Department of Medical Microbiology, Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein Zuid 28, 6525 GA, Nijmegen, The Netherlands.
Present affiliation: TropIQ Health Sciences, Transistorweg 5-C02, 6534 AT, Nijmegen, The Netherlands.
BMC Med. 2023 Apr 7;21(1):137. doi: 10.1186/s12916-023-02788-9.
Whole sporozoite immunization under chemoprophylaxis (CPS regime) induces long-lasting sterile homologous protection in the controlled human malaria infection model using Plasmodium falciparum strain NF54. The relative proficiency of liver-stage parasite development may be an important factor determining immunization efficacy. Previous studies show that Plasmodium falciparum strain NF135 produces relatively high numbers of large liver-stage schizonts in vitro. Here, we evaluate this strain for use in CPS immunization regimes.
In a partially randomized, open-label study conducted at the Radboudumc, Nijmegen, the Netherlands, healthy, malaria-naïve adults were immunized by three rounds of fifteen or five NF135-infected mosquito bites under mefloquine prophylaxis (cohort A) or fifteen NF135-infected mosquito bites and presumptive treatment with artemether/lumefantrine (cohort B). Cohort A participants were exposed to a homologous challenge 19 weeks after immunization. The primary objective of the study was to evaluate the safety and tolerability of CPS immunizations with NF135.
Relatively high liver-to-blood inocula were observed during immunization with NF135 in both cohorts. Eighteen of 30 (60%) high-dose participants and 3/10 (30%) low-dose participants experienced grade 3 adverse events 7 to 21 days following their first immunization. All cohort A participants and two participants in cohort B developed breakthrough blood-stage malaria infections during immunizations requiring rescue treatment. The resulting compromised immunizations induced modest sterile protection against homologous challenge in cohort A (5/17; 29%).
These CPS regimes using NF135 were relatively poorly tolerated and frequently required rescue treatment, thereby compromising immunization efficiency and protective efficacy. Consequently, the full potential of NF135 sporozoites for induction of immune protection remains inconclusive. Nonetheless, the high liver-stage burden achieved by this strain highlights it as an interesting potential candidate for novel whole sporozoite immunization approaches.
The trial was registered at ClinicalTrials.gov under identifier NCT03813108.
在使用恶性疟原虫 NF54 株的人体疟疾感染受控模型中，采用全孢子免疫接种联合化学预防（CPS 方案）可诱导持久的同源性无菌保护。肝期寄生虫发育的相对效率可能是决定免疫接种效果的一个重要因素。先前的研究表明，恶性疟原虫 NF135 株在体外产生相对大量的大型肝期裂殖体。在此，我们评估该株用于 CPS 免疫接种方案。
在荷兰奈梅亨拉德布德大学医学中心进行的一项部分随机、开放性标签研究中，健康的、无疟疾史的成年人接受三轮十五或五剂感染 NF135 的蚊子叮咬进行免疫接种，同时采用甲氟喹预防（队列 A）或十五剂感染 NF135 的蚊子叮咬并假定采用青蒿琥酯/ 阿莫地喹治疗（队列 B）。队列 A 参与者在免疫接种后 19 周接受同源性挑战。该研究的主要目的是评估采用 NF135 进行 CPS 免疫接种的安全性和耐受性。
在两轮研究中，用 NF135 进行免疫接种时，观察到相对较高的肝血接种量。高剂量组的 18 名参与者（60%）和低剂量组的 3 名参与者（30%）在首次免疫接种后 7 至 21 天出现 3 级不良事件。所有队列 A 参与者和队列 B 的两名参与者在免疫接种期间发生突破性血期疟疾感染，需要进行抢救治疗。由此导致免疫接种效率受损，在队列 A 中仅对同源性挑战产生适度的无菌保护（17 名参与者中 5 名，29%）。
这些采用 NF135 的 CPS 方案耐受性相对较差，且经常需要抢救治疗，从而影响了免疫接种效率和保护效果。因此，NF135 孢子虫诱导免疫保护的全部潜力仍不确定。尽管如此，该株的高肝期负担突出了其作为新型全孢子免疫接种方法的潜在候选者的地位。
该试验在 ClinicalTrials.gov 注册，编号为 NCT03813108。
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