Safety, Immunogenicity, and Protective Efficacy against Controlled Human Malaria Infection of Plasmodium falciparum Sporozoite Vaccine in Tanzanian Adults
Safety, Immunogenicity, and Protective Efficacy against Controlled Human Malaria Infection of Plasmodium falciparum Sporozoite Vaccine in Tanzanian Adults
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DOI：
10.4269/ajtmh.17-1014
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发表时间：
2018-01-01
影响因子：
3.3
通讯作者：
Hoffman, Stephen L.
中科院分区：
文献类型：
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作者：
Jongo, Said A.;Shekalaghe, Seif A.;Hoffman, Stephen L.
我们正在通过直接静脉接种（DVI）冷冻保存的感染性恶性疟原虫（Pf）子孢子（SPZ）（PfSPZ挑战）来使用受控的人类疟疾感染（CHMI），以尝试减少开发PfSPZ疫苗的时间和成本，以预防非洲的疟疾。在第0、4、8、12和20周接种5剂2.7 x 10（5）PfSPZ PfSPZ疫苗，在美国成人中24周时对蚊虫叮咬CHMI的疫苗效力（VE）为65%，在马里成人中24周内对自然传播的Pf的疫苗效力（VE）为52%（至事件发生时间）或29%（比例）。我们在坦桑尼亚人中评估了针对PfSPZ挑战的VE的相同方案。在一项双盲试验中，20至30岁的男性随机接受5剂生理盐水或PfSPZ疫苗。在3周和24周后评估疫苗效力。接种者和对照组的不良反应相似。对Pf环子孢子蛋白的抗体应答显著低于未患疟疾的美国人，但显著高于马里人。所有18名对照在CHMI后均发生Pf寄生虫血症。20名接种者中有4名（20%）在3周CHMI后保持未感染（按事件发生时间计算P = 0.015，按比例分析P = 0.543），所有4名（100%）在重复24周CHMI后均未感染（按比例计算P = 0.005，按事件发生时间分析P = 0.004）。恶性疟原虫SPZ疫苗在4名受试者中安全，耐受性良好，并诱导持久的VE。在24周内，通过PfSPZ挑战的DVI控制的人疟疾感染似乎比美国的蚊子叮咬CHMI或马里成年人的自然暴露更严格，从而在非洲提供了严格的VE测试。
We are using controlled human malaria infection (CHMI) by direct venous inoculation (DVI) of cryopreserved, infectious Plasmodium falciparum (Pf) sporozoites (SPZ) (PfSPZ Challenge) to try to reduce time and costs of developing PfSPZ Vaccine to prevent malaria in Africa. Immunization with five doses at 0, 4, 8, 12, and 20 weeks of 2.7 x 10(5) PfSPZ of PfSPZ Vaccine gave 65% vaccine efficacy (VE) at 24 weeks against mosquito bite CHMI in U.S. adults and 52% (time to event) or 29%(proportional) VE over 24 weeks against naturally transmitted Pf in Malian adults. We assessed the identical regimen in Tanzanians for VE against PfSPZ Challenge. Twenty-to thirty-year-old men were randomized to receive five doses normal saline or PfSPZ Vaccine in a double-blind trial. Vaccine efficacy was assessed 3 and 24 weeks later. Adverse events were similar in vaccinees and controls. Antibody responses to Pf circumsporozoite protein were significantly lower than in malaria-naive Americans, but significantly higher than in Malians. All 18 controls developed Pf parasitemia after CHMI. Four of 20 (20%) vaccinees remained uninfected after 3 week CHMI (P = 0.015 by time to event, P = 0.543 by proportional analysis) and all four (100%) were uninfected after repeat 24 week CHMI (P = 0.005 by proportional, P = 0.004 by time to event analysis). Plasmodium falciparum SPZ Vaccine was safe, well tolerated, and induced durable VE in four subjects. Controlled human malaria infection by DVI of PfSPZ Challenge appeared more stringent over 24 weeks than mosquito bite CHMI in United States or natural exposure in Malian adults, thereby providing a rigorous test of VE in Africa.