Center for Global Infectious Disease Research, Seattle Children's Hospital, Seattle, WA, USA.
Malaria Department, Naval Medical Research Center, Silver Spring, MD, USA.
Malar J. 2021 Jul 9;20(1):308. doi: 10.1186/s12936-021-03839-3.
Vaccination with radiation-attenuated Plasmodium falciparum sporozoites is known to induce protective immunity. However, the mechanisms underlying this protection remain unclear. In this work, two recent radiation-attenuated sporozoite vaccination studies were used to identify potential transcriptional correlates of vaccination-induced protection.
Longitudinal whole blood RNAseq transcriptome responses to immunization with radiation-attenuated P. falciparum sporozoites were analysed and compared across malaria-naïve adult participants (IMRAS) and malaria-experienced adult participants (BSPZV1). Parasite dose and method of delivery differed between trials, and immunization regimens were designed to achieve incomplete protective efficacy. Observed protective efficacy was 55% in IMRAS and 20% in BSPZV1. Study vaccine dosings were chosen to elicit both protected and non-protected subjects, so that protection-associated responses could be identified.
Analysis of comparable time points up to 1 week after the first vaccination revealed a shared cross-study transcriptional response programme, despite large differences in number and magnitude of differentially expressed genes between trials. A time-dependent regulatory programme of coherent blood transcriptional modular responses was observed, involving induction of inflammatory responses 1-3 days post-vaccination, with cell cycle responses apparent by day 7 in protected individuals from both trials. Additionally, strongly increased induction of inflammation and interferon-associated responses was seen in non-protected IMRAS participants. All individuals, except for non-protected BSPZV1 participants, showed robust upregulation of cell-cycle associated transcriptional responses post vaccination.
In summary, despite stark differences between the two studies, including route of vaccination and status of malaria exposure, responses were identified that were associated with protection after PfRAS vaccination. These comprised a moderate early interferon response peaking 2 days post vaccination, followed by a later proliferative cell cycle response steadily increasing over the first 7 days post vaccination. Non-protection is associated with deviations from this model, observed in this study with over-induction of early interferon responses in IMRAS and failure to mount a cell cycle response in BSPZV1.
已证实，辐射减毒疟原虫孢子囊的疫苗接种可诱导保护性免疫。然而，这种保护作用的机制仍不清楚。在这项工作中，我们使用了两项最近的辐射减毒孢子囊疫苗接种研究，以确定疫苗接种诱导保护的潜在转录相关性。
对来自疟原虫初免的成年参与者（IMRAS）和疟原虫感染成年参与者（BSPZV1）的纵向全血 RNAseq 转录组对辐射减毒疟原虫孢子囊免疫接种的反应进行了分析，并进行了比较。两项试验中寄生虫剂量和接种方法不同，免疫方案旨在实现不完全的保护效力。在 IMRAS 中观察到 55%的保护效力，在 BSPZV1 中观察到 20%的保护效力。研究疫苗剂量被选择为了引起既受保护又不受保护的个体，从而可以确定与保护相关的反应。
在第一次接种后 1 周内分析可比时间点发现，尽管两个试验之间差异表达基因的数量和幅度存在很大差异，但存在一个共享的跨研究转录反应方案。观察到一个与时间相关的血液转录模块反应的调节程序，在接种后 1-3 天诱导炎症反应，在两个试验的保护性个体中，第 7 天可见细胞周期反应。此外，在未受保护的 IMRAS 参与者中，强烈诱导炎症和干扰素相关反应。除了未受保护的 BSPZV1 参与者外，所有个体在接种疫苗后均表现出细胞周期相关转录反应的强烈上调。
尽管两个研究之间存在很大差异，包括接种途径和疟疾暴露状态，但识别出了与 PfRAS 疫苗接种后保护相关的反应。这些反应包括接种后 2 天达到峰值的中度早期干扰素反应，随后是细胞周期反应的后期增殖，在接种后第 1 天逐渐增加。在这项研究中，未受保护的个体表现出这种模式的偏差，表现为 IMRAS 中早期干扰素反应过度诱导，而 BSPZV1 中未能产生细胞周期反应。
