MICA: Large-Scale Vaccine Fill and Phase I Clinical Trial of the RH5.1/Matrix-M Vaccine against Blood-Stage Plasmodium falciparum Malaria

MICA:针对血期恶性疟原虫疟疾的 RH5.1/Matrix-M 疫苗的大规模疫苗填充和 I 期临床试验

基本信息

  • 批准号:
    MR/V038427/1
  • 负责人:
  • 金额:
    $ 236.62万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2021
  • 资助国家:
    英国
  • 起止时间:
    2021 至 无数据
  • 项目状态:
    未结题

项目摘要

Vaccines that elicit functional antibodies form the foundation of success for human vaccinology. Consequently, delivery approaches that can impart improved and durable antibody responses are essential to the success of vaccines against a wide variety of difficult human diseases. Examples include seasonal respiratory viruses (such as influenza, RSV), emerging/pandemic pathogens (such as SARS-CoV-2) as well as parasites (such as Plasmodium - the causative agent of malaria).Plasmodium falciparum is a parasite that causes the most deadly form of human malaria. Current estimates suggest P. falciparum malaria affects ~200 million people annually, resulting in the death of ~430,000 individuals - primarily children under the age of 5 in sub-Saharan Africa. Thus, despite increasing implementation of control measures, the burden of this devastating disease remains far too high and a vaccine is urgently needed. Most efforts focus on vaccines encoding malaria proteins - so called 'subunit vaccines'. The most advanced malaria subunit vaccine, called RTS,S/AS01 and encoding a protein from the parasite called CSP, is in pilot implementation trials in Africa but can only provide ~36% efficacy against clinical malaria over four years. Calls have been made by the WHO for a second generation vaccine to exert 75% efficacy. If this ambitious rhetoric is to be realised, new approaches to malaria subunit vaccines are required, especially those that can induce longer-lasting antibody responses.The malaria parasite has a number of complex life-cycle stages, and it is known that numerous stages of this cycle are susceptible to antibodies. Over the last decade, we have developed a vaccine against a malaria protein called RH5 that performs a function that is essential for a parasite to invade red blood cells. It binds a protein called Basigin on the red blood cell's surface and this interaction is critical. Importantly, this interaction can be blocked by antibodies, and even more remarkably, the protein is highly conserved, showing limited variation across different parasite strains. This means antibodies induced by a vaccine can function against all the different types of P. falciparum parasite found in endemic areas. The RH5-basigin interaction appears to be the first Achilles' heel