Seattle Children's Research Institute, Seattle, WA, USA.
MSTP program, University of Washington, Seattle, WA, USA.
Cell Rep. 2021 Aug 3;36(5):109489. doi: 10.1016/j.celrep.2021.109489.
Both subunit and attenuated whole-sporozoite vaccination strategies against Plasmodium infection have shown promising initial results in malaria-naive westerners but less efficacy in malaria-exposed individuals in endemic areas. Here, we demonstrate proof of concept by using a rodent malaria model in which non-neutralizing antibodies (nNAbs) can directly interfere with protective anti-circumsporozoite protein (CSP) humoral responses. We characterize a monoclonal antibody, RAM1, against Plasmodium yoelii sporozoite major surface antigen CSP. Unlike the canonical PyCSP repeat domain binding and neutralizing antibody (NAb) 2F6, RAM1 does not inhibit sporozoite traversal or entry of hepatocytes in vitro or infection in vivo. Although 2F6 and RAM1 bind non-overlapping regions of the CSP-repeat domain, pre-treatment with RAM1 abrogates the capacity of NAb to block sporozoite traversal and invasion in vitro. Importantly, RAM1 reduces the efficacy of the polyclonal humoral response against PyCSP in vivo. Collectively, our data provide a proof of concept that nNAbs can alter the efficacy of malaria vaccination.
针对疟原虫感染，亚单位和减毒全孢子疫苗接种策略在无疟疾西方人中显示出有希望的初步结果，但在流行地区有疟疾暴露史的个体中效果较差。在这里，我们使用一种啮齿动物疟疾模型证明了这一概念，在该模型中，非中和抗体（nNAb）可以直接干扰保护性环子孢子蛋白（CSP）体液反应。我们对一种针对疟原虫 yoelii 孢子虫主要表面抗原 CSP 的单克隆抗体 RAM1 进行了特征描述。与典型的 PyCSP 重复结构域结合和中和抗体（NAb）2F6 不同，RAM1 不会抑制体外孢子虫穿越或进入肝细胞，也不会抑制体内感染。尽管 2F6 和 RAM1 结合 CSP 重复结构域的非重叠区域，但 RAM1 的预处理可消除 NAb 阻断体外孢子虫穿越和入侵的能力。重要的是，RAM1 降低了针对 PyCSP 的多克隆体液反应在体内的功效。总的来说，我们的数据提供了一个概念验证，即 nNAb 可以改变疟疾疫苗接种的效果。
