PATH's Malaria Vaccine Initiative, 455 Massachusetts Avenue, NW, Suite 1000, Washington, DC, 20001, USA.
Vaccine and Infectious Disease Division, Fred Hutchison Cancer Research Center, Seattle, WA, 98109, USA.
Malar J. 2020 Mar 17;19(1):113. doi: 10.1186/s12936-020-03181-0.
New strategies are needed to reduce the incidence of malaria, and promising approaches include the development of vaccines and monoclonal antibodies (mAbs) that target the circumsporozoite protein (CSP). To select the best candidates and speed development, it is essential to standardize preclinical assays to measure the potency of such interventions in animal models.
Two assay configurations were studied using transgenic Plasmodium berghei expressing Plasmodium falciparum full-length circumsporozoite protein. The assays measured (1) reduction in parasite infection of the liver (liver burden) following an intravenous (i.v) administration of sporozoites and (2) protection from parasitaemia following mosquito bite challenge. Two human CSP mAbs, AB311 and AB317, were compared for their ability to inhibit infection. Multiple independent experiments were conducted to define assay variability and resultant impact on the ability to discriminate differences in mAb functional activity.
Overall, the assays produced highly consistent results in that all individual experiments showed greater functional activity for AB317 compared to AB311 as calculated by the dose required for 50% inhibition (ID50) as well as the serum concentration required for 50% inhibition (IC50). The data were then used to model experimental designs with adequate statistical power to rigorously screen, compare, and rank order novel anti-CSP mAbs.
The results indicate that in vivo assays described here can provide reliable information for comparing the functional activity of mAbs. The results also provide guidance regarding selection of the appropriate experimental design, dose selection, and group sizes.
需要新的策略来降低疟疾的发病率，有前途的方法包括开发针对环子孢子蛋白（CSP）的疫苗和单克隆抗体（mAbs）。为了选择最佳候选物并加速开发，必须标准化临床前测定法以在动物模型中测量此类干预措施的效力。
使用表达恶性疟原虫全长环子孢子蛋白的转基因伯氏疟原虫研究了两种测定配置。测定法测量了（1）静脉内（i.v）给予孢子后寄生虫对肝脏的感染减少（肝负担），以及（2）蚊叮咬挑战后对寄生虫血症的保护。比较了两种人类 CSP mAb，AB311 和 AB317，以评估它们抑制感染的能力。进行了多个独立的实验来定义测定的可变性以及对区分 mAb 功能活性差异的能力的影响。
总体而言，测定结果高度一致，所有单个实验均表明 AB317 的功能活性均大于 AB311，这是通过 50％抑制所需剂量（ID50）以及 50％抑制所需血清浓度（IC50）计算得出的。然后，使用这些数据对实验设计进行建模，以提供足够的统计能力来严格筛选，比较和对新型抗 CSP mAb 进行排序。
结果表明，这里描述的体内测定可以为比较 mAb 的功能活性提供可靠的信息。结果还为选择适当的实验设计，剂量选择和组大小提供了指导。
