Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex
Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex
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开发针对基本 RH5-CyRPA-RIPR 入侵复合物的改良血期疟疾疫苗
DOI：
10.1101/2024.02.08.579322
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发表时间：
2024
影响因子：
16.6
通讯作者：
S. Draper
中科院分区：
文献类型：
--
作者：
Barnabas G. Williams;L. King;D. Pulido;D. Quinkert;A. Lias;S. Silk;R. Ragotte;Hannah Davies;J. Barrett;K. McHugh;Cassandra A. Rigby;D. Alanine;Lea Barfod;Michael W. Shea;Li An Cowley;Rebecca A. Dabbs;David J. Pattinson;Alexander D. Douglas;Oliver R. Lyth;J. Illingworth;Jing Jin;C. Carnrot;V. Kotraiah;J. Christen;A. Noe;R. MacGill;C. King;Ashley J. Birkett;L. Soisson;Katherine Skinner;K. Miura;Carole A. Long;Matthew K. Higgins;S. Draper
近年来，网织红细胞结合蛋白同源物5(RH5)已成为恶性疟疫苗主要的血液期抗原。2b期临床试验中最先进的血液阶段候选疫苗RH5.1/MATRIX-M™是基于全长可溶蛋白和佐剂配方。RH5与富含半胱氨酸的保护性抗原(CyRPA)和RH5相互作用蛋白(RIPR)相互作用，形成必需的异源三聚体“RCR-复合体”。在这里，我们调查了基于三元rcr-复合体的候选疫苗是否能在临床前研究中显著改善领先的临床候选RH5.1/Matrix-M™。使用一组单抗，我们证实了每个抗原上的寄生虫生长抑制表位暴露在RCR-复合体的表面，并且与不同抗原结合的mAb对在体外可以相加或协同地发挥介导寄生虫生长抑制活性(GIA)的作用。然而，用RCR复合体免疫大鼠始终不能超过单独使用RH5.1。我们证明这是由于RIPR的免疫优势，加上与抗RH5和抗CyRPA反应相比，抗全长RIPR多克隆抗体的效力较弱。为了解决这一问题，我们发现RIPR的生长抑制抗体表位聚集在RIPR的C末端EGF样结构域中。将这些EGF结构域与CyRPA融合，称为“R78C”，与RH5.1相结合，提供了一种新的疫苗接种策略，该策略提高了单独使用RH5.1的体外GIA水平。联合抗原候选疫苗的优势是通过诱导数量更高但质量相似的多克隆抗体应答来实现的，该多克隆抗体应答在三个抗原靶点上表现出相加的GIA。这些临床前数据证明了RH5.1+R78C/MATRIX-M™组合疫苗进入第一阶段临床试验的合理性。
In recent years, reticulocyte-binding protein homologue 5 (RH5) has emerged as a leading blood-stage Plasmodium falciparum malaria vaccine antigen. The most advanced blood-stage vaccine candidate in a Phase 2b clinical trial, RH5.1/Matrix-M™, is based on a full-length soluble protein-with-adjuvant formulation. RH5 interacts with cysteine-rich protective antigen (CyRPA) and RH5- interacting protein (RIPR) to form an essential heterotrimeric “RCR-complex”. Here, we investigated whether a vaccine candidate based on the ternary RCR-complex could substantially improve upon the leading clinical candidate RH5.1/Matrix-M™ in preclinical