Cytomegalovirus vectors expressing Plasmodium knowlesi antigens induce immune responses that delay parasitemia upon sporozoite challenge
Cytomegalovirus vectors expressing Plasmodium knowlesi antigens induce immune responses that delay parasitemia upon sporozoite challenge
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DOI：
10.1371/journal.pone.0210252
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发表时间：
2019-01-23
期刊：
影响因子：
3.7
通讯作者：
Fruh, Klaus
中科院分区：
文献类型：
--
作者：
Hansen, Scott G.;Womack, Jennie;Fruh, Klaus
研制疟疾杀菌疫苗仍然是全球卫生研究的最高优先事项之一。虽然靶向红细胞前阶段的子孢子疫苗显示出很大的前景，但不可能长期维持功效，这可能是由于这些疫苗不能维持肝脏中的效应记忆T细胞应答。基于人巨细胞病毒（HCMV）的疫苗可以克服这种限制，因为基于恒河猴CMV（RhCMV）（恒河猴（RM）中的同源病毒）的载体在淋巴外组织（包括肝脏）中引发并无限期地维持高频率、非耗尽效应记忆T细胞。此外，RhCMV株68 - 1激发CD8 + T细胞广泛识别仅由MHC-II和MHC-E限制的非常规表位。为了评估这些独特的免疫应答保护免受疟疾的潜力，我们在RhCMV 68 - 1或Rh189缺失的68 - 1中表达了四种诺氏疟原虫（Plasmodium knowlesi，Pk）抗原（CSP、AMA1、SSP 2/TRAP、MSP 1c），其另外增强了典型的MHC-Ia限制性CD8 + T细胞。在用这些表达Pk Ag的RhCMV疫苗中的任一种接种RM后，我们获得了对四种Pk抗原中的每一种的T细胞应答。在用Pk子孢子攻击后，我们观察到接种疫苗的RM中血液期寄生虫的延迟出现，这与从肝脏释放的寄生虫减少75 - 80%一致。此外，Rh189缺失的RhCMV/Pk载体在一个RM中引起不育保护。一旦进入血液，寄生虫的生长不会受到影响。与Pk感染诱导的T细胞应答相反，RhCMV载体在攻击后维持对肝脏中所有四种疟疾抗原的持续T细胞应答。因此，血液阶段寄生虫的延迟出现可能是由于T细胞介导的对肝脏阶段寄生虫发育的抑制。因此，这种疫苗方法可用于有效地测试新的T细胞抗原，改进靶向肝脏阶段的现有疫苗和靶向红细胞抗原的补充疫苗。
The development of a sterilizing vaccine against malaria remains one of the highest priorities for global health research. While sporozoite vaccines targeting the pre-erythrocytic stage show great promise, it has not been possible to maintain efficacy long-term, likely due to an inability of these vaccines to maintain effector memory T cell responses in the liver. Vaccines based on human cytomegalovirus (HCMV) might overcome this limitation since vectors based on rhesus CMV (RhCMV), the homologous virus in rhesus macaques (RM), elicit and indefinitely maintain high frequency, non-exhausted effector memory T cells in extralymphoid tissues, including the liver. Moreover, RhCMV strain 68-1 elicits CD8+ T cells broadly recognizing unconventional epitopes exclusively restricted by MHC-II and MHC-E. To evaluate the potential of these unique immune responses to protect against malaria, we expressed four Plasmodium knowlesi (Pk) antigens (CSP, AMA1, SSP2/TRAP, MSP1c) in RhCMV 68-1 or in Rh189-deleted 68-1, which additionally elicits canonical MHC-la-restricted CD8+ T cells. Upon inoculation of RM with either of these Pk Ag expressing RhCMV vaccines, we obtained T cell responses to each of the four Pk antigens. Upon challenge with Pk sporozoites we observed a delayed appearance of blood stage parasites in vaccinated RM consistent with a 75-80% reduction of parasite release from the liver. Moreover, the Rh189-deleted RhCMV/Pk vectors elicited sterile protection in one RM. Once in the blood, parasite growth was not affected. In contrast to T cell responses induced by Pk infection, RhCMV vectors maintained sustained T cell responses to all four malaria antigens in the liver post-challenge. The delayed appearance of blood stage parasites is thus likely due to a T cell-mediated inhibition of liver stage parasite development. As such, this vaccine approach can be used to efficiently test new T cell antigens, improve current vaccines targeting the liver stage and complement vaccines targeting erythrocytic antigens.