Vaccination with a structure-based stabilized version of malarial antigen Pfs48/45 elicits ultra-potent transmission-blocking antibody responses.
Vaccination with a structure-based stabilized version of malarial antigen Pfs48/45 elicits ultra-potent transmission-blocking antibody responses.
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DOI：
10.1016/j.immuni.2022.07.015
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发表时间：
2022-09-13
期刊：
影响因子：
32.4
通讯作者：
Julien, Jean-Philippe
中科院分区：
文献类型：
--
作者：
McLeod, Brandon;Mabrouk, Moustafa T.;Miura, Kazutoyo;Ravichandran, Rashmi;Kephart, Sally;Hailemariam, Sophia;Pham, Thao P.;Semesi, Anthony;Kucharska, Iga;Kundu, Prasun;Huang, Wei-Chiao;Johnson, Max;Blackstone, Alyssa;Pettie, Deleah;Murphy, Michael;Kraft, John C.;Leaf, Elizabeth M.;Jiao, Yang;Van de Vegte-Bolmer, Marga;Van Gemert, Geert-Jan;Ramjith, Jordache;King, C. Richter;MacGill, Randall S.;Wu, Yimin;Lee, Kelly K.;Jore, Matthijs M.;King, Neil P.;Lovell, Jonathan F.;Julien, Jean-Philippe
疟疾传播阻断疫苗（TBVs）旨在激发人体抗体，抑制恶性疟原虫在蚊子体内的孢子生殖发育，从而防止其进一步传播。Pfs48/45是一种主要的临床传播阻断疫苗候选抗原，可被迄今所描述的最有效的传播阻断单克隆抗体（mAb）识别；然而，Pfs48/45抗原的临床开发受到阻碍，主要是由于其不良的生化特性。在此，我们利用基于结构的计算方法设计了在最具抑制性的单克隆抗体所识别的构象中稳定的Pfs48/45抗原，与野生型蛋白质相比，其热稳定性提高了>25°C。用基于脂质体或基于蛋白质纳米颗粒的疫苗平台展示这些工程化抗原免疫小鼠所激发的抗体，与携带野生型抗原的免疫原相比，由于抗体质量提高，其传播阻断活性提高了1 - 2个数量级。我们的数据为仅利用来自抗体结构 - 功能信息的分子稳定化来推动针对寄生虫疫苗靶点的免疫反应改善提供了基本原则。
基于组合结构的Pfs48/45 - 6C抗原工程改造提高了其稳定性
与野生型抗原相比，热稳定性和重组蛋白产量均提高
2.18 Å分辨率的晶体结构为稳定性提高提供了分子层面的见解
多聚化稳定抗原在体内激发了强大的传播阻断活性
传播阻断疟疾疫苗Pfs48/45抗原的临床开发因其不良的生化特性而受阻。麦克劳德等人利用蛋白质工程技术改善了Pfs48/45 - 6C的稳定性和生物物理特性，与三个疫苗平台上的野生型抗原相比，其免疫反应的抑制能力提高了1 - 2个数量级。
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. Combinatorial structure-based engineering of Pfs48/45-6C antigen improves its stability Thermostability and recombinant protein yield are increased over WT antigen 2.18 Å resolution crystal structure provides molecular insights into stability gain Multimerized stabilized antigens elicit potent transmission-reducing activity in vivo Clinical development of transmission-blocking malaria vaccine Pfs48/45 antigens has been hindered by its poor biochemical characteristics. McLeod et al. utilized protein engineering techniques to improve the stability and biophysical properties of Pfs48/45-6C, which enhanced the inhibitory capacity of the immune response by 1–2 orders of magnitude, compared with the wild-type antigen across three vaccine platforms.
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影响因子：
38.3
作者：
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