Clinical Evaluation of "Prime-Target" Immunisation

“主靶点”免疫的临床评价

• 批准号: MR/R015236/1
• 负责人: Adrian Hill
• 金额: $ 85.4万
• 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: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR015236%2F1
• 关键词: Clinical; Evaluation; Prime; Target; Immunisation

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.

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，约有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已经证明非常困难。这种寄生虫具有复杂的多阶段生命周期，由按蚊传播，具有数千种可能与疫苗设计相关的潜在抗原，并且接触疟疾本身会导致免疫抑制。尽管如此，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研究和开发新病毒载体疫苗的基础上，以评估一种新的方法，在人类肝脏中的临床沉默早期阶段靶向疟疾寄生虫。我们建议评估开发疟疾疫苗的可行性，使用一种新的“prime-target”免疫方法，包括通过一种新的疫苗接种策略将具有杀死疟疾寄生虫能力的白色血细胞（所谓的CD 8+杀伤T细胞）靶向肝脏。而不是仅仅诱导血液中的循环杀手T细胞，使用标准的肌肉注射免疫，并希望他们可以找到肝脏中的寄生虫并杀死它们，这里要尝试的方法是通过不同的给药途径使用顺序免疫，将杀伤T细胞靶向疟疾感染的肝细胞。小鼠中的阶段疟疾疫苗候选物可以用这种方法从0-30%的功效提高到100%。为了实现这种高疫苗效力，我们通过导致抗原主要在肝脏中表达的途径，用重组病毒载体（例如重组腺病毒疫苗）施用加强疫苗接种。这是最好的实现静脉注射免疫。我们已经发现，这种“初免和靶向”方法，即使重复使用相同的疫苗载体，也大大增加了保留在肝脏中的所谓“组织驻留记忆T细胞”的数量，并且可以非常有效地在该器官中提供保护。这些细胞的数量与改进的疫苗诱导的保护相关，这表明它们与更好的疫苗efficacy.We建议在这里进行的第一次临床试验的有效性，这种方法在人类中使用，第一次，两个肝脏阶段特异性疟疾抗原的疫苗。今年正在进行小规模的安全性评估，到目前为止，临床数据显示出良好的安全性，我们建议在2018年使用标准的控制人类疟疾感染（CHMI）方案评估新方法的有效性。我们和其他人使用这样的感染模型来安全有效地评估疫苗性能，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，这项工作可以导致确定和开发一种具有成本效益的高效疟疾疫苗，这种疫苗可以广泛用于帮助预防疟疾造成的疾病和死亡，并促进最终在许多地区消除疟疾。这种新的引发-靶向免疫方法，如果在人类中有效，也可能提供一种有效的将细胞免疫靶向肝脏的通用方法，因此也可能用于制造针对其他肝脏感染的新疫苗，如由B和C型肝炎病毒引起的感染。

项目成果

Prime and target immunization protects against liver-stage malaria in mice

• DOI: 10.1126/scitranslmed.aap9128
• 发表时间: 2018-09-26
• 期刊: SCIENCE TRANSLATIONAL MEDICINE
• 影响因子: 17.1
• 作者: Gola, Anita;Silman, Daniel;Hill, Adrian V. S.
• 通讯作者: Hill, Adrian V. S.

Deep Immune Phenotyping and Single-Cell Transcriptomics Allow Identification of Circulating TRM-Like Cells Which Correlate With Liver-Stage Immunity and Vaccine-Induced Protection From Malaria.

• DOI: 10.3389/fimmu.2022.795463
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Noé A;Datoo MS;Flaxman A;Husainy MA;Jenkin D;Bellamy D;Makinson RA;Morter R;Ramos Lopez F;Sheridan J;Voukantsis D;Prasad N;Hill AVS;Ewer KJ;Spencer AJ
• 通讯作者: Spencer AJ