Charoenvit Y, Sedegah M, Yuan L F, Gross M, Cole C, Bechara R, Leef M F, Robey F A, Lowell G H, Beaudoin R L
Infectious Diseases Department, Naval Medical Research Institute, Bethesda, MD.
Bull World Health Organ. 1990;68 Suppl(Suppl):26-32.
Three subunit vaccines based on the major repeat, (QGPGAP)n, and flanking regions of the Plasmodium yoelii circumsporozoite protein were designed, produced, and tested. All were immunogenic, but none gave consistent protection against a 40-200 sporozoite challenge. To demonstrate that antibodies to P. yoelii CS protein could provide protection we established a passive transfer model. Passive transfer of NYS1, an IgG3 MAb against the P. yoelii CS protein, protected 100% of mice against challenge with 5000 P. yoelii sporozoites. Binding of NYS1 to sporozoites was inhibited by incubation with (QGPGAP)2, indicating that the epitope on sporozoites recognized by this MAb was included within this peptide. The levels of antibodies to (QGPGAP)2 by ELISA, and to sporozoites by IFAT and CS precipitation reaction were similar in sera from mice that received NYS1 in passive transfer and were protected against challenge with 5000 sporozoites, and from mice that had been immunized with subunit vaccines containing QGPGAP but were not protected against challenge with 40-200 sporozoites. To determine if antibody avidity, not the absolute concentration, could explain the striking differences in protection, we established a thiocyanate elution assay. The results suggest that NYS1, the protective MAb, has a lower avidity for (QGPGAP)2 and for sporozoites than do the vaccine-induced antibodies. The data clearly demonstrate that antibodies to the CS protein can protect against intense sporozoite infection. Improved understanding of the differences between protective MAbs and non-protective polyclonal antibodies will be important in the further development of malaria vaccines.
基于约氏疟原虫环子孢子蛋白主要重复序列（QGPGAP）n及其侧翼区域设计、生产并测试了三种亚单位疫苗。所有疫苗都具有免疫原性，但没有一种能对40 - 200个孢子体攻击提供持续的保护。为了证明针对约氏疟原虫CS蛋白的抗体可以提供保护，我们建立了一个被动转移模型。针对约氏疟原虫CS蛋白的IgG3单克隆抗体NYS1的被动转移，保护了100%的小鼠免受5000个约氏疟原虫孢子体的攻击。NYS1与孢子体的结合通过与（QGPGAP）2孵育而受到抑制，这表明该单克隆抗体识别的孢子体上的表位包含在该肽段内。通过ELISA检测针对（QGPGAP）2的抗体水平，以及通过间接荧光抗体试验（IFAT）和CS沉淀反应检测针对孢子体的抗体水平，在被动转移中接受NYS1并免受5000个孢子体攻击的小鼠血清中，与用含有QGPGAP的亚单位疫苗免疫但未免受40 - 200个孢子体攻击的小鼠血清中相似。为了确定是否是抗体亲和力而非绝对浓度可以解释保护效果上的显著差异，我们建立了硫氰酸盐洗脱试验。结果表明，保护性单克隆抗体NYS1对（QGPGAP）2和孢子体的亲和力低于疫苗诱导的抗体。数据清楚地表明，针对CS蛋白的抗体可以保护免受强烈的孢子体感染。更好地理解保护性单克隆抗体和非保护性多克隆抗体之间的差异对于疟疾疫苗的进一步开发将是重要的。
