Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12735 Twinbrook Parkway, Rockville, MD, 20852, USA.
Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
Sci Rep. 2020 Jul 16;10(1):11802. doi: 10.1038/s41598-020-67877-8.
Plasmodium invasion of red blood cells involves malaria proteins, such as reticulocyte-binding protein homolog 5 (RH5), RH5 interacting protein (RIPR), cysteine-rich protective antigen (CyRPA), apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2), all of which are blood-stage malaria vaccine candidates. So far, vaccines containing AMA1 alone have been unsuccessful in clinical trials. However, immunization with AMA1 bound with RON2L (AMA1-RON2L) induces better protection against P. falciparum malaria in Aotus monkeys. We therefore sought to determine whether combinations of RH5, RIPR, CyRPA and AMA1-RON2L antibodies improve their biological activities and sought to develop a robust method for determination of synergy or additivity in antibody combinations. Rabbit antibodies against AMA1-RON2L, RH5, RIPR or CyRPA were tested either alone or in combinations in P. falciparum growth inhibition assay to determine Bliss' and Loewe's additivities. The AMA1-RON2L/RH5 combination consistently demonstrated an additive effect while the CyRPA/RIPR combination showed a modest synergistic effect with Hewlett's [Formula: see text] Additionally, we provide a publicly-available, online tool to aid researchers in analyzing and planning their own synergy experiments. This study supports future blood-stage vaccine development by providing a solid methodology to evaluate additive and/or synergistic (or antagonistic) effect of vaccine-induced antibodies.
疟原虫入侵红细胞涉及疟原蛋白,如网织红细胞结合蛋白同源物 5(RH5)、RH5 相互作用蛋白(RIPR)、富含半胱氨酸的保护性抗原(CyRPA)、顶膜抗原 1(AMA1)和 泡颈蛋白 2(RON2),它们都是血期疟疾疫苗候选物。到目前为止,仅含有 AMA1 的疫苗在临床试验中都不成功。然而,用 AMA1 与 RON2L(AMA1-RON2L)免疫可在食蟹猴中更好地预防恶性疟原虫疟疾。因此,我们试图确定 RH5、RIPR、CyRPA 和 AMA1-RON2L 抗体的组合是否能提高它们的生物学活性,并寻求开发一种用于确定抗体组合协同作用或相加作用的稳健方法。针对 AMA1-RON2L、RH5、RIPR 或 CyRPA 的兔抗体分别或组合用于恶性疟原虫生长抑制试验,以确定 Bliss 和 Loewe 的相加性。AMA1-RON2L/RH5 组合始终表现出相加作用,而 CyRPA/RIPR 组合与 Hewlett 的 [公式:见文本] 具有适度的协同作用。此外,我们提供了一个公开的在线工具,以帮助研究人员分析和计划他们自己的协同实验。这项研究通过提供一种评估疫苗诱导的抗体的相加和/或协同(或拮抗)作用的可靠方法,为未来的血期疫苗开发提供支持。
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