Structure guided design of a transmission-blocking malaria vaccine targeting Pfs48/45

针对 Pfs48/45 的阻断传播疟疾疫苗的结构引导设计

• 批准号: MR/R001138/1
• 负责人: Matthew Higgins
• 金额: $ 56.6万
• 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: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR001138%2F1
• 关键词: Structure; guided; design; transmission; blocking

Malaria is one of the most devastating infectious diseases to affect humankind. It kills around half a million people, mostly young children in Africa. It also places a huge disease burden on large parts of the world, leading to hundreds of millions of serious infections. As well as directly causing suffering and death, this limits the development of large parts of the globe, reducing productivity and maintaining inequality.Malaria is caused by a tiny, single celled parasite, known as Plasmodium. An individual contracts malaria when bitten by an infected mosquito. The parasites are injected into the blood stream as the mosquito feeds. These first develop and divide within the liver without causing disease. They next emerge from the liver and infect red blood cells, replicating and increasing in number and driving the symptoms of malaria. At the same time, a fraction of the parasites within the blood take a different developmental route, adopting a form known as the gametocytes. When a mosquito takes a blood meal from an infected person, they are likely to ingest some of these gametocytes. Within the midgut of the mosquito these develop into male and female gametes, and fuse together. This completes the infection cycle and the parasites move to the salivary glands of the mosquito, ready to be injected into another human victim.Development of a vaccine to prevent malaria has proved very challenging and it is likely that the vaccines of the future will simultaneously target multiple stages of the parasite life cycle, blocking both liver and blood cell entry. One component of such a vaccine is likely to target the gametes of the parasite and to stop them from fusing. This is known as a transmission-blocking vaccine component as it will prevent the development of the parasite within the mosquito and will therefore stop the disease from being passed from person to person through the action of this blood-sucking insect. We study a molecule called Pfs48/45 that is found on the surface of the gametocytes and gametes of Plasmodium parasites. Pfs48/45 is essential for a male gamete to fuse with a female gamete and if the immune system of an animal is exposed to Pfs48/45, it produces molecules called antibodies that bind to Pfs48/45 and prevent gametes from fusing. This means that if we can include Pfs48/45 in a vaccine, it will trigger the human body to make antibodies that will prevent malaria from being transmitted to other people. This will reduce the prevalence of malaria in the community and will help to eradicate the disease.Despite this promise, Pfs48/45 is a challenging molecule to produce in a functional form and in large quantities. In addition, if we are to make vaccines that simultaneously contain multiple components, it will be important for each component to be as small and focused as possible, to make it easier and cheaper for them to be produced and distributed. For this reason we aim to understand the structure and shape of Pfs48/45 and also to understand the location and the nature of the sites where the gamete-fusion-preventing antibodies bind. This information will allow us to use the latest computational tools to design novel molecules which contain just the regions of Pfs48/45 that are needed to bind to inhibitory antibodies.We will then inject mice with these novel immunogens and study the antibodies that are produced in a mosquito-infection experiment. If mosquitoes are fed on human blood containing malaria parasites, gametes can fuse, leading to the formation of cysts in the gut wall of the mosquito. If gamete fusion is prevented, the cysts are no longer formed. We will therefore study the ability of the antibodies induced by our novel immunogens to prevent cyst formation revealing which of our designs is most effective at blocking gamete fusion and preventing transmission of the malaria parasite. These newly designed molecules will form part of the malaria vaccines of the future.

