Combination of RTS,S and Pfs25-IMX313 Induces a Functional Antibody Response Against Malaria Infection and Transmission in Mice
Combination of RTS,S and Pfs25-IMX313 Induces a Functional Antibody Response Against Malaria Infection and Transmission in Mice
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DOI：
10.3389/fimmu.2018.02780
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发表时间：
2018-12-04
影响因子：
7.3
通讯作者：
Biswas, Sumi
中科院分区：
文献类型：
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作者：
Brod, Florian;Miura, Kazutoyo;Biswas, Sumi
在过去二十年中，疟疾发病率大幅下降，但最近这种下降已经停滞，表明控制措施开始失效。一种有效的疫苗，特别是对疾病传播有显著影响的疫苗，无疑将是控制和消除疟疾努力的宝贵工具。RTS，S/AS 01是迄今为止最先进的疟疾疫苗，在寄生虫侵入肝脏之前就将其作为目标，并有可能通过预防血液阶段感染和配子体发生来预防疟疾疾病和传播。不幸的是，在III期临床试验中的功效有限，并且人们普遍认为疟疾疫苗需要含有来自不同生命周期阶段的多种抗原才有现实的成功机会。最近在小鼠中进行的一项研究表明，针对红细胞前期和性生命周期阶段的部分有效干预措施在消除多代人群中的疟疾方面具有协同作用。因此，RTS，S/AS 01与传播阻断疫苗（TBV）的组合作为增加疫苗效力的实用且有力的方式是高度吸引人的。在这里，我们证明，结合Pfs 25-IMX 313，目前在临床开发的TBV候选之一，RTS，S/AS 01容易诱导功能性免疫反应，对这两种抗原在远交的CD 1小鼠。当与在Alhydrogel中的制剂相比时，在AS 01中的Pfs 25-顶X 313的制剂显著增加抗体滴度，导致在标准膜饲养测定（SMFA）中的改善的传递降低活性。在Pfs 25-IMX 313与RTS，S/AS 01共制剂后，两种疫苗的免疫原性得以维持，并且通过SMFA和子孢子侵入试验（ISI）抑制诱导的抗体应答的功能评估显示针对两个生命周期阶段的寄生虫的生物活性没有降低。如果这一发现可以转化为人类疫苗接种，这将大大有助于消除并最终根除疟疾的努力。
The last two decades saw a dramatic reduction in malaria incidence rates, but this decrease has been stalling recently, indicating control measures are starting to fail. An effective vaccine, particularly one with a marked effect on disease transmission, would undoubtedly be an invaluable tool for efforts to control and eliminate malaria. RTS,S/AS01, the most advanced malaria vaccine to date, targets the parasite before it invades the liver and has the potential to prevent malaria disease as well as transmission by preventing blood stage infection and therefore gametocytogenesis. Unfortunately efficacy in a phase III clinical trial was limited and it is widely believed that a malaria vaccine needed to contain multiple antigens from different life-cycle stages to have a realistic chance of success. A recent study in mice has shown that partially efficacious interventions targeting the pre-erythrocytic and the sexual lifecycle stage synergise in eliminating malaria from a population over multiple generations. Hence, the combination of RTS,S/AS01 with a transmission blocking vaccine (TBV) is highly appealing as a pragmatic and powerful way to increase vaccine efficacy. Here we demonstrate that combining Pfs25-IMX313, one of the TBV candidates currently in clinical development, with RTS,S/AS01 readily induces a functional immune response against both antigens in outbred CD1mice. Formulation of Pfs25-IMX313 in AS01 significantly increased antibody titres when compared to formulation in Alhydrogel, resulting in improved transmission reducing activity in standard membrane feeding assays (SMFA). Upon co-formulation of Pfs25-IMX313 with RTS,S/AS01, the immunogenicity of both vaccines was maintained, and functional assessment of the induced antibody response by SMFA and inhibition of sporozoite invasion assay (ISI) showed no reduction in biological activity against parasites of both lifecycle stages. Should this findings be translatable to human vaccination this could greatly aid efforts to eliminate and eventually eradicate malaria.