Malaria Transmission Blocking Vaccine Discovery

抗原发现的重点是使用从自然接触疟疾的人身上收集的人类血清样本，作为识别候选疫苗抗原的工具。这些人似乎具有有效的免疫力，可以防止配子细胞症或阻止寄生虫传播给蚊子。具体地说，将具有感兴趣活性的血清样本或抗体与缺乏这种活性的血清/抗体进行比较，以了解它们选择或识别恶性疟原虫个别重组蛋白结构的能力。然后，通过差异筛选鉴定的重组蛋白被制备成免疫原，并测试它们诱导有效的抗配子体或传播阻断抗体的能力。 从我们今年的出版物中，我们报告了2023财年的以下进展： Simons LM，Ferrer P，Gombakomba N，Underwood K，Herrera R，Narum DL，Canepa G，Acquah F，Amoah L，Duffy PE，Barillas-Mury C，Long C，Lee SM，Locke E，Miura K，Williamson KC。扩大恶性疟传播阻断抗体的使用范围。2023年。疫苗。4月24：S0264-410X(23)00453-X。DOI：10.1016/j.accine.2023.04.042. 使用流式细胞术有效地筛选恶性疟原虫配子/受精卵表面的反应性，这项由USUHS同事领导的合作研究鉴定了82种抗体，这些抗体与活的恶性疟原虫配子/受精卵结合。这些抗体中有8个通过标准的膜喂养试验激发了显著的TRA，并且不识别当前任何重组传播阻断疫苗候选Pfs230D1M、Pfs48/45.6C、Pf47D2和rPfs25中存在的表位。一个TRA单抗免疫沉淀两种表面抗原Pfs47和Pfs230，它们在配子细胞和配子/受精卵中都有表达。这两种蛋白以前没有报道过相互关联，单一的TRA单抗对两者的识别表明Pfs47/Pfs230复合体是一个新的疫苗靶点。总体而言，Pfs230是主要的靶抗原，8个TRA单抗中有5个和11个非配子/受精卵表面反应性单抗中的8个与Pfs230相互作用。在剩下的三个TRA单抗中，两个被识别为非还原的寄生虫产生的Pfs25和一个结合的非还原的寄生虫产生的Pfs48/45。新的TRA表位都不是线性的。识别8个新的TRA单抗，这些单抗结合的表位没有包括在目前正在推进的任何结构中，作为传播阻断疫苗候选，可能提供值得进一步研究的新靶点。 首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容设计一种稳定的非糖基化Pfs48/45抗原使一种有效的阻断疟疾传播的纳米疫苗成为可能。2023年。NpjVaccines。2月18日；8(1)：20。DOI：10.1038/s41541-023-00619-9。 Pfs48/45是一种很有希望作为传播阻断疫苗的抗原，这项由Tolia实验室领导的合作项目实施了SPEEDesign计算设计和体外筛选流水线，以创建稳定的非糖基化Pfs48/45D3抗原，并改进其制造特性，用于疫苗生产。

Antigen discovery has focused on using human serum samples collected from individuals that are naturally exposed to malaria and appear to develop effective immunity that prevents gametocytemia or blocks parasite transmission to mosquitoes, as tools to identify candidate vaccine antigens. Specifically, serum samples or antibodies that have activity of interest are compared to sera/antibodies that lack this activity, for their ability to select or recognize individual recombinant proteins constructs of P. falciparum. Recombinant proteins identified through differential screening are then prepared as immunogens and tested for their ability to induce effective anti-gametocyte or transmission-blocking antibodies. From our publications this year, we report the following advances in FY2023: Simons LM, Ferrer P, Gombakomba N, Underwood K, Herrera R, Narum DL, Canepa G, Acquah F, Amoah L, Duffy PE, Barillas-Mury C, Long C, Lee SM, Locke E, Miura K, Williamson KC. Extending the range of Plasmodium falciparum transmission blocking antibodies. 2023. Vaccine. Apr 24:S0264-410X(23)00453-X. doi: 10.1016/j.vaccine.2023.04.042. Using flow cytometry to efficiently screen for P. falciparum gamete/zygote surface reactivity, this collaborative study led by USUHS colleagues identified 82 antibodies that bound live P. falciparum gametes/zygotes. Eight of these antibodies elicited significant TRA via standard membrane feeding assay, and do not recognize epitopes present in any of the current recombinant transmission-blocking vaccine candidates, Pfs230D1M, Pfs48/45.6C, Pf47 D2 and rPfs25. One TRA mAb immunoprecipitates two surface antigens, Pfs47 and Pfs230, that are expressed by both gametocytes and gametes/zygotes. These two proteins have not previously been reported to associate and the recognition of both by a single TRA mAb suggests the Pfs47/Pfs230 complex is a new vaccine target. In total, Pfs230 was the dominant target antigen, with five of the eight TRA mAbs and 8 of 11 nonTRA gamete/zygote surface reactive mAbs interacting with Pfs230. Of the three remaining TRA mAbs, two recognized non-reduced, parasite-produced Pfs25 and one bound non-reduced, parasite-produced Pfs48/45. None of the new TRA epitopes are linear. The identification of eight new TRA mAbs that bind epitopes not included in any of the constructs currently under advancement as transmission-blocking vaccine candidates may provide new targets worthy of further study. Dickey TH, Gupta R, McAleese H, Ouahes T, Orr-Gonzales S, Ma R, Muratova O, Hume JCC, Lambert LE, Duffy PE, Tolia NH. Design of a stabilized non-glycosylated Pfs48/45 antigen enables a potent malaria transmission-blocking nanoparticle vaccine. 2023. npjVaccines. Feb 18;8(1):20. doi: 10.1038/s41541-023-00619-9. Pfs48/45 is a promising antigen in development as a transmission blocking vaccine (TBV)This collaborative project led by Tolia lab implemented a SPEEDesign computational design and in vitro screening pipeline to create a stabilized non-glycosylated Pfs48/45 D3 antigen with improved manufacture characteristics for vaccine manufacture.