Advances in neglected tropical disease vaccines: Developing relative potency and functional assays for the Na-GST-1/Alhydrogel hookworm vaccine.
Advances in neglected tropical disease vaccines: Developing relative potency and functional assays for the Na-GST-1/Alhydrogel hookworm vaccine.
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DOI：
10.1371/journal.pntd.0005385
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发表时间：
2017-02
影响因子：
3.8
通讯作者：
Bethony JM
中科院分区：
文献类型：
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作者：
Brelsford JB;Plieskatt JL;Yakovleva A;Jariwala A;Keegan BP;Peng J;Xia P;Li G;Campbell D;Periago MV;Correa-Oliveira R;Bottazzi ME;Hotez PJ;Diemert D;Bethony JM
针对被忽视的热带疾病(NTDS)的新一代疫苗现已进入临床开发阶段，Na-GST-1/阿尔水凝胶钩虫疫苗已经在健康成年人的第一阶段研究中进行了测试。目前的手稿集中在经常被忽视的NTD疫苗产品开发的关键方面，更具体地说，疫苗稳定性测试计划。疫苗稳定性测试的一个关键指标是“相对效力”，即疫苗在储存期间的免疫原性。与大多数NTD疫苗一样，Na-GST-1/Alwater Gel钩虫疫苗不是通过对病原体(美洲钩端螺旋体)的减毒或灭活来开发的，因此传统的相对效力测量方法与该研究产品无关。在这里，我们描述了一种新的相对效力测试程序，并首次报告了这种NTD疫苗在2-8°C的头60个月的临床批次。我们还描述了一种互补功能分析的发展，该方法可以测量Na-GST-1/Alwater Gel免疫的动物或人的免疫球蛋白中和这种重要的钩虫酶的能力。在Na-GST-1/Alwater Gel免疫的动物中，Na-GST-1的催化活性被抑制了90%，而在免疫的人中观察到了较低的抑制水平。此外，来自非钩虫流行区志愿者的抗Na-GST-1抗体比来自钩虫流行区志愿者的抗Na-GST-1抗体更能抑制催化活性。本文所述结果为NTD疫苗的产品开发提供了关键工具。随着针对非传染性疾病的疫苗进入临床试验，产品开发和疫苗维护成为这些疫苗成功的关键活动。疫苗研发这一阶段的一个关键活动是疫苗的“相对效力”，或疫苗在储存期间在动物模型中引起的免疫反应的质量，以确保其免疫原性保持不变。与大多数NTD疫苗一样，Na-GST-1/Alwater Gel钩虫疫苗不是使用传统方法开发的，因此不能使用传统的相对效力指标，如测试疫苗抵御致命攻击的能力。第一次，我们描述了NTD疫苗在2-8°C的五年保存期内相对效力测试程序的开发。我们还描述了一种互补功能测试的开发，该测试用于测量Na-GST-1/Alwater Gel免疫的动物或人类的免疫球蛋白中和这种重要的钩虫酶的能力。这里描述的结果第一次以开放获取的形式为未来NTD疫苗的开发提供了关键工具。
A new generation of vaccines for the neglected tropical diseases (NTDs) have now advanced into clinical development, with the Na-GST-1/Alhydrogel Hookworm Vaccine already being tested in Phase 1 studies in healthy adults. The current manuscript focuses on the often overlooked critical aspects of NTD vaccine product development, more specifically, vaccine stability testing programs. A key measure of vaccine stability testing is "relative potency" or the immunogenicity of the vaccine during storage. As with most NTD vaccines, the Na-GST-1/Alhydrogel Hookworm Vaccine was not developed by attenuation or inactivation of the pathogen (Necator americanus), so conventional methods for measuring relative potency are not relevant for this investigational product. Herein, we describe a novel relative potency testing program and report for the first time on the clinical lot of this NTD vaccine during its first 60 months of storage at 2–8°C. We also describe the development of a complementary functional assay that measures the ability of IgG from animals or humans immunized with Na-GST-1/Alhydrogel to neutralize this important hookworm enzyme. While 90% inhibition of the catalytic activity of Na-GST-1 was achieved in animals immunized with Na-GST-1/Alhydrogel, lower levels of inhibition were observed in immunized humans. Moreover, anti-Na-GST-1 antibodies from volunteers in non-hookworm endemic areas were better able to inhibit catalytic activity than anti-Na-GST-1 antibodies from volunteers resident in hookworm endemic areas. The results described herein provide the critical tools for the product development of NTD vaccines. As vaccines targeting NTDs advance into clinical trials, product development and vaccine maintenance become critical activities for the success of these vaccines. A key activity during this phase of vaccine development is the “relative potency” of a vaccine or the quality of the immune response that the vaccine elicits in an animal model during storage to ensure its immunogenicity is maintained. As with most NTD vaccines, the Na-GST-1/Alhydrogel Hookworm Vaccine was not developed using traditional methods of attenuating the pathogen (Necator americanus), so traditional measures of relative potency, such as testing the vaccine’s ability to protect against lethal challenge, could not be used. For the first time, we describe the development of a relative potency testing program for an NTD vaccine during five years of storage at 2–8°C. We also describe the development of a complementary functional assay that measures the ability of IgG from animals or humans immunized with Na-GST-1/Alhydrogel to neutralize this important hookworm enzyme. The results described herein provide, for the first time in an open access format, critical tools for the development of future NTD vaccines.