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Endpoint and epitope-specific antibody responses as correlates of vaccine-mediated protection of mice against ricin toxin

机译：终点和表位特异性抗体应答作为疫苗介导的小鼠对蓖麻毒素的保护的相关性

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The successful licensure of vaccines for biodefense is contingent upon the availability of well-established correlates of protection (CoP) in at least two animal species that can be applied to humans, without the need to assess efficacy in the clinic. In this report we describe a multivariate model that combines pre-challenge serum antibody endpoint titers (EPT) and values derived from an epitope profiling immune-competition capture (EPICC) assay as a predictor in mice of vaccine-mediated immunity against ricin toxin (RT), a Category B biothreat. EPICC is a modified competition ELISA in which serum samples from vaccinated mice were assessed for their ability to inhibit the capture of soluble, biotinylated (b)-RT by a panel of immobilized monoclonal antibodies (mAbs) directed against four immunodominant toxin-neutralizing regions on the enzymatic A chain (RTA) of RT. In a test cohort of mice (n = 40) vaccinated with suboptimal doses of the RTA subunit vaccine, RiVax (R), we identified two mAbs, PB10 and SyH7, which had EPICC inhibition values in pre-challenge serum samples that correlated with survival following a challenge with 5 x LD50 of RT administered by intraperitoneal (IP) injection. Analysis of a larger cohort of mice (n = 645) revealed that a multivariate model combining endpoint titers and EPICC values for PB10 and SyH7 as predictive variables had significantly higher statistical power than any one of the independent variables alone. Establishing the correlates of vaccine-mediated protection in mice represents an important steppingstone in the development of RiVax (R) as a medical countermeasure under the United States Food and Drug Administration's "Animal Rule." (C) 2020 Elsevier Ltd. All rights reserved.
机译：疫苗的生物防卫成功执照是在在可应用于人类至少两个动物物种的保护（COP）的行之有效的相关因素的可用性队伍，而不需要在诊所评估疗效。在本报告中，我们描述一个多变量模型，结合攻击前血清抗体的终点效价（EPT）和值从表位衍生仿形免疫竞争捕获（EPICC）测定法如在针对蓖麻毒素疫苗介导的免疫的小鼠的预测（RT ），B类生物威胁。 EPICC是修饰的竞争性ELISA，其中来自接种小鼠的血清样品评估它们通过固定的单克隆抗体（mAbs）的面板，以抑制可溶的，生物素化的（b）中-RT的捕获针对4免疫毒素中和区上的能力酶A链的RT（RTA）。在小鼠中的测试群组（N = 40）接种次优剂量的RTA亚单位疫苗，RiVax（R），我们确定了两种mAb，PB10和SyH7，其具有与存活相关攻击前血清样品中EPICC抑制值以下与RT的5×LD50是一个挑战，通过腹膜内（IP）注射施用。小鼠的更大群体的分析（N = 645）透露，多变量模型PB10和SyH7结合终点效价和EPICC值作为预测变量有显著较高的统计力量比单独的独立变量中的任何一个。建立疫苗介导的保护的相关因素在小鼠表示作为根据美国食品和药物管理局的医疗对策RiVax（R）的发展的重要踏脚石“动物规则”。 （c）2020 elestvier有限公司保留所有权利。

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