Kenya Medical Research Institute, Centre for Global Health Research, Kisumu, Kenya.
Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Nat Med. 2021 Sep;27(9):1636-1645. doi: 10.1038/s41591-021-01470-y. Epub 2021 Sep 13.
The radiation-attenuated Plasmodium falciparum sporozoite (PfSPZ) vaccine provides protection against P. falciparum infection in malaria-naïve adults. Preclinical studies show that T cell-mediated immunity is required for protection and is readily induced in humans after vaccination. However, previous malaria exposure can limit immune responses and vaccine efficacy (VE) in adults. We hypothesized that infants with less previous exposure to malaria would have improved immunity and protection. We conducted a multi-arm, randomized, double-blind, placebo-controlled trial in 336 infants aged 5-12 months to determine the safety, tolerability, immunogenicity and efficacy of the PfSPZ Vaccine in infants in a high-transmission malaria setting in western Kenya ( NCT02687373 ). Groups of 84 infants each received 4.5 × 10, 9.0 × 10 or 1.8 × 10 PfSPZ Vaccine or saline three times at 8-week intervals. The vaccine was well tolerated; 52 (20.6%) children in the vaccine groups and 20 (23.8%) in the placebo group experienced related solicited adverse events (AEs) within 28 d postvaccination and most were mild. There was 1 grade 3-related solicited AE in the vaccine group (0.4%) and 2 in the placebo group (2.4%). Seizures were more common in the highest-dose group (14.3%) compared to 6.0% of controls, with most being attributed to malaria. There was no significant protection against P. falciparum infection in any dose group at 6 months (VE in the 9.0 × 10 dose group = -6.5%, P = 0.598, the primary statistical end point of the study). VE against clinical malaria 3 months after the last dose in the highest-dose group was 45.8% (P = 0.027), an exploratory end point. There was a dose-dependent increase in antibody responses that correlated with VE at 6 months in the lowest- and highest-dose groups. T cell responses were undetectable across all dose groups. Detection of Vδ2Vγ9 T cells, which have been correlated with induction of PfSPZ Vaccine T cell immunity and protection in adults, were infrequent. These data suggest that PfSPZ Vaccine-induced T cell immunity is age-dependent and may be influenced by Vδ2Vγ9 T cell frequency. Since there was no significant VE at 6 months in these infants, these vaccine regimens will likely not be pursued further in this age group.
辐射减毒恶性疟原虫孢子（PfSPZ）疫苗可预防无疟疾史的成年人感染恶性疟原虫。临床前研究表明，T 细胞介导的免疫是预防的必要条件，且在接种疫苗后可在人类中迅速诱导。然而，先前的疟疾暴露会限制成年人的免疫反应和疫苗效力（VE）。我们假设，先前较少接触疟疾的婴儿会具有更好的免疫和保护作用。我们在肯尼亚西部一个高疟疾传播地区的 336 名 5-12 个月大的婴儿中进行了一项多臂、随机、双盲、安慰剂对照试验，以确定 PfSPZ 疫苗在该人群中的安全性、耐受性、免疫原性和疗效（NCT02687373）。每组 84 名婴儿分别接受 4.5×10、9.0×10 或 1.8×10 PfSPZ 疫苗或生理盐水三次，间隔 8 周。疫苗具有良好的耐受性；接种疫苗的 52 名儿童（20.6%）和安慰剂组的 20 名儿童（23.8%）在接种疫苗后 28 天内发生了 52 次与疫苗相关的不良事件（AE），大多数为轻度。疫苗组有 1 例 3 级相关不良事件（0.4%），安慰剂组有 2 例（2.4%）。与对照组相比，最高剂量组（14.3%）更常见癫痫发作，而对照组为 6.0%，大多数癫痫发作归因于疟疾。在任何剂量组中，6 个月时对恶性疟原虫感染均无显著保护作用（9.0×10 剂量组的 VE=-6.5%，P=0.598，是本研究的主要统计学终点）。最高剂量组末次接种后 3 个月时对临床疟疾的 VE 为 45.8%（P=0.027），这是一个探索性终点。在最低和最高剂量组中，抗体反应呈剂量依赖性增加，与 6 个月时的 VE 相关。所有剂量组均未检测到 T 细胞反应。在成年人中，与 PfSPZ 疫苗 T 细胞免疫诱导和保护相关的 Vδ2Vγ9 T 细胞的检测频率较低。这些数据表明，PfSPZ 疫苗诱导的 T 细胞免疫与年龄相关，可能受 Vδ2Vγ9 T 细胞频率的影响。由于在这些婴儿中 6 个月时没有显著的 VE，因此不太可能在该年龄组进一步研究这些疫苗方案。
