Enabling rapid conversion of antigen to vaccine, applied to multi-stage malaria vaccination

接种疫苗是拯救生命和改善健康的最具成本效益的方法之一。尽管许多人类和动物疫苗取得了巨大的成功，但我们仍然缺乏针对疟疾、结核病和艾滋病毒等主要全球杀手的有效疫苗。新的疫苗通常是从病毒样颗粒（VLP）开发的。VLP在大小和形状上类似于病毒，但不携带致病遗传物质，因此不会引起疾病。VLP可以被改造成在其表面展示来自病原体的蛋白质，以产生有效和安全的疫苗。用来自病原体的这种蛋白质装饰VLP是疫苗开发领域的核心挑战之一，需要昂贵的试错实验，并需要数月至数年的时间。我们已经验证了克服这一关键挑战的初步步骤。我们设计了一种“细菌强力胶”，这样装饰VLP只需要将VLP与致病蛋白混合。这种附着是快速的、不可逆的和广泛适用的。由于该过程的简单性，我们将该平台称为即插即用疫苗接种。我们关注的附着在VLP上的致病蛋白来自疟原虫。疟疾是全球最大的健康挑战之一，每年约有200万人感染，50万人死亡。由于难以分发有效药物和抗药性增加，迫切需要研制疟疾疫苗。我们研究了疟疾寄生虫在其生命周期不同阶段的表面蛋白质，并确定了可能有助于创造更有效疫苗的关键目标。在这项提案中，我们将以几种方式推进即插即用的疫苗接种方法，以最大限度地提高对这些疟疾蛋白的免疫反应。我们将建立使用我们的细菌强力胶装饰一种不同的VLP经常在临床上使用。我们将创造新的VLP，能够展示三倍多的疟疾蛋白拷贝，因为这可以刺激更强的免疫反应。此外，VLP将被两种不同的疟疾蛋白精确修饰，以帮助产生一种有效对抗更广泛疟疾菌株的疫苗。由于我们的即插即用VLP不仅可用于疟疾，还可用于一系列人类和动物疾病，因此我们还将增加我们生产的VLP的规模和稳定性，以便它们可以成为全球科学家的通用资源，并加快针对重大健康挑战的有效疫苗的开发。

Vaccination is one of the most cost-effective ways to save lives and improve health. Despite the great success-stories of many human and animal vaccines, we still lack effective vaccines against major global killers such as malaria, tuberculosis and HIV. New vaccines are often developed from Virus-like particles (VLPs). VLPs resemble viruses in their size and shape, but carry no pathogenic genetic material and so do not cause disease. VLPs can be engineered to display a protein from a pathogen on their surface, to create an effective and safe vaccine. Decorating VLPs with such proteins from pathogens is one of the central challenges in the field of vaccine development, requiring expensive trial-and-error experiments and taking months to years. We have validated initial steps to overcome this key challenge. We engineered a "bacterial superglue" so that decorating VLPs simply requires mixing the VLP with the pathogenic protein. This attachment is fast, irreversible and broadly applicable. Due to the ease of the process, we have termed this platform Plug-and-Display vaccination. The pathogenic proteins we have focused on attaching to VLPs come from the malaria parasite. Malaria is one of the largest global health challenges, each year infecting approximately two million people and killing half a million people. With the difficulty in distributing effective drugs and the increase in drug resistance, there is urgent need to develop a malaria vaccine. We have investigated proteins on the surface of the malaria parasite at different stages of its life cycle and established key targets that could help create a more effective vaccine. In this proposal we will advance the Plug-and-Display vaccination approach in several ways, to maximise the immune responses to these malarial proteins. We will establish the use of our bacterial superglue for decoration of a different kind of VLP frequently used in the clinic. We will create new VLPs able to display three times more copies of the malarial protein, since that could stimulate an even stronger immune response. Also, VLPs will be precisely decorated with two different malarial proteins, to help generate a vaccine effective against a wider range of malaria strains. Since our Plug-and-Display VLPs could be useful not just for malaria but for a range of human and animal diseases, we will also increase the scale and stability of VLPs we produce, so that they can be a general resource for scientists worldwide and speed up the creation of effective vaccines against major health challenges.