Understanding the human antibody response to a malaria transmission-blocking vaccine

了解人类抗体对疟疾传播阻断疫苗的反应

• 批准号: MR/X009491/1
• 负责人: Sumi Biswas
• 金额: $ 88.61万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX009491%2F1
• 关键词: Understanding; human; antibody; response; malaria

Malaria still kills over 620,000 people a year in some of the poorest nations on earth, with over 75% being children. Malaria is an ancient and complicated parasite that is transmitted by bites of infected mosquitoes when they feed on human blood, hence much effort has been aimed directly as the mosquito itself with some success. Whilst there has been progress to reduce the death toll of this disease, progress is faltering and made worse by the prospect of insecticide resistant strains of mosquitoes and drug resistant parasites.As has been demonstrated many times in the past and the recent Covid-19 pandemic, vaccines are one of the most effective weapons to combat any infectious disease. However despite huge efforts over the past 50 years progress has been limited, with only recently vaccines offering protection from life-threatening malaria infections. To improve the protection that vaccines can provide against malaria, the goal of the scientific community is to make a multi-component vaccine that targets the different life cycle stages of the parasite.Malarias life cycle is complex, with an asexual stage in the human host and a sexual stage in the mosquito midgut. When a mosquito feeds on a malaria infected person, they transmit the parasite to another uninfected human. Transmission blocking vaccines (TBVs) work by generating antibodies in the human host, that when a mosquito feeds on a malaria infected person, are taken up with the bloodmeal into the mosquito midgut. These antibodies find their molecular targets and latch onto proteins that only reveal themselves in the mosquito midgut, preventing these proteins from performing their function and preventing the parasite from completing it's life cycle. This leaves the mosquito unable to transmit malaria to the next individual.One of the leading malaria TBV candidates is a protein called Pfs48/45 which shows excellent results in pre-clinical studies and a human clinical trial is scheduled to start in May 2022. In this project, we will understand the antibody response generated against Pfs48/45 in vaccinated volunteers and use this information to help design better vaccines. This will significantly enhance our understanding of the human immune response to Pfs48/45, as most of our knowledge is currently based on pre-clinical studies, which might not be representative of how the human immune system would react and which areas of Pfs48/45 human antibodies might target. We will isolate antibody producing cells from Pfs48/45 vaccinated clinical trial volunteers and from them extract the genetic information coding for antibodies that target Pfs48/45, allowing us to easily produce them in the lab. We will then study these antibodies, test how good they are at blocking transmission of the malaria parasite in a pre-clinical model, find out how strongly they bind to, and where on, Pfs48/45 they bind. This will allow us to define what makes a good blocking antibody and which regions of Pfs48/45 are useful to target.We will also look at the total antibody response in the sera of volunteers, seeing which regions of Pfs48/45 are targeted, and whether this changes as volunteers receive multiple doses or different doses of the vaccine. Using advances in computer modelling of proteins, we will also make versions of Pfs48/45 that can be produced with reduced cost and are more stable, an important consideration for any vaccine to be deployed in Africa. We will test the stability of these proteins and their ability to be produced in a simple cell expression systems.This research will help build our understanding of the human antibody response to Pfs48/45 and use this information to design improved vaccines. This combined with making more stable versions of Pfs48/45 will lay the foundation for the next generation of Pfs48/45 vaccines.

在地球上一些最贫穷的国家，疟疾每年仍造成62万多人死亡，其中75%以上是儿童。疟疾是一种古老而复杂的寄生虫，当它们以人类血液为食时，通过受感染的蚊子叮咬传播，因此许多努力直接针对蚊子本身并取得了一些成功。虽然在减少这种疾病的死亡人数方面取得了进展，但进展正在蹒跚，并因蚊子和抗药性寄生虫的杀虫剂抗性菌株的前景而变得更糟。正如过去多次和最近的新冠肺炎大流行所证明的那样，疫苗是对抗任何传染病的最有效武器之一。然而，尽管过去50年来做出了巨大努力，但进展有限，直到最近疫苗才提供保护，免受危及生命的疟疾感染。为了提高疫苗对疟疾的保护作用，科学界的目标是研制一种针对疟原虫不同生命周期阶段的多组分疫苗。疟疾的生命周期很复杂，在人类宿主中有一个无性阶段，在蚊子中肠中有一个有性阶段。当蚊子以疟疾感染者为食时，它们将寄生虫传播给另一个未感染的人。传播阻断疫苗（TBV）的工作原理是在人类宿主中产生抗体，当蚊子以疟疾感染者为食时，这些抗体与血粉一起进入蚊子中肠。这些抗体找到它们的分子靶点，并锁定只在蚊子中肠中显示自己的蛋白质，阻止这些蛋白质发挥功能，并阻止寄生虫完成其生命周期。这使得蚊子无法将疟疾传播给下一个个体。疟疾TBV的主要候选者之一是一种名为Pfs48/45的蛋白质，该蛋白质在临床前研究中显示出优异的效果，并计划于2022年5月开始人体临床试验。在这个项目中，我们将了解接种疫苗的志愿者对Pfs48/45产生的抗体反应，并利用这些信息来帮助设计更好的疫苗。这将显著增强我们对Pfs 48/45的人类免疫应答的理解，因为我们目前的大部分知识都是基于临床前研究，这可能不能代表人类免疫系统将如何反应以及Pfs 48/45人类抗体可能靶向哪些区域。我们将从接种Pfs 48/45疫苗的临床试验志愿者中分离抗体产生细胞，并从中提取编码靶向Pfs 48/45的抗体的遗传信息，使我们能够在实验室中轻松生产它们。然后，我们将研究这些抗体，测试它们在临床前模型中阻断疟原虫传播的效果，找出它们与Pfs 48/45结合的强度以及结合的位置。这将使我们能够确定什么是好的阻断抗体，以及Pfs 48/45的哪些区域是有用的靶点。我们还将观察志愿者血清中的总抗体反应，看看Pfs 48/45的哪些区域是靶点，以及志愿者接受多剂量或不同剂量的疫苗时，这种反应是否会发生变化。利用蛋白质计算机建模方面的进展，我们还将制造出成本更低、更稳定的Pfs 48/45版本，这是在非洲部署任何疫苗的重要考虑因素。我们将测试这些蛋白质的稳定性以及它们在简单的细胞表达系统中产生的能力。这项研究将有助于建立我们对Pfs 48/45的人类抗体应答的理解，并利用这些信息设计改进的疫苗。这与制造更稳定的Pfs 48/45版本相结合，将为下一代Pfs 48/45疫苗奠定基础。