Prime and target immunization protects against liver-stage malaria in mice
Prime and target immunization protects against liver-stage malaria in mice
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DOI：
10.1126/scitranslmed.aap9128
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发表时间：
2018-09-26
影响因子：
17.1
通讯作者：
Hill, Adrian V. S.
中科院分区：
文献类型：
--
作者：
Gola, Anita;Silman, Daniel;Hill, Adrian V. S.
尽管最近在治疗和病媒控制方面取得了进展，但疟疾仍然是导致死亡的主要原因，这突出表明需要有效的疫苗。疟疾的生命周期可分为三个阶段：在肝细胞内的侵入和生长（红细胞前期），血液阶段（红细胞期），最后是性阶段（发生在蚊子媒介内）。抗原（Ag）特异性CD8（+）T细胞通过异源初免-加强病毒载体免疫有效诱导，并且已知与肝脏阶段保护相关。然而，肝脏期疟疾疫苗一直难以产生和维持提供无菌保护所需的大量疟原虫特异性循环T细胞。我们描述了一种替代的“总理和目标”的疫苗接种策略，专门针对诱导大量的组织驻留记忆T细胞存在于肝脏感染时的肝脏。这种方法绕过了对非常高数量的循环T细胞的需要，并且在鼠攻击模型中显著增加了用临床相关的Ag和临床测试的病毒载体进行的针对肝脏期疟疾的亚单位免疫的功效。临床应用的转化已经开始，在人类静脉注射黑猩猩腺病毒疫苗的安全性和可行性试验中取得了令人鼓舞的结果。这项工作突出了针对疟疾的免疫接种的主要目标方法的价值，并表明这种策略可能代表了其他肝脏感染和疾病的预防或免疫治疗的更普遍的方法。
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 Plasmodium-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.