美国国立卫生研究院Robert A. Seder、肯尼亚医学研究所Martina Oneko等研究人员合作完成PfSPZ疫苗对肯尼亚西部婴儿疟疾的安全性、免疫原性和有效性的临床2期评估。这一研究成果于2021年9月13日在线发表在国际学术期刊《自然—医学》上。

据研究人员介绍，辐射减毒的恶性疟原虫孢子虫（PfSPZ）疫苗能够保护未感染疟疾的成年人免受恶性疟原虫感染。临床前研究表明，T细胞介导的免疫力是保护的必要条件，并且在接种疫苗后很容易在人体中诱发。然而，以前的疟疾接触会限制成人的免疫反应和疫苗效力（VE）。

研究人员假设，以前接触疟疾较少的婴儿会有更好的免疫力和保护力。研究人员在336名5-12个月的婴儿中进行了一项多臂、随机、双盲、安慰剂对照试验，用于确定PfSPZ疫苗在肯尼亚西部高传播疟疾环境下的安全性、耐受性、免疫原性和疗效（NCT02687373）。每组84名婴儿接受4.5×10⁵、9.0×10⁵或1.8×10⁶的PfSPZ疫苗或生理盐水，间隔8周，共三次。疫苗的耐受性良好；疫苗组的52名（20.6%）儿童和安慰剂组的20名（23.8%）儿童在接种后28天内发生了相关的诱发性不良事件（AE），大多数是轻度的。疫苗组有1例3级相关的诱发AE（0.4%），安慰剂组有2例（2.4%）。癫痫发作在最高剂量组更为常见（14.3%），而对照组为6.0%，其中大多数是由疟疾引起的。任何剂量组在6个月时对恶性疟原虫感染都没有明显的保护作用（9.0×10⁵剂量组的VE=-6.5%，P=0.598，是这项研究的主要统计终点）。

在最后一剂药后3个月，最高剂量组对临床疟疾的VE为45.8%（P=0.027），这是一个探索性终点。在最低剂量组和最高剂量组中，抗体反应呈剂量依赖性增加，与6个月后的VE相关。所有剂量组的T细胞反应都无法检测到。Vδ2⁺Vγ9⁺T细胞的检测并不频繁，而这些T细胞与诱导PfSPZ疫苗T细胞免疫和成人保护有关。这些数据表明，PfSPZ疫苗诱导的T细胞免疫力与年龄有关，并可能受到Vδ2⁺Vγ9⁺T细胞频率的影响。由于这些婴儿在6个月时没有明显的VE，这些疫苗方案很可能不会在这个年龄组中进一步推行。

附：英文原文

Title: Safety, immunogenicity and efficacy of PfSPZ Vaccine against malaria in infants in western Kenya: a double-blind, randomized, placebo-controlled phase 2 trial

Author: Oneko, Martina, Steinhardt, Laura C., Yego, Reuben, Wiegand, Ryan E., Swanson, Phillip A., KC, Natasha, Akach, Dorcas, Sang, Tony, Gutman, Julie R., Nzuu, Elizabeth L., Dungani, Allan, Kim Lee Sim, B., Oloo, Paul Ndaya, Otieno, Kephas, Bii, Dennis K., Billingsley, Peter F., James, Eric R., Kariuki, Simon, Samuels, Aaron M., Jongo, Said, Chebore, Winnie, Abdulla, Salim, Daubenberger, Claudia, Mpina, Maxmillian, Styers, David, Potter, Gail E., Abarbanell, Ginnie, Richie, Thomas L., Hoffman, Stephen L., Seder, Robert A.

Issue&Volume: 2021-09-13

Abstract: The radiation-attenuated Plasmodium falciparum sporozoite (PfSPZ) vaccine provides protection against P. falciparum infection in malaria-nave 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 4.5×105, 9.0×105 or 1.8×106 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 28d 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 9.0×105 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 Vδ2+Vγ9+ 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 Vδ2+Vγ9+ 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.

DOI: 10.1038/s41591-021-01470-y

Source: https://www.nature.com/articles/s41591-021-01470-y