Malaria vaccine evaluation in a novel infant NHP challenge model

项目总结 本提案的目的是开发一种新的婴儿恒河猴疟疾挑战模型，并使用该模型来 确定年龄对疟疾疫苗接种和挑战保护的免疫反应有何影响。疟疾， 由疟原虫引起，每年造成2.25亿人感染和40万人死亡。疟疾 负担按年龄分配不均，婴儿和儿童遭受的痛苦最大。目前没有获得许可的 疟疾疫苗可以提供高水平的疗效并减少在这些人群中的传播。最多的 先进的候选疫苗针对的是疟疾的子孢子和肝脏阶段，这两个阶段在症状出现之前 感染的血液阶段。这些疫苗包括亚单位疫苗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表现出了良好的疫苗效果， 年龄降级试验表明，疫苗的免疫原性和效力随着年龄的变化而变化，有变差的趋势。 疫苗在较小婴儿中的效力。这归因于婴儿天生的耐受性。 免疫系统，随着个体年龄的增长而逐渐变化，并在免疫上变得更加成熟。 非人灵长类动物是研究人类免疫系统和成人临床前研究的优秀模型。 恒河猴已直接通知疟疾疫苗临床试验。用于诱导肝脏特异性T细胞的疫苗 细胞反应，自肝脏以来，NHP对于识别与保护相关的组织特别有价值 在疫苗临床试验中通常是无法获得的。然而，尽管婴儿和儿童是艾滋病的目标人群 关于疟疾疫苗，目前还没有用于疟疾疫苗评估的婴儿NHP挑战模型。这项建议 将通过建立一种新的婴儿恒河猴疟疾挑战模型并使用它来定义 年龄对疟疾疫苗免疫应答的影响及攻击时的保护。该型号将使用 NHP适应诺氏疟原虫(PK)的原虫及其特性良好的PkSPZ减毒活疫苗 子孢子虫疫苗，相当于最近在人类婴儿身上测试的PfSPZ疫苗。这种疫苗 该策略是理想的，因为众所周知，它可以在外周和肝脏中诱导抗体和T细胞反应，并 为成年恒河猴提供实质性的保护。研究设计将降低年龄并招收一名学生 将年轻的成年动物和另一只5-12个月大的婴儿分组。假设是年龄相关的 外周和肝脏对接种疫苗的免疫反应不同将导致疫苗减少 对婴儿的疗效。由于研究疫苗在婴儿肝脏中诱导的T细胞反应是不可行的， 这项研究将首次评估发育中的婴儿免疫系统的固有特征 在翻译相关模型中影响肝脏T细胞反应。这些研究的目的是推出这个新颖的婴儿 建立NHP研究模型，加快开发用于人类婴儿的高效疟疾疫苗。

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.