Rational structure-guided design of a blood stage malaria vaccine immunogen presenting a single epitope from PfRH5
Rational structure-guided design of a blood stage malaria vaccine immunogen presenting a single epitope from PfRH5
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具有 PfRH5 单一表位的血期疟疾疫苗免疫原的合理结构指导设计
DOI：
10.1101/2024.02.29.582763
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Harrison T
中科院分区：
文献类型：
--
作者：
Harrison T
迫切需要改进疟疾疫苗免疫原。恶性疟原虫侵入红细胞对其生命周期至关重要，是疾病和寄生虫传播的前期症状。靶向PfRH 5的抗体在防止红细胞侵入方面非常有效，并且最有效的生长抑制抗体结合单个表位。在这里，我们使用结构指导的方法来设计一个小的合成免疫原，RH 5 - 34 EM，它概括了这个表位。结构生物学和生物物理学证明RH 5 - 34 EM正确折叠，并以纳摩尔亲和力结合中和单克隆抗体。在免疫大鼠中，RH 5 - 34 EM诱导PfRH 5靶向抗体，抑制寄生虫生长。虽然通过RH 5 - 34 EM诱导的PfRH 5特异性抗体的浓度低于通过PfRH 5诱导的PfRH 5特异性抗体的浓度，但是作为PfRH 5特异性抗体浓度的因子，RH 5 - 34 EM诱导的抗体的生长抑制性是PfRH 5特异性抗体浓度的千倍。最后，我们表明，用RH 5 - 34 EM引发和用PfRH 5加强达到抗体质量和数量之间的最佳平衡，并诱导最有效的生长抑制反应。这种合理设计的疫苗免疫原现在可单独或与其他免疫原组合用作未来疟疾疫苗的一部分。
There is an urgent need for improved malaria vaccine immunogens. Invasion of erythrocytes byPlasmodium falciparumis essential for its life cycle, preceding symptoms of disease and parasite transmission. Antibodies which target PfRH5 are highly effective at preventing erythrocyte invasion and the most potent growth-inhibitory antibodies bind a single epitope. Here we use structure-guided approaches to design a small synthetic immunogen, RH5-34EM which recapitulates this epitope. Structural biology and biophysics demonstrate that RH5-34EM is correctly folded and binds neutralising monoclonal antibodies with nanomolar affinity. In immunised rats, RH5-34EM induces PfRH5-targeting antibodies that inhibit parasite growth. While PfRH5-specific antibodies were induced at a lower concentration by RH5-34EM than by PfRH5, RH5-34EM induced antibodies that were a thousand-fold more growth-inhibitory as a factor of PfRH5-specific antibody concentration. Finally, we show that priming with RH5-34EM and boosting with PfRH5 achieves the best balance between antibody quality and quantity and induces the most effective growth-inhibitory response. This rationally designed vaccine immunogen is now available for use as part of future malaria vaccines, alone or in combination with other immunogens.
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影响因子：
16.6
作者：
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影响因子：
28.3
作者：
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影响因子：
64.8
作者：
Wright, Katherine E.;Hjerrild, Kathryn A.;Bartlett, Jonathan;Douglas, Alexander D.;Jin, Jing;Brown, Rebecca E.;Illingworth, Joseph J.;Ashfield, Rebecca;Clemmensen, Stine B.;de Jongh, Willem A.;Draper, Simon J.;Higgins, Matthew K.
通讯作者：
Higgins, Matthew K.
DOI：
10.1107/s2059798319011471
发表时间：
2019-10-01
影响因子：
2.2
作者：
Liebschner, Dorothee;Afonine, Pavel V.;Adams, Paul D.
通讯作者：
Adams, Paul D.
影响因子：
64.8
作者：
Crosnier, Cecile;Bustamante, Leyla Y.;Bartholdson, S. Josefin;Bei, Amy K.;Theron, Michel;Uchikawa, Makoto;Mboup, Souleymane;Ndir, Omar;Kwiatkowski, Dominic P.;Duraisingh, Manoj T.;Rayner, Julian C.;Wright, Gavin J.
通讯作者：
Wright, Gavin J.