疟疾是影响人类的最具破坏性的传染病之一。它导致大约50万人死亡，其中大多数是非洲的儿童。它还给世界大部分地区带来巨大的疾病负担，导致数亿人严重感染。除了直接造成痛苦和死亡外，这还限制了地球仪大部分地区的发展，降低了生产力，维持了不平等。疟疾是由一种被称为疟原虫的微小单细胞寄生虫引起的。一个人被受感染的蚊子叮咬后就会感染疟疾。当蚊子进食时，寄生虫被注射到血液中。这些首先在肝脏内发展和分裂而不引起疾病。它们接下来从肝脏中出现并感染红细胞，复制并增加数量并引发疟疾症状。与此同时，血液中的一部分寄生虫采取不同的发育途径，采用称为配子体的形式。当蚊子从感染者身上吸血时，它们很可能会摄入一些配子母细胞。在蚊子的中肠内，这些配子发育成雄性和雌性配子，并融合在一起。这完成了感染周期，寄生虫移动到蚊子的唾液腺，准备注射到另一个人类受害者身上。开发预防疟疾的疫苗已经证明是非常具有挑战性的，未来的疫苗可能会同时针对寄生虫生命周期的多个阶段，阻止肝脏和血细胞进入。这种疫苗的一个组成部分可能是针对寄生虫的配子并阻止它们融合。这被称为传播阻断疫苗成分，因为它将防止蚊子体内寄生虫的发展，因此将阻止疾病通过这种吸血昆虫的作用在人与人之间传播。我们研究了一种名为Pfs 48/45的分子，这种分子存在于疟原虫的配子母细胞和配子表面。Pfs 48/45是雄性配子与雌性配子融合所必需的，如果动物的免疫系统暴露于Pfs 48/45，它会产生称为抗体的分子，与Pfs 48/45结合并阻止配子融合。这意味着，如果我们能在疫苗中加入Pfs 48/45，它将触发人体产生抗体，防止疟疾传播给其他人。这将减少社区中疟疾的流行，并有助于根除这种疾病。尽管有这样的前景，Pfs 48/45是一种具有挑战性的分子，要以功能形式大量生产。此外，如果我们要制造同时含有多种成分的疫苗，那么每种成分都必须尽可能小和集中，以便更容易和更便宜地生产和销售。出于这个原因，我们的目标是了解Pfs 48/45的结构和形状，并了解防止配子融合的抗体结合的位点的位置和性质。这些信息将使我们能够使用最新的计算工具来设计新的分子，这些分子只包含Pfs 48/45的区域，这些区域是与抑制性抗体结合所必需的。然后，我们将向小鼠注射这些新的免疫原，并研究在蚊子感染实验中产生的抗体。如果蚊子以含有疟原虫的人类血液为食，配子可以融合，导致蚊子肠壁中形成包囊。如果配子融合被阻止，包囊就不再形成。因此，我们将研究由我们的新型免疫原诱导的抗体防止囊肿形成的能力，揭示我们的设计中哪一种在阻断配子融合和防止疟原虫传播方面最有效。这些新设计的分子将成为未来疟疾疫苗的一部分。

项目成果

Structural basis for recognition of the malaria vaccine candidate Pfs48/45 by a transmission blocking antibody.

• DOI: 10.1038/s41467-018-06340-9
• 发表时间: 2018-09-20
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Lennartz F;Brod F;Dabbs R;Miura K;Mekhaiel D;Marini A;Jore MM;Søgaard MM;Jørgensen T;de Jongh WA;Sauerwein RW;Long CA;Biswas S;Higgins MK
• 通讯作者: Higgins MK

Structure of the malaria vaccine candidate Pfs48/45 and its recognition by transmission blocking antibodies

候选疟疾疫苗 Pfs48/45 的结构及其传播阻断抗体的识别

• DOI: 10.1101/2022.05.24.493318
• 发表时间: 2022
• 作者: Ko K

Structure of the malaria vaccine candidate Pfs48/45 and its recognition by transmission blocking antibodies.

• DOI: 10.1038/s41467-022-33379-6
• 发表时间: 2022-09-24
• 期刊: Nature communications
• 影响因子: 16.6

Assessment of Antibodies Induced by Multivalent Transmission-Blocking Malaria Vaccines.

评估由多价传播阻断疟疾疫苗诱导的抗体。

• DOI: 10.3389/fimmu.2017.01998
• 发表时间: 2017
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Menon V;Kapulu MC;Taylor I;Jewell K;Li Y;Hill F;Long CA;Miura K;Biswas S
• 通讯作者: Biswas S