Nardin E, Zavala F, Nussenzweig V, Nussenzweig R S
Department of Medical and Molecular Parasitology, New York University School of Medicine, NY 10010, USA.
Parassitologia. 1999 Sep;41(1-3):397-402.
In order to provide a rational basis for the development of a pre-erythrocytic malaria vaccine we have aimed at: (a) elucidating the mechanisms of protection, and (b) identifying vaccine formulations that best elicit protection in experimental animals and humans. Based on earlier successful immunization of experimental animals with irradiated sporozoites, human volunteers were exposed to the bites of large numbers of Plasmodium falciparum or P. vivax infected irradiated mosquitoes. The result of this vaccine trial demonstrated for the first time that a pre-erythrocytic vaccine, administered to humans, can result in their complete resistance to malaria infection. However, since infected irradiated mosquitoes are unavailable for large scale vaccination, the alternative is to develop subunit vaccines. The human trials using irradiated sporozoites provided valuable information on the human immune responses to pre-erythrocytic stages and studies on mice an excellent experimental model to characterize protective immune mechanisms. The circumsporozoite protein, the first pre-erythrocytic antigen identified, is present in all malaria species, displaying a similar structure, with a central region of repeats, and two conserved regions, essential for parasite development. Most pre-erythrocytic vaccine candidates are based on the CS protein, expressed in various cell lines, microorganisms, and recently the corresponding DNA. We and others have identified CS-specific B and T cell epitopes, recognized by the rodent and human immune systems, and used them for the development of synthetic vaccines. We used synthetic peptide vaccines, multiple antigen peptides and polyoximes, for immunization, first in experimental animals, and recently in two human safety and immunogenicity trials. We also report here on our work on T cell mediated immunity, particularly the protection of mice immunized with viral vectors expressing CS-specific cytotoxic CD8+ T cell epitopes, and the striking booster effect of recombinant vaccinia virus. To what degree CD8+ T cells, and/or other T cells specific for sporozoites and/or liver stage epitopes, contribute to pre-erythrocytic protective immunity in humans, remains to be determined.
为了为开发一种红细胞前期疟疾疫苗提供合理依据，我们旨在：(a) 阐明保护机制；(b) 确定在实验动物和人类中能最佳引发保护作用的疫苗配方。基于早期用辐照子孢子成功免疫实验动物的研究，人类志愿者暴露于大量感染恶性疟原虫或间日疟原虫的辐照蚊子叮咬之下。该疫苗试验的结果首次证明，给予人类的红细胞前期疫苗可使其对疟疾感染产生完全抗性。然而，由于无法获得感染的辐照蚊子用于大规模接种，替代方法是开发亚单位疫苗。使用辐照子孢子的人体试验提供了关于人体对红细胞前期阶段免疫反应的宝贵信息，而对小鼠的研究则是表征保护性免疫机制的优秀实验模型。环子孢子蛋白是首个被确定的红细胞前期抗原，存在于所有疟原虫物种中，具有相似结构，有一个重复的中心区域以及两个对寄生虫发育至关重要的保守区域。大多数红细胞前期候选疫苗基于在各种细胞系、微生物中表达的环子孢子蛋白，以及最近基于相应的DNA。我们和其他人已经确定了被啮齿动物和人类免疫系统识别的环子孢子蛋白特异性B细胞和T细胞表位，并将其用于合成疫苗的开发。我们首先在实验动物中，最近在两项人体安全性和免疫原性试验中，使用合成肽疫苗、多抗原肽和聚肟进行免疫。我们还在此报告了我们关于T细胞介导免疫的工作，特别是用表达环子孢子蛋白特异性细胞毒性CD8+ T细胞表位的病毒载体免疫小鼠的保护作用，以及重组痘苗病毒显著的增强效应。CD8+ T细胞和/或其他针对子孢子和/或肝期表位的T细胞在多大程度上对人类红细胞前期保护性免疫有贡献，仍有待确定。
