Infectious Disease Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
PLoS One. 2012;7(2):e31247. doi: 10.1371/journal.pone.0031247. Epub 2012 Feb 15.
Live attenuated malaria vaccines are more potent than the recombinant protein, bacterial or viral platform vaccines that have been tested, and an attenuated sporozoite vaccine against falciparum malaria is being developed for humans. In mice, attenuated malaria sporozoite vaccines induce CD8(+) T cells that kill parasites developing in the liver. We were curious to know if CD8(+) T cells were also important in protecting primates against malaria. We immunized 9 rhesus monkeys with radiation attenuated Plasmodium knowlesi sporozoites, and found that 5 did not develop blood stage infections after challenge with live sporozoites. We then injected 4 of these protected monkeys with cM-T807, a monoclonal antibody to the CD8 molecule which depletes T cells. The fifth monkey received equivalent doses of normal IgG. In 3 of the 4 monkeys receiving cM-T807 circulating CD8(+) T cells were profoundly depleted. When re-challenged with live sporozoites all 3 of these depleted animals developed blood stage malaria. The fourth monkey receiving cM-T807 retained many circulating CD8(+) T cells. This monkey, and the vaccinated monkey receiving normal IgG, did not develop blood stage malaria at re-challenge with live sporozoites. Animals were treated with antimalarial drugs and rested for 4 months. During this interval CD8(+) T cells re-appeared in the circulation of the depleted monkeys. When all vaccinated animals received a third challenge with live sporozoites, all 5 monkeys were once again protected and did not develop blood stage malaria infections. These data indicate that CD8(+) T cells are important effector cells protecting monkeys against malaria sporozoite infection. We believe that malaria vaccines which induce effector CD8+ T cells in humans will have the best chance of protecting against malaria.
减毒疟疾疫苗比经过测试的重组蛋白、细菌或病毒平台疫苗更有效，针对恶性疟原虫的减毒子孢子疫苗正在开发中，用于人类。在小鼠中，减毒疟原虫子孢子疫苗诱导杀伤在肝脏中发育的寄生虫的 CD8+T 细胞。我们很好奇 CD8+T 细胞是否也对保护灵长类动物免受疟疾感染很重要。我们用辐射减毒的伯氏疟原虫子孢子免疫 9 只恒河猴，发现其中 5 只在受到活子孢子的攻击后没有发展为血液期感染。然后，我们给其中 4 只受保护的猴子注射 cM-T807，这是一种针对 CD8 分子的单克隆抗体，可以耗竭 T 细胞。第 5 只猴子接受了等量的正常 IgG。在接受 cM-T807 注射的 4 只猴子中，循环 CD8+T 细胞被严重耗竭。当再次受到活子孢子的攻击时，所有 3 只耗竭的动物都发展为血液期疟疾。接受 cM-T807 注射的第 4 只猴子保留了许多循环 CD8+T 细胞。这只猴子和接种了正常 IgG 的猴子在再次受到活子孢子的攻击时没有发展为血液期疟疾。动物用抗疟药物治疗并休息了 4 个月。在此期间，耗竭猴子的循环中再次出现 CD8+T 细胞。当所有接种疫苗的动物再次受到活子孢子的第三次攻击时，所有 5 只猴子再次受到保护，没有发展为血液期疟疾感染。这些数据表明，CD8+T 细胞是保护猴子免受疟疾子孢子感染的重要效应细胞。我们相信，能在人体内诱导效应 CD8+T 细胞的疟疾疫苗将最有机会预防疟疾。
