Malaria vaccine protection against intradermal or venous parasites: a randomized phase 2b human challenge trial.

In animal models, intradermal (ID) sporozoites are more readily blocked than intravenous sporozoites.

在动物模型中，皮内（ID）子孢子比静脉内子孢子更容易被阻断。

We hypothesized that this complicates human studies, where infectious mosquito bites deliver a mixture of ID and venous sporozoites.

我们假设这种情况会使得人体研究复杂化，在这些研究中，感染性的蚊子叮咬会同时传递皮下和静脉的孢子虫。

Here, to test whether vaccine efficacy varies by route of inoculation, we undertook a phase 2b open, randomized controlled trial, recruiting healthy volunteers in Kenya for randomization to the circumsporozoite protein-based R21/Matrix-M vaccine (n = 38), thrombospondin-related adhesive protein fused to a multi-epitope string (ME-TRAP)-based vaccines (n = 24) or to control (n = 18).

在这里，为了测试疫苗效力是否因接种途径而异，我们进行了一项2b期开放、随机对照试验，招募肯尼亚的健康志愿者进行随机分组，接受基于环孢子蛋白的R21/Matrix-M疫苗（n = 38），基于血小板反应蛋白相关粘附蛋白与多表位链融合的疫苗（ME-TRAP）（n = 24）或对照组（n = 18）。

We enrolled 37 of these volunteers to controlled human malaria infection (CHMI) using ID or direct venous injection (DVI) of sporozoites, with PCR monitoring of parasitemia.

我们招募了37名志愿者进行控制性人类疟疾感染(CHMI)，通过皮下注射(ID)或直接静脉注射(DVI)接种孢子虫，并通过PCR监测疟原虫血症。

Systemic and local postvaccination adverse events and systemic CHMI-related events were detected in 4.8%, 12.9% and 72.9% of volunteers, respectively, most commonly fever, headache and fatigue.

在志愿者中，分别检测到4.8%、12.9%和72.9%的人出现了全身性和局部的接种后不良事件以及全身性的CHMI相关事件，最常见的症状是发热、头痛和疲劳。

No serious or severe adverse events were seen.

未观察到严重或危及生命的不良事件。

Seven of 8 (88%) control volunteers and 11 of 12 (92%) ME-TRAP vaccinated volunteers, but none of the 12 R21 vaccinated volunteers receiving ID challenge met the prespecified treatment criteria for the primary endpoint.

在对照组志愿者中有8人中的7人（88%）和接受ME-TRAP疫苗接种的志愿者中有12人中的11人（92%）达到了主要终点的预定治疗标准，而接受R21疫苗接种并接受ID挑战的12名志愿者中没有一人达到。

However, five of five R21 vaccinated volunteers receiving DVI sporozoites met the primary endpoint (P < 0.0005 by log rank across all groups).

然而，所有接受DVI子孢子的5名R21疫苗接种志愿者均达到了主要终点（所有组别中通过对数秩检验，P < 0.0005）。

Secondary efficacy outcomes were similar; that is, R21 vaccinated volunteers receiving ID challenge did not meet any secondary endpoints, whereas volunteers for other groups met secondary endpoints between days 7 and 21 (P < 0.0005, P = 0.0001, P = 0.0007 and P < 0.0005 by log rank for time to parasitemia >20, >500, >1,000 and >10,000, respectively).

次要疗效结果相似；也就是说，接受ID挑战的R21疫苗接种志愿者没有达到任何次要终点，而其他组的志愿者在第7天至第21天之间达到了次要终点（通过对数秩检验，分别在寄生虫血症>20、>500、>1,000和>10,000时，P < 0.0005、P = 0.0001、P = 0.0007和P < 0.0005）。

R21/Matrix-M was highly protective against CHMI using ID. inoculation of sporozoites, but not against DVI sporozoites.

R21/Matrix-M对使用皮内注射的子孢子引起的控制性人类疟疾感染(CHMI)具有很高的保护作用，但对DVI子孢子无效。

CHMI is used in clinical development to select efficacious vaccines and to define correlates of efficacy.

CHMI在临床开发中用于选择有效的疫苗，并定义疗效的相关指标。

Correlates of efficacy for antibodies to sporozoites should also be assessed by separate DVI and ID challenges.

抗体对子孢子的疗效相关因素也应通过单独的DVI和ID挑战进行评估。

The study was registered with ClinicalTrials.gov ( NCT03947190 ) and PACTR ( PACTR202108505632810 ).

该研究已在ClinicalTrials.gov (NCT03947190)和PACTR (PACTR202108505632810)上注册。