Clinical Evaluation of "Prime-Target" Immunisation

疟疾是许多发展中国家发病和死亡的最大原因之一。每年有数以亿计的临床病例和大约50万人死亡。疟疾是由一种原生动物寄生虫引起的，这种微生物的疫苗开发被证明非常困难。这种寄生虫有一个复杂的多阶段生活史，由按蚊传播，具有数千种可能与设计疫苗相关的潜在抗原，暴露在疟疾本身会导致免疫抑制。然而，一些疫苗开发方法现在显示出希望。在这里，我们建立在英国和其他地方多年来对新病毒载体疫苗的研究和开发的基础上，以评估一种新的方法来针对疟疾寄生虫在人类肝脏中处于临床沉默的早期阶段。我们建议评估使用一种新的“主要目标”免疫方法开发疟疾疫苗的可行性，这种方法涉及通过一种新的疫苗接种策略将具有杀死疟疾寄生虫的能力的白细胞(即所谓的CD8+杀伤T细胞)靶向肝脏。这里尝试的方法不是只在血液中诱导循环中的杀伤T细胞，使用标准的肌肉免疫，并希望它们能在肝脏中发现寄生虫并杀死它们，而是通过不同的给药途径连续免疫，将杀伤T细胞靶向感染疟疾的肝细胞。我们发现，通过这种方法，领先的肝期疟疾疫苗候选小鼠的疗效可以从0-30%提高到100%。为了达到这种高的疫苗效力，我们用重组病毒载体，例如重组腺病毒疫苗，通过导致抗原主要在肝脏表达的途径，实施加强免疫接种。这最好是通过静脉接种来实现的。我们发现，即使重复使用相同的疫苗载体，这种“主要和靶向”的方法也能显著增加留在肝脏的所谓“组织驻留记忆T细胞”的数量，并在该器官中提供非常有效的保护。这些细胞的数量与疫苗诱导的保护作用的提高相关，这表明它们与更好的疫苗效果之间存在因果关系。在这里，我们建议在人类身上首次使用疫苗中的两个肝脏阶段特异性疟疾抗原进行这种方法的有效性的临床试验。今年正在进行小规模的安全评估，到目前为止，临床数据显示出良好的安全状况，我们建议在2018年使用标准的受控人类疟疾感染(CHMI)方案评估新方法的有效性。我们和其他人使用这种感染模型来安全有效地评估疫苗的性能，我们已经在英国志愿者中安全地进行了20次这样的CHMI试验。我们认为，这项工作可能导致确定和开发一种具有成本效益的高效力疟疾疫苗，该疫苗可被广泛用于帮助预防疟疾造成的疾病和死亡，并有助于从许多地区最终消除疟疾。如果这种新的主要目标免疫方法对人类有效，它还可能提供一种有效的一般方法，将细胞免疫靶向肝脏，因此也可能有助于制造针对其他肝脏感染的新疫苗，如由乙肝和丙型肝炎病毒引起的感染。

Malaria is one of the biggest causes of morbidity and mortality in many developing countries. There are hundreds of millions of clinical cases each year and about half a million deaths. Malaria is caused by a protozoan parasite, a type of microbe for which vaccine development has proved very difficult. This parasite has a complex multi-stage life cycle, is transmitted by Anopheles mosquitoes, has thousands of potential antigens that might be relevant to designing a vaccine, and exposure to malaria itself can cause immunosuppression.Nonetheless, some approaches to vaccine development are now showing promise. Here we build on many years of research and development of new viral vectors vaccines in the UK and elsewhere to assess a new approach to targeting the malaria parasite during its clinically silent early stage in the human liver. We propose to assess the feasibility of developing a malaria vaccine using a new "prime-target" immunisation approach that involves targeting white blood cells with the capacity to kill malaria parasites, so-called CD8+ killer T cells, to the liver by a novel vaccination strategy. Instead of just inducing circulating killer T cells in the blood, using a standard intramuscular immunisation, and hoping that they can find parasites in the liver and kill them, the approach to be tried here is to use sequential immunisations by different administration routes to target killer T cells to malaria-infected liver cells.We have found that the efficacy of leading liver-stage malaria vaccine candidates in mice can be enhanced with this approach from 0-30% efficacy to 100%. To achieve this high vaccine efficacy we administer a booster vaccination with a recombinant viral vector, e.g. a recombinant adenovirus vaccine, by a route that leads to antigen expression predominantly in the liver. This is best achieved by an intravenous immunization. We have found that this "prime and target" approach, even with repeated use of the same vaccine vector, increased substantially the number of so-called "tissue resident memory T cells" that remain in the liver and can be very effective in providing protection in that organ. The numbers of these cells correlated with improved vaccine-induced protection suggesting that they are causally related to the better vaccine efficacy.We propose here to undertake the first clinical trial of the efficacy of this approach in humans using, for the first time, two liver-stage-specific malaria antigens in the vaccine. Small-scale safety assessments are underway this year, with the clinical data showing a good safety profile so far, and we here propose to assess efficacy of the new approach in 2018 using a standard controlled human malaria infection (CHMI) protocol. We and others use such an infection model to evaluate vaccine performance safely and efficiently and we have undertaken safely twenty such CHMI trials in UK volunteers. We believe that this work could lead to the identification and development of a cost-effective high efficacy malaria vaccine that could be used quite widely to help prevent disease and death caused by malaria, also and facilitate its eventual elimination from many areas. The new prime-target immunisation approach, if it works in humans, may also provide an effective general means of targeting cellular immunity to the liver and so might also be useful in making new vaccines against other liver infections such as those caused by the hepatitis B and C viruses.