BACKGROUND Currently licensed and approved malaria subunit vaccines provide modest, short-lived protection against malaria. Immunization with live-attenuated Plasmodium falciparum malaria parasites is an alternative vaccination strategy that has potential to improve protection. METHODS We conducted a double-blind, controlled clinical trial to evaluate the safety, side-effect profile, and efficacy of immunization, by means of mosquito bites, with a second-generation genetically attenuated parasite (GA2) - a mei2 single knockout P. falciparum NF54 parasite (sporozoite form) with extended development into the liver stage. After an open-label dose-escalation safety phase in which participants were exposed to the bites of 15 or 50 infected mosquitoes (stage A), healthy adults who had not had malaria were randomly assigned to be exposed to 50 mosquito bites per immunization of GA2, an early-arresting parasite (GA1), or placebo (bites from uninfected mosquitoes) (stage B). After the completion of three immunization sessions with 50 mosquito bites per session, we compared the protective efficacy of GA2 against homologous P. falciparum controlled human malaria infection with that of GA1 and placebo. The primary end points were the number and severity of adverse events (in stages A and B) and blood-stage parasitemia greater than 100 P. falciparum parasites per milliliter after bites from GA2-infected mosquitoes (in stage A) and after controlled human malaria infection (in stage B). RESULTS Adverse events were similar across the trial groups. Protective efficacy against subsequent controlled human malaria infection was observed in 8 of 9 participants (89%) in the GA2 group, in 1 of 8 participants (13%) in the GA1 group, and in 0 of 3 participants in the placebo group. A significantly higher frequency of P. falciparum-specific polyfunctional CD4+ and Vδ2+ γδ T cells were observed among participants who received GA2 than among those who received GA1, whereas GA2 and GA1 induced similar antibody titers targeting the P. falciparum circumsporozoite protein. CONCLUSIONS In this small trial, GA2 was associated with a favorable immune induction profile and protective efficacy, findings that warrant further evaluation. (Funded by the Bontius Foundation; ClinicalTrials.gov number, NCT04577066.).

中文翻译：

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使用晚期肝期减毒疟疾寄生虫免疫的安全性和有效性。


背景 目前获得许可和批准的疟疾亚单位疫苗提供适度、短暂的疟疾保护。使用恶性疟原虫疟疾寄生虫减毒活免疫是一种替代疫苗接种策略，有可能提高保护作用。方法 我们进行了一项双盲、对照临床试验，以评估通过蚊虫叮咬免疫的安全性、副作用和有效性，使用第二代基因减毒寄生虫 （GA2） - 一种 mei2 单敲除恶性疟原虫 NF54 寄生虫（子孢子形式）延长发育到肝脏阶段。在参与者暴露于 15 或 50 只受感染蚊子叮咬（A 阶段）的开放标签剂量递增安全阶段之后，未患疟疾的健康成年人被随机分配在每次免疫 GA2、早期阻止寄生虫 （GA1） 或安慰剂（未感染蚊子叮咬）时暴露于 50 次蚊子叮咬（B 阶段）。在完成 3 次免疫接种（每次 50 次蚊虫叮咬）后，我们将 GA2 对恶性疟原虫控制的同源疟疾感染的保护效能与 GA1 和安慰剂的保护效能进行了比较。主要终点是不良事件的数量和严重程度（A 期和 B 期）以及血液期寄生虫血症在 GA2 感染蚊子叮咬后（A 阶段）和受控人类疟疾感染后（B 阶段）每毫升大于 100 个恶性疟原虫寄生虫。结果 各试验组的不良事件相似。在 GA2 组的 9 名参与者中有 8 名 （89%） 、GA1 组 8 名参与者中有 1 名 （13%） 和安慰剂组 3 名参与者中有 0 名观察到对随后受控的人类疟疾感染的保护效果。 在接受 GA2 的参与者中观察到恶性疟原虫特异性多功能 CD4 + 和 Vδ2+ γδ T 细胞的频率显著高于接受 GA1 的参与者，而 GA2 和 GA1 诱导针对恶性疟原虫圆子孢子蛋白的抗体滴度相似。结论 在这项小型试验中，GA2 与良好的免疫诱导特征和保护功效相关，这些发现值得进一步评估。（由 Bontius 基金会资助;ClinicalTrials.gov 编号，NCT04577066 ）。