加拿大儿童医院研究所Jean-Philippe Julien团队近期取得重要工作进展，他们研究发现接种基于结构的稳定版疟疾抗原Pfs48/45的疫苗可引发超强的传播阻断抗体反应。相关研究成果2022年8月16日在线出版于《免疫》杂志上。

研究人员使用基于结构的计算方法来设计Pfs48/45抗原，该抗原稳定在被最有效的抑制性mAb识别的构象中，与野生型蛋白质相比，实现了>25°C更高的热稳定性。与携带野生型抗原的免疫原相比，在基于脂质体或基于蛋白质纳米颗粒的疫苗递送平台上展示的，这些工程化抗原免疫小鼠中引发的抗体表现出1-2个数量级的传播活性降低，这是由改进的抗体质量驱动的。他们的数据提供了仅从抗体结构-功能信息中，使用分子稳定化来推动改善对寄生虫疫苗目标的免疫反应的基础原则。

据介绍，疟疾传播阻断疫苗（TBVs）的目的是诱导出抑制恶性疟原虫在蚊子体内的孢子发育的人类抗体，从而防止进一步传播。Pfs48/45是一种领先的临TBV候选抗原，并被认为是迄今为止最有效的阻断传播的单克隆抗体（mAb）。尽管如此，Pfs48/45抗原的临床开发一直受到阻碍，主要是由于其较差的生化特性。

附：英文原文

Title: Vaccination with a structure-based stabilized version of malarial antigen Pfs48/45 elicits ultra-potent transmission-blocking antibody responses

Author: Brandon McLeod, Moustafa T. Mabrouk, Kazutoyo Miura, Rashmi Ravichandran, Sally Kephart, Sophia Hailemariam, Thao P. Pham, Anthony Semesi, Iga Kucharska, Prasun Kundu, Wei-Chiao Huang, Max Johnson, Alyssa Blackstone, Deleah Pettie, Michael Murphy, John C. Kraft, Elizabeth M. Leaf, Yang Jiao, Marga van de Vegte-Bolmer, Geert-Jan van Gemert, Jordache Ramjith, C. Richter King, Randall S. MacGill, Yimin Wu, Kelly K. Lee, Matthijs M. Jore, Neil P. King, Jonathan F. Lovell, Jean-Philippe Julien

Issue&Volume: 2022-08-16

Abstract: 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.

DOI: 10.1016/j.immuni.2022.07.015

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00350-8