Virus-like particles (VLPs) induce strong humoral and cellular responses and have formed the basis of some currently licensed vaccines. Here, we present the method used for the production of R21, a VLP-based anti-sporozoite malaria vaccine, under current Clinical Good Manufacturing Practice regulations (cGMP). Previous preclinical studies in BALB/c mice showed that R21 produced almost complete protection against sporozoite challenge with transgenic Plasmodium berghei parasites. Here, we have modified the preclinical production process to enable the production of sufficient quantities of highly pure, clinical-grade material for use in human clinical trials. The R21 construct was re-engineered to include a C-tag to allow affinity-based separation from the major contaminant alcohol oxidase 1 (AOX 1, ~74 kDa). To our knowledge, this is the first use of C-tag technology to purify a VLP vaccine candidate for use in human clinical trials. The R21 vaccine has shown high-level efficacy in an African Phase IIb trial, and multiple clinical trials are underway to assess the safety and efficacy of the vaccine. Our findings support the future use of C-tag platform technologies to enable cGMP-compliant biomanufacturing of high purity yeast-expressed VLP-based vaccines for early phase clinical trials when clinical grade material is required in smaller quantities in a quick time frame.

中文翻译：

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在 cGMP 条件下生产用于在毕赤酵母中表达的高纯度、C 标记的乙型肝炎表面抗原融合蛋白 VLP 疫苗

病毒样颗粒 (VLP) 可诱导强烈的体液和细胞反应，并已成为一些目前获得许可的疫苗的基础。在这里，我们介绍了根据当前临床良好生产规范 (cGMP) 生产基于 VLP 的抗子孢子疟疾疫苗 R21 的方法。先前在 BALB/c 小鼠中的临床前研究表明，R21 对转基因伯氏疟原虫的子孢子攻击产生了几乎完全的保护作用寄生虫。在这里，我们修改了临床前生产工艺，以生产足够数量的高纯度临床级材料，用于人体临床试验。R21 结构经过重新设计，包括一个 C-标签，以允许与主要污染物醇氧化酶 1 (AOX 1, ~74 kDa) 进行基于亲和力的分离。据我们所知，这是首次使用 C-tag 技术来纯化用于人体临床试验的 VLP 候选疫苗。R21 疫苗在非洲 IIb 期试验中显示出高水平的疗效，并且正在进行多项临床试验以评估疫苗的安全性和有效性。