GMP manufacture and Phase I clinical trial of a thermostable single-dose rabies vaccine for pre-exposure prophylaxis for children in endemic areas

尽管狂犬病是最早开发出有效疫苗的疾病之一，但每年仍有超过5万人死于狂犬病--其中大部分是南亚和非洲发展中国家的儿童，他们被狂犬病狗咬伤。狂犬病在人类病毒感染中是独一无二的，因为它有100%的致死率：感染者遭受缓慢而可怕的死亡。这个问题持续如此规模的原因是，目前可用的狂犬病控制工具存在重大缺陷。目前的疫苗是基于灭活的狂犬病病毒，与1885年巴斯德接种的第一种狂犬病疫苗相比变化相对较小。它们过于昂贵，不能作为常规儿童疫苗接种方案的一部分提供给所有人口，部分原因是它们需要冷藏，需要多次接种才能实现保护。如果一个未接种疫苗的儿童被一只可能是狂犬病的狗咬伤，所需的疫苗和抗体治疗的组合甚至更昂贵，而且不可靠-因此许多人被迫冒着不接受治疗的风险。给狗接种疫苗可能非常有效，但在许多地区，缺乏兽医卫生基础设施，或者狗的行为模式使它们很难接触到。这个项目旨在对人类测试一种新的狂犬病疫苗，我们使用现代技术生产了这种疫苗。这种新疫苗将比目前的疫苗便宜得多，不需要冷藏，而且只需要一剂。因此，它应该适用于所有有感染狂犬病风险的儿童的大规模接种。我们的疫苗由一种普通感冒病毒组成，这种病毒不能在人体内生长，但会使人体的免疫系统暴露在狂犬病病毒外壳的主要蛋白质积木中。通过这样做，它刺激免疫系统产生能够杀死狂犬病病毒的抗体。我们在实验动物身上的研究表明，我们的小剂量疫苗足以保护动物免受狂犬病感染近两年。该项目的另一个关键部分涉及通过将疫苗在定义的糖溶液中干燥在纸状薄膜上来稳定疫苗-这项技术的灵感来自于某些含糖植物在炎热、干燥的条件下存活的能力。干燥的疫苗能够承受高温，而不需要冷藏或冷冻。这将使向低资源地区分发疫苗的成本大大降低，也更加可靠。重要的是，干燥技术非常简单，可以应用于许多其他疫苗-我们的目的是，这项研究，使用我们的新狂犬病疫苗，将提供一个概念验证，鼓励该技术应用于其他疫苗。我们已经在实验室制造了疫苗，并(如上所述)表明它在动物身上非常有效。该项目将使我们能够按照更严格的标准来生产疫苗，这些标准被称为“良好的制造规范”，这是制造可以在人体试验中测试的“药剂级”产品所必需的。我们将以传统的液体形式和干燥、耐热的形式生产“药剂级”疫苗。该项目的最后部分将是在健康的英国成年志愿者身上进行临床试验，仔细测试疫苗的安全性。这也将使我们能够将我们的两种疫苗相互比较，并与现有的狂犬病疫苗进行比较，以了解它们诱导抗狂犬病抗体的能力。这项试验的良好结果将使疫苗能够在狂犬病问题严重的国家的儿童身上进行进一步的试验。

Although rabies is one of the first diseases for which effective vaccines were developed, it still kills more than 50,000 people every year- mostly children in developing countries in South Asia and Africa who are bitten by rabid dogs. The disease is unique among human viral infections in that it has a 100% fatality rate: infected people suffer a slow and terrifying death.The reason that the problem persists on this scale is that currently available rabies control tools have major shortcomings. Current vaccines, based upon killed rabies viruses, have changed relatively little from the first rabies vaccine administered by Pasteur in 1885. They are too expensive to be given to whole populations as part of routine childhood vaccination packages, partly because they require refrigeration and need multiple doses to achieve protection. The combination of vaccine and antibody treatment needed if an unvaccinated child is bitten by a dog which might be rabid is even more expensive and not reliably available- so many people are forced to take the risk of going without treatment. Vaccinating dogs can be very effective, but in many areas, there is a lack of veterinary health infrastructure or the behaviour patterns of dogs make them difficult to reach.This project aims to test in humans a new rabies vaccine which we have produced using modern techniques. This new vaccine will be considerably cheaper than current vaccines, will not require refrigeration, and will only require a single dose. As such, it should be suitable for mass vaccination of all children at risk of rabies.Our vaccine consists of a version of a common cold virus which cannot grow in the human body but exposes the body's immune system to the major protein building block of the rabies virus' coat. By doing this, it stimulates the immune system to produce antibodies that are capable of killing the rabies virus. We have shown in studies in experimental animals that a small dose of our vaccine is sufficient to protect the animals against infection with rabies for nearly two years.The other key part of this project involves the stabilisation of the vaccine by drying it in a defined sugar solution on a paper-like membrane- a technique inspired by the ability of certain sugar-containing plants to survive in hot, dry conditions. The dried vaccine is able to withstand high temperatures, instead of needing refrigeration or freezing. This will make the distribution of vaccine to low-resource areas considerably cheaper and more reliable. Importantly, the drying technique is very straightforward and could be applied to many other vaccines- our intention is that this study, using our new rabies vaccine, will provide a proof-of-concept encouraging the technique to be adopted for other vaccines.We have already manufactured the vaccine in the laboratory and (as stated above) have shown that it is highly effective in animals. This project will allow us to manufacture the vaccine to the stricter standards known as 'Good Manufacturing Practice', which are needed in order to make a 'pharmaceutical-grade' product which can be tested in human trials. We will produce 'pharmaceutical-grade' versions of the vaccine in both conventional liquid form and the dried, thermostable form. The final part of the project will be to test the vaccines carefully for safety in a clinical trial in healthy British adult volunteers. This will also allow us to compare the two forms of our vaccine with each other and with an existing rabies vaccine for their ability to induce anti-rabies antibodies. Good results in this trial will allow the vaccine to progress into further trials in children in countries which have major rabies problems.