Background

WHO recently approved a partially effective vaccine that reduces clinical malaria in children, but increased vaccine activity is required to pursue malaria elimination. A phase 1 clinical trial was done in Mali, west Africa, to assess the safety, immunogenicity, and protective efficacy of a three-dose regimen of Plasmodium falciparum sporozoite (PfSPZ) Vaccine (a metabolically active, non-replicating, whole malaria sporozoite vaccine) against homologous controlled human malaria infection (CHMI) and natural P falciparum infection.

Methods

We recruited healthy non-pregnant adults aged 18–50 years in Donéguébougou, Mali, and surrounding villages (Banambani, Toubana, Torodo, Sirababougou, Zorokoro) for an open-label, dose-escalation pilot study and, thereafter, a randomised, double-blind, placebo-controlled main trial. Pilot study participants were enrolled on an as-available basis to one group of CHMI infectivity controls and three staggered vaccine groups receiving: one dose of 4·5 × 10⁵, one dose of 9 × 10⁵, or three doses of 1·8 × 10⁶ PfSPZ via direct venous inoculation at approximately 8 week intervals, followed by homologous CHMI 5 weeks later with infectious PfSPZ by direct venous inoculation (PfSPZ Challenge). Main cohort participants were stratified by village and randomly assigned (1:1) to receive three doses of 1·8 × 10⁶ PfSPZ or normal saline at 1, 13, and 19 week intervals using permuted block design by the study statistician. The primary outcome was safety and tolerability of at least one vaccine dose; the secondary outcome was vaccine efficacy against homologous PfSPZ CHMI (pilot study) or against naturally transmitted P falciparum infection (main study) measured by thick blood smear. Combined artesunate and amodiaquine was administered to eliminate pre-existing parasitaemia. Outcomes were analysed by modified intention to treat (mITT; including all participants who received at least one dose of investigational product; safety and vaccine efficacy) and per protocol (vaccine efficacy). This trial is registered with ClinicalTrials.gov, number NCT02627456.

Findings

Between Dec 20, 2015, and April 30, 2016, we enrolled 56 participants into the pilot study (five received the 4·5 × 10⁵ dose, five received 9 × 10⁵, 30 received 1·8 × 10⁶, 15 were CHMI controls, and one withdrew before vaccination) and 120 participants into the main study cohort with 60 participants assigned PfSPZ Vaccine and 60 placebo in the main study. Adverse events and laboratory abnormalities post-vaccination in all dosing groups were few, mainly mild, and did not differ significantly between vaccine groups (all p>0·05). Unexpected severe transaminitis occured in four participants: one participant in pilot phase that received 1·8 × 10⁶ PfSPZ Vaccine, one participant in main phase that received 1·8 × 10⁶ PfSPZ Vaccine, and two participants in the main phase placebo group. During PfSPZ CHMI, approximately 5 weeks after the third dose of 1·8 × 10⁶ PfSPZ, none of 29 vaccinees and one of 15 controls became positive on thick blood smear; subsequent post-hoc PCR analysis for submicroscopic blood stage infections detected P falciparum parasites in none of the 29 vaccine recipients and eight of 15 controls during CHMI. In the main trial, 32 (58%) of 55 vaccine recipients and 42 (78%) of 54 controls became positive on thick blood smear during 24-week surveillance after vaccination. Vaccine efficacy (1–hazard ratio) was 0·51 per protocol (95% CI 0·20–0·70; log-rank p=0·0042) and 0·39 by mITT (0·04–0·62; p=0·033); vaccine efficacy (1–risk ratio) was 0·24 per-protocol (0·02–0·41; p=0·031) and 0·22 mITT (0·01–0·39; p=0·041).

Interpretation

A three-dose regimen of PfSPZ Vaccine was safe, well tolerated, and conferred 51% vaccine efficacy against intense natural P falciparum transmission, similar to 52% vaccine efficacy reported for a five-dose regimen in a previous trial.

Funding

US National Institute of Allergy and Infectious Diseases, National Institutes of Health, Sanaria.

Translation

For the French translation of the abstract see Supplementary Materials section.