identified in the blood-stage parasite.We previously manufactured a vaccine targeting this aspect of malaria biology, called RH5.1, using novel production methods that have since been used to make other vaccines, e.g. those for Covid-19. We then undertook a clinical trial in healthy adults in the UK formulating the RH5.1 vaccine in an adjuvant (which stimulates the immune system) called AS01 from GSK. We observed highly promising results, in particular that a delayed and reduced dose third shot (or booster) could dramatically improve the maintenance of the antibody response over time. In this project we will now produce more vials of RH5.1 in the UK and will then undertake a Phase I clinical trial in healthy UK adults using a different adjuvant called Matrix-M (from our new partner Novavax, who have used the same adjuvant in their vaccine for Covid-19 tested in a Phase 3 trial in the UK). Our clinical trial will address whether the delayed and/or reduced dose of the third booster vaccination leads to dramatic improvements in the antibody response. The RH5.1/Matrix-M vaccine offers the possibility of an efficacious blood-stage malaria vaccine that can proceed to future field efficacy testing in Africa, as well as a route to identification of a delayed-booster immunisation regimen that affords long-lasting human immunity. Importantly, this work will also exemplify robust vaccine platform delivery technologies that have broad applicability to a range of human diseases.
引发功能性抗体的疫苗构成了人类疫苗学成功的基础。因此,可以赋予改善的和持久的抗体应答的递送方法对于针对多种困难的人类疾病的疫苗的成功是必不可少的。例子包括季节性呼吸道病毒(如流感病毒、RSV)、新出现/大流行病原体(如SARS-CoV-2)以及寄生虫(如疟原虫-疟疾的病原体)。恶性疟原虫是一种导致最致命形式的人类疟疾的寄生虫。目前的估计表明,恶性疟原虫疟疾每年影响约2亿人,导致约43万人死亡-主要是撒哈拉以南非洲5岁以下的儿童。因此,尽管越来越多地执行控制措施,但这一毁灭性疾病的负担仍然太高,迫切需要疫苗。大多数努力集中在编码疟疾蛋白质的疫苗-所谓的“亚单位疫苗”。最先进的疟疾亚单位疫苗,称为RTS,S/AS 01,编码一种来自寄生虫的蛋白质,称为CSP,正在非洲进行试点实施试验,但在四年内只能提供约36%的临床疟疾疗效。世卫组织呼吁研制第二代疫苗,以发挥75%的效力。如果要实现这一雄心勃勃的目标,就需要开发疟疾亚单位疫苗的新方法,特别是那些能够诱导更持久抗体反应的方法。疟疾寄生虫有许多复杂的生命周期阶段,众所周知,这个周期的许多阶段都容易受到抗体的影响。在过去的十年里,我们已经开发出一种针对疟疾蛋白质的疫苗,这种蛋白质被称为RH 5,它具有寄生虫入侵红细胞所必需的功能。它与红细胞表面一种叫做Basigin的蛋白质结合,这种相互作用至关重要。重要的是,这种相互作用可以被抗体阻断,更值得注意的是,这种蛋白质是高度保守的,在不同的寄生虫株中显示出有限的变异。这意味着疫苗诱导的抗体可以对流行地区发现的所有不同类型的恶性疟原虫起作用。RH 5-basigin相互作用似乎是在血液阶段寄生虫中发现的第一个阿喀琉斯之踵。我们之前制造了一种针对疟疾生物学这一方面的疫苗,称为RH5.1,使用的是新的生产方法,后来被用于制造其他疫苗,例如Covid-19疫苗。然后,我们在英国的健康成年人中进行了一项临床试验,在GSK的AS 01佐剂(刺激免疫系统)中配制RH5.1疫苗。我们观察到非常有希望的结果,特别是延迟和减少剂量的第三次注射(或加强剂)可以显着改善抗体应答随时间的维持。在这个项目中,我们现在将在英国生产更多的RH 5. 1小瓶,然后将在健康的英国成年人中进行一项I期临床试验,使用一种名为Matrix-M的不同佐剂(来自我们的新合作伙伴Novavax,他们在英国的3期试验中使用了相同的佐剂)。我们的临床试验将解决第三次加强疫苗接种的延迟和/或减少剂量是否会导致抗体应答的显著改善。RH5.1/Matrix-M疫苗提供了一种有效的血液阶段疟疾疫苗的可能性,该疫苗可以在非洲进行未来的田间效力测试,以及确定提供持久人类免疫力的延迟加强免疫方案的途径。重要的是,这项工作还将提供强大的疫苗平台交付技术,这些技术对一系列人类疾病具有广泛的适用性。

