Over 75% of malaria-attributable deaths occur in children under the age of 5 years. However, the first malaria vaccine recommended by the World Health Organization (WHO) for pediatric use, RTS,S/AS01 (Mosquirix), has modest efficacy. Complementary strategies, including monoclonal antibodies, will be important in efforts to eradicate malaria. Here we characterize the circulating B cell repertoires of 45 RTS,S/AS01 vaccinees and discover monoclonal antibodies for development as potential therapeutics. We generated >28,000 antibody sequences and tested 481 antibodies for binding activity and 125 antibodies for antimalaria activity in vivo. Through these analyses we identified correlations suggesting that sequences in Plasmodium falciparum circumsporozoite protein, the target antigen in RTS,S/AS01, may induce immunodominant antibody responses that limit more protective, but subdominant, responses. Using binding studies, mouse malaria models, biomanufacturing assessments and protein stability assays, we selected AB-000224 and AB-007088 for advancement as a clinical lead and backup. We engineered the variable domains (Fv) of both antibodies to enable low-cost manufacturing at scale for distribution to pediatric populations, in alignment with WHO’s preferred product guidelines. The engineered clone with the optimal manufacturing and drug property profile, MAM01, was advanced into clinical development.

超过 75% 的疟疾归因死亡发生在 5 岁以下儿童中。然而，世界卫生组织 （WHO） 推荐用于儿科的第一种疟疾疫苗 RTS，S/AS01 （Mosquirix） 的疗效不大。包括单克隆抗体在内的补充策略对于根除疟疾的努力将很重要。在这里，我们表征了 45 名 RTS，S/AS01 疫苗接种者的循环 B 细胞库，并发现了用于开发作为潜在疗法的单克隆抗体。我们生成了 >28,000 个抗体序列，并在体内测试了 481 个抗体的结合活性和 125 个抗体的抗疟疾活性。通过这些分析，我们确定了相关性，表明恶性疟原虫周围子孢子蛋白（RTS，S/AS01 中的靶抗原）中的序列可能诱导免疫显性抗体反应，从而限制更具保护性但次显性的反应。使用结合研究、小鼠疟疾模型、生物制造评估和蛋白质稳定性测定，我们选择了 AB-000224 和 AB-007088 作为临床指导和备份。我们设计了两种抗体的可变结构域 （Fv），以实现低成本的大规模生产，以分发给儿科人群，符合 WHO 的首选产品指南。具有最佳生产和药物特性特征的工程克隆 MAM01 已进入临床开发阶段。