Program in Molecular Medicine, The Hospital for Sick Children Research Institute, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY 14260, USA.
Immunity. 2022 Sep 13;55(9):1680-1692.e8. doi: 10.1016/j.immuni.2022.07.015. Epub 2022 Aug 16.
Malaria transmission-blocking vaccines (TBVs) aim to elicit human antibodies that inhibit sporogonic development of Plasmodium falciparum in mosquitoes, thereby preventing onward transmission. Pfs48/45 is a leading clinical TBV candidate antigen and is recognized by the most potent transmission-blocking monoclonal antibody (mAb) yet described; still, clinical development of Pfs48/45 antigens has been hindered, largely by its poor biochemical characteristics. Here, we used structure-based computational approaches to design Pfs48/45 antigens stabilized in the conformation recognized by the most potently inhibitory mAb, achieving >25°C higher thermostability compared with the wild-type protein. Antibodies elicited in mice immunized with these engineered antigens displayed on liposome-based or protein nanoparticle-based vaccine platforms exhibited 1-2 orders of magnitude superior transmission-reducing activity, compared with immunogens bearing the wild-type antigen, driven by improved antibody quality. Our data provide the founding principles for using molecular stabilization solely from antibody structure-function information to drive improved immune responses against a parasitic vaccine target.
疟疾传播阻断疫苗（TBV）旨在诱导人体抗体，抑制疟原虫在蚊子中的孢子生殖发育，从而防止疾病传播。Pfs48/45 是一种主要的临床 TBV 候选抗原，可被迄今为止描述的最有效传播阻断单克隆抗体（mAb）识别；尽管如此，Pfs48/45 抗原的临床开发受到阻碍，主要是因为其生化特性较差。在这里，我们使用基于结构的计算方法设计了 Pfs48/45 抗原，使其在与最具抑制性 mAb 识别的构象中稳定，与野生型蛋白相比，热稳定性提高了>25°C。用这些工程抗原免疫小鼠产生的抗体在基于脂质体或蛋白纳米颗粒的疫苗平台上显示出 1-2 个数量级的更高的传播减少活性，与携带野生型抗原的免疫原相比，这是由于抗体质量的提高所致。我们的数据为仅使用抗体结构-功能信息的分子稳定化提供了基本原则，以驱动针对寄生虫疫苗靶标的改善免疫反应。
