细胞杀死肝脏中感染细胞的细胞。尽管这些候选人在成年人中显示出有希望的疫苗功效 年龄降级试验显示，疫苗免疫原性和疗效随着年龄而有所不同，趋势较差 年轻婴儿的疫苗功效。这归因于婴儿的固有耐受性 免疫系统随着个体年龄的增长而逐渐变化，并且在免疫学上变得更加成熟。 非人类灵长类动物（NHP）是成人人类免疫系统和临床前研究的出色模型 恒河猕猴直接了解了疟疾疫苗临床试验。对于诱导肝特异性T的疫苗 细胞反应，NHP对于识别肝脏的保护相关性特别有价值 在疫苗临床试验中通常无法访问。然而，尽管婴儿和儿童是目标人群 疟疾疫苗，目前没有用于疟疾疫苗评估的婴儿NHP挑战模型。这个建议 将通过建立新的婴儿恒河猴挑战模型来解决这一关键差距，并使用它来定义 年龄对挑战时对疟疾疫苗接种和保护的免疫反应的影响。该模型将使用 NHP适应的疟原虫（PK）疟疾寄生虫和特征良好的PKSPZ实时侵入 Sporozoite疫苗，相当于最近在人类婴儿中测试的PFSPZ疫苗。这种疫苗 策略是理想的，因为众所周知可以在外围和肝脏中诱导抗体和T细胞反应 在成人恒河猕猴中提供大量保护。研究设计将使降级并注册一个 队列年轻的成年动物和另外5-12个月大的婴儿。假设是年龄依赖的 外周和肝特异性免疫反应对疫苗接种的差异将导致疫苗降低 婴儿的功效。由于研究疫苗诱导的T细胞反应在人类婴儿的肝脏中是不可行的，所以 这项研究将是第一个评估发育中婴儿免疫系统固有特征的固有特征 在翻译相关的模型中影响肝T细胞反应。这些研究旨在发射这个新颖的婴儿 NHP研究模型并加速了针对人类婴儿的高效疟疾疫苗的开发。