Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
The Jenner Institute, University of Oxford, Oxford, United Kingdom.
Front Immunol. 2022 Aug 22;13:984323. doi: 10.3389/fimmu.2022.984323. eCollection 2022.
In endemic settings it is known that natural malaria immunity is gradually acquired following repeated exposures. Here we sought to assess whether similar acquisition of blood-stage malaria immunity would occur following repeated parasite exposure by controlled human malaria infection (CHMI). We report the findings of repeat homologous blood-stage (3D7 clone) CHMI studies VAC063C (ClinicalTrials.gov NCT03906474) and VAC063 (ClinicalTrials.gov NCT02927145). In total, 24 healthy, unvaccinated, malaria-naïve UK adult participants underwent primary CHMI followed by drug treatment. Ten of these then underwent secondary CHMI in the same manner, and then six of these underwent a final tertiary CHMI. As with primary CHMI, malaria symptoms were common following secondary and tertiary infection, however, most resolved within a few days of treatment and there were no long term sequelae or serious adverse events related to CHMI. Despite detectable induction and boosting of anti-merozoite serum IgG antibody responses following each round of CHMI, there was no clear evidence of anti-parasite immunity (manifest as reduced parasite growth ) conferred by repeated challenge with the homologous parasite in the majority of volunteers. However, three volunteers showed some variation in parasite growth dynamics following repeat CHMI that were either modest or short-lived. We also observed no major differences in clinical symptoms or laboratory markers of infection across the primary, secondary and tertiary challenges. However, there was a trend to more severe pyrexia after primary CHMI and the absence of a detectable transaminitis post-treatment following secondary and tertiary infection. We hypothesize that this could represent the initial induction of clinical immunity. Repeat homologous blood-stage CHMI is thus safe and provides a model with the potential to further the understanding of naturally acquired immunity to blood-stage infection in a highly controlled setting.
ClinicalTrials.gov, identifier NCT03906474, NCT02927145.
在流行地区，已知自然疟疾免疫力会随着反复暴露而逐渐获得。本研究旨在评估通过受控的人体疟疾感染（CHMI）重复寄生虫暴露是否会产生类似的血期疟疾免疫力。
我们报告了重复同源血期（3D7 克隆）CHMI 研究 VAC063C（ClinicalTrials.gov NCT03906474）和 VAC063（ClinicalTrials.gov NCT02927145）的结果。共有 24 名健康、未接种疫苗、无疟疾的英国成年参与者接受了初次 CHMI 治疗，然后接受药物治疗。其中 10 人以同样的方式接受了二次 CHMI，然后其中 6 人接受了最后一次三次 CHMI。与初次 CHMI 一样，二次和三次感染后常出现疟疾症状，但大多数在治疗后几天内消退，没有与 CHMI 相关的长期后遗症或严重不良事件。尽管每次 CHMI 后都检测到抗裂殖体血清 IgG 抗体反应的诱导和增强，但在大多数志愿者中，重复用同源寄生虫感染并未明显证明具有抗寄生虫免疫力（表现为寄生虫生长减少）。然而，三名志愿者在重复 CHMI 后，寄生虫生长动力学有一些变化，这些变化要么适度，要么短暂。我们还观察到在原发性、继发性和三次性挑战中，临床症状或感染的实验室标志物没有明显差异。然而，在初次 CHMI 后有发热加剧的趋势，并且在二次和三次感染后治疗后没有可检测的转氨酸升高。我们假设这可能代表临床免疫的初始诱导。因此，重复同源血期 CHMI 是安全的，并提供了一个模型，有可能在高度受控的环境中进一步了解自然获得的血期感染免疫力。
ClinicalTrials.gov，标识符 NCT03906474，NCT02927145。
