Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Sci Transl Med. 2018 Sep 26;10(460). doi: 10.1126/scitranslmed.aap9128.
Despite recent advances in treatment and vector control, malaria is still a leading cause of death, emphasizing the need for an effective vaccine. The malaria life cycle can be subdivided into three stages: the invasion and growth within liver hepatocytes (pre-erythrocytic stage), the blood stage (erythrocytic stage), and, finally, the sexual stage (occurring within the mosquito vector). Antigen (Ag)-specific CD8 T cells are effectively induced by heterologous prime-boost viral vector immunization and known to correlate with liver-stage protection. However, liver-stage malaria vaccines have struggled to generate and maintain the high numbers of -specific circulating T cells necessary to confer sterile protection. We describe an alternative "prime and target" vaccination strategy aimed specifically at inducing high numbers of tissue-resident memory T cells present in the liver at the time of hepatic infection. This approach bypasses the need for very high numbers of circulating T cells and markedly increases the efficacy of subunit immunization against liver-stage malaria with clinically relevant Ags and clinically tested viral vectors in murine challenge models. Translation to clinical use has begun, with encouraging results from a pilot safety and feasibility trial of intravenous chimpanzee adenovirus vaccination in humans. This work highlights the value of a prime-target approach for immunization against malaria and suggests that this strategy may represent a more general approach for prophylaxis or immunotherapy of other liver infections and diseases.
尽管在治疗和病媒控制方面取得了一些进展，但疟疾仍然是主要的死亡原因之一，这强调了需要一种有效的疫苗。疟原虫的生命周期可以细分为三个阶段：在肝脏肝细胞内的入侵和生长（肝前期）、血液阶段（红细胞期），最后是性阶段（在蚊子媒介中发生）。异源初免-加强病毒载体免疫可有效诱导抗原（Ag）特异性 CD8 T 细胞，并且与肝期保护相关。然而，肝期疟疾疫苗难以产生和维持大量特异性循环 T 细胞，这些细胞对于提供无菌保护是必要的。我们描述了一种替代的“初免和靶向”接种策略，旨在专门诱导在肝感染时存在于肝脏中的大量组织驻留记忆 T 细胞。这种方法绕过了对循环 T 细胞数量的非常高的要求，并显著提高了针对肝期疟疾的亚单位免疫的功效，该免疫使用了临床上相关的 Ag 和经过临床测试的病毒载体，在小鼠挑战模型中。已经开始向临床应用转化，对人类进行静脉内黑猩猩腺病毒疫苗接种的安全性和可行性初步试验取得了令人鼓舞的结果。这项工作突出了针对疟疾的初免-靶向方法的价值，并表明该策略可能代表其他肝脏感染和疾病的预防或免疫治疗的更一般方法。