项目成果

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Simon Draper其他文献

Analysis of peripheral blood B and Tfh cells as predictors of antibody responses in individuals receiving candidate blood-stage malaria vaccines in a Phase Ia clinical trial
  • DOI:
    10.1186/1475-2875-13-s1-p28
  • 发表时间:
    2014-09-22
  • 期刊:
  • 影响因子:
    3.000
  • 作者:
    Sean Elias;Kathryn Milne;Cecilia Chui;Susanne Hodgson;Persephone Borrow;Simon Draper
  • 通讯作者:
    Simon Draper
Towards a multi-antigen multi-stage malaria vaccine
  • DOI:
    10.1186/1475-2875-13-s1-o31
  • 发表时间:
    2014-09-22
  • 期刊:
  • 影响因子:
    3.000
  • 作者:
    Adrian VS Hill;Sumi Biswas;Simon Draper;Thomas Rampling;Arturo Reyes-Sandoval
  • 通讯作者:
    Arturo Reyes-Sandoval
Safety and immunogenicity of the heterologous prime-boost Ebolavirus vaccine regimen CHAD3-EBO Z and MVA-BN<sup>®</sup> FILO in healthy UK adults
  • DOI:
    10.1016/j.jinf.2015.09.031
  • 发表时间:
    2015-12-01
  • 期刊:
  • 影响因子:
  • 作者:
    Tommy Rampling;Katie Ewer;Georgina Bowyer;Danny Wright;Navin Venkatraman;Ruth Payne;Alfredo Nicosia;Nancy Sullivan;Barney Graham;Andrew Pollard;Simon Draper;Ripley Ballou;Alison Lawrie;Sarah Gilbert;Adrian Hill
  • 通讯作者:
    Adrian Hill
Evaluation of simian adenoviral vector AdCh63 expressing MSP-1 as a candidate blood-stage malaria vaccine
  • DOI:
    10.1016/j.jinf.2009.10.008
  • 发表时间:
    2009-12-01
  • 期刊:
  • 影响因子:
  • 作者:
    Anna Goodman;Sarah Gilbert;Stefano Colloca;Matthew Dicks;Adrian Hill;Simon Draper
  • 通讯作者:
    Simon Draper
Clinical Evaluation Of New Viral Vectored Vaccines Targeting The Plasmodium Falciparum Blood-Stage Antigens; Msp1 And Ama1
  • DOI:
    10.1016/j.jinf.2011.04.226
  • 发表时间:
    2011-12-01
  • 期刊:
  • 影响因子:
  • 作者:
    Susanne Sheehy;Christopher Duncan;Nicholas Anagnostou;Sean Elias;Fenella Halstead;Katharine Collins;Katie Ewer;Nick Edwards;Alexander Douglas;Katherine Gantlett;Alison Lawrie;Eleanor Berrie;Sarah Moyles;Carole Long;Robert Sinden;Andrew Blagborough;Jittawadee Murphy;Alfredo Nicosia;Adrian Hill;Simon Draper
  • 通讯作者:
    Simon Draper

Simon Draper的其他文献

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{{ truncateString('Simon Draper', 18)}}的其他基金

Carterra LSA for the University of Oxford - Enabling High-Throughput SPR and Antibody Characterisation
牛津大学的 Carterra LSA - 实现高通量 SPR 和抗体表征
  • 批准号:
    MR/X012085/1
  • 财政年份:
    2022
  • 资助金额:
    $ 236.62万
  • 项目类别:
    Research Grant
A. Olotu, Ifakara Health Institute - Immune responses in malaria-exposed children immunised with a new generation blood-stage malaria vaccine.
A. Olotu,伊法卡拉健康研究所 - 接种新一代血期疟疾疫苗的疟疾暴露儿童的免疫反应。
  • 批准号:
    MR/P020593/1
  • 财政年份:
    2017
  • 资助金额:
    $ 236.62万
  • 项目类别:
    Research Grant
MICA: Development and GMP manufacture of a PfRH5 protein vaccine to induce strain-transcending immunity against blood-stage Plasmodium falciparum.
MICA:开发和 GMP 生产 PfRH5 蛋白疫苗,以诱导针对血液阶段恶性疟原虫的菌株超越免疫力。
  • 批准号:
    MR/K025554/1
  • 财政年份:
    2013
  • 资助金额:
    $ 236.62万
  • 项目类别:
    Research Grant
Developmental Clinical Studies - Clinical evaluation of an AdCh63-MVA PvDBP_RII vaccine for blood-stage Plasmodium vivax
发育性临床研究 - AdCh63-MVA PvDBP_RII 血液期疟原虫疫苗的临床评估
  • 批准号:
    G1100086/1
  • 财政年份:
    2011
  • 资助金额:
    $ 236.62万
  • 项目类别:
    Research Grant
Clinical and Immunological Evaluation of T cell- and Antibody-Inducing Viral Vector Vaccines against Blood-Stage Malar
针对血期颧骨的 T 细胞和抗体诱导病毒载体疫苗的临床和免疫学评价
  • 批准号:
    G1000527/1
  • 财政年份:
    2010
  • 资助金额:
    $ 236.62万
  • 项目类别:
    Fellowship

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