Kedzierski Lukasz, Black Casilda G, Goschnick Matthew W, Stowers Anthony W, Coppel Ross L
Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia.
Infect Immun. 2002 Dec;70(12):6606-13. doi: 10.1128/IAI.70.12.6606-6613.2002.
It is widely believed that subunit vaccines composed of multiple components will offer greater protection against challenge by malaria, and yet there is little experimental evidence to support this view. We set out to test this proposition in the Plasmodium yoelii challenge system in rodents by comparing the degree of protection conferred by immunization with a mixture of merozoite surface proteins to that conferred by single proteins. We therefore examined a defined protein mixture made of the epidermal growth factor-like domains of P. yoelli merozoite surface protein 1 (MSP1) and MSP4/5, the homologue of P. falciparum MSP4 and MSP5. In the present study we demonstrate that this combination of recombinant proteins dramatically enhances protection against lethal malaria challenge compared to either protein administered alone. Many mice immunized with the MSP4/5 plus MSP1(19) combination did not develop detectable parasitemia after challenge. Combined immunization with MSP1(19) and yMSP4/5, a product characterized by lower protective efficacy, also greatly enhanced protection by reducing peak parasitemias and increasing the numbers of survivors. In some combination trials, levels of antibodies to MSP1(19) were elevated compared to the MSP1(19) alone group; however, improved protection occurred regardless of whether boosting of the anti-MSP1(19) response was observed. Boosting of anti-MSP1(19) did not appear to be due to contaminating endotoxin in the EcMSP4/5 material since enhanced protection was observed in C3H/HeJ mice, which are endotoxin insensitive. Collectively, these experiments show that multiantigen combinations offer enhanced levels of protection against asexual stage infection and suggest that combinations of MSP1, MSP4, and MSP5 should be evaluated further for use in humans.
人们普遍认为，由多种成分组成的亚单位疫苗对疟疾攻击将提供更强的保护，然而，几乎没有实验证据支持这一观点。我们着手在啮齿动物的约氏疟原虫攻击系统中验证这一论点，比较用裂殖子表面蛋白混合物免疫所提供的保护程度与单一蛋白所提供的保护程度。因此，我们检测了一种特定的蛋白混合物，该混合物由约氏疟原虫裂殖子表面蛋白1（MSP1）的表皮生长因子样结构域和恶性疟原虫MSP4和MSP5的同源物MSP4/5组成。在本研究中，我们证明，与单独给予任何一种蛋白相比，这种重组蛋白组合显著增强了对致命性疟疾攻击的保护作用。许多用MSP4/5加MSP1（19）组合免疫的小鼠在攻击后未出现可检测到的寄生虫血症。用保护效力较低的产物MSP1（19）和yMSP4/5联合免疫，也通过降低峰值寄生虫血症和增加存活小鼠数量大大增强了保护作用。在一些联合试验中，与单独的MSP1（19）组相比，针对MSP1（19）的抗体水平有所升高；然而，无论是否观察到抗MSP1（19）反应的增强，都出现了保护作用的改善。抗MSP1（19）反应的增强似乎不是由于EcMSP4/5材料中污染的内毒素，因为在内毒素不敏感的C3H/HeJ小鼠中也观察到了增强的保护作用。总体而言，这些实验表明，多抗原组合可提供更高水平的针对无性阶段感染的保护作用，并表明应进一步评估MSP1、MSP4和MSP5组合在人类中的应用。