中文翻译：

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在马里严重的疟疾传播季节期间，成人恶性疟原虫子孢子疫苗三剂方案的安全性和有效性：一项随机、对照的 1 期试验

背景

世卫组织最近批准了一种部分有效的疫苗，可减少儿童的临床疟疾，但需要提高疫苗活性才能消除疟疾。在西非马里进行了 1 期临床试验，以评估恶性疟原虫子孢子( PfSPZ) 疫苗（一种具有代谢活性、非复制性的全疟疾子孢子疫苗）三剂方案的安全性、免疫原性和保护功效) 对抗同源受控人类疟疾感染 (CHMI) 和自然恶性疟原虫感染。

方法

我们在马里 Donéguébougou 和周边村庄（Banambani、Toubana、Torodo、Sirababougou、Zorokoro）招募了 18-50 岁的健康未怀孕成年人进行开放标签、剂量递增试验研究，然后进行随机、双-盲法、安慰剂对照的主要试验。试点研究参与者在可用的基础上被纳入一组 CHMI 感染性控制和三个交错的疫苗组接受：一剂 4·5 × 10 5 ，一剂 9 × 10 5 ，或三^剂1 ^· 8 × 10 ⁶以大约 8 周的间隔通过直接静脉接种 PfSPZ，然后在 5 周后通过直接静脉接种与感染性 PfSPZ 进行同源 CHMI（PfSPZ 挑战）。主要队列参与者按村庄分层并随机分配 (1:1) 接受三剂 1·8 × 10 6 ^PfSPZ或生理盐水，间隔为 1、13 和 19 周，由研究统计学家使用置换区组设计。主要结果是至少一剂疫苗的安全性和耐受性；次要结果是针对同源 PfSPZ CHMI（试点研究）或针对自然传播的恶性疟原虫的疫苗效力感染（主要研究）通过厚血涂片测量。给予联合青蒿琥酯和阿莫地喹以消除预先存在的寄生虫血症。通过修改后的治疗意向（mITT；包括接受至少一剂研究产品的所有参与者；安全性和疫苗效力）和符合方案（疫苗效力）分析结果。该试验已在 ClinicalTrials.gov 注册，编号为 NCT02627456。

发现

2015 年 12 月 20 日至 2016 年 4 月 30 日期间，我们招募了 56 名参与者参加试点研究（5 人接受 4·5 × 10 5 剂量，5 人接受⁹ × 10 ^{5 剂量}，30 人接受 1·8 × 10 ^{6 剂量}，15 人接受CHMI 对照组，一名在接种疫苗前退出）和 120 名参与者进入主要研究队列，其中 60 名参与者在主要研究中分配了 PfSPZ 疫苗和 60 名安慰剂。所有剂量组接种疫苗后的不良事件和实验室异常很少，主要是轻微的，并且疫苗组之间没有显着差异（所有 p > 0·05）。4 名参与者发生意外的严重转氨酶炎：1 名试验阶段参与者接受 1·8 × 10 ⁶ PfSPZ 疫苗，1 名参与者在主要阶段接受 1·8 × 10 ⁶PfSPZ 疫苗，以及主要阶段安慰剂组的两名参与者。^{在 PfSPZ CHMI 期间，在第三次 1·8 × 10 6} PfSPZ给药后约 5 周，29 名接种者和 15 名对照者中没有一人在厚血涂片上呈阳性；随后对检测到的恶性疟原虫进行亚显微血液阶段感染的事后 PCR 分析在 CHMI 期间，29 名疫苗接种者和 15 名对照者中的 8 名均未发现寄生虫。在主要试验中，55 名疫苗接种者中的 32 名 (58%) 和 54 名对照者中的 42 名 (78%) 在接种疫苗后的 24 周监测期间厚血涂片呈阳性。疫苗效力（1-风险比）为每方案 0·51（95% CI 0·20–0·70；对数秩 p=0·0042）和 mITT 为 0·39（0·04–0·62； p=0·033); 疫苗效力（1-风险比）为 0·24 每方案 (0·02–0·41；p=0·031) 和 0·22 mITT (0·01–0·39；p=0·041) .

解释

PfSPZ 疫苗的三剂方案安全、耐受性良好，并赋予 51% 的疫苗效力来对抗强烈的自然恶性疟原虫传播，类似于先前试验中报告的五剂方案的 52% 疫苗效力。

资金

美国国立过敏和传染病研究所，国立卫生研究院，Sanaria。

翻译

有关摘要的法语翻译，请参阅补充材料部分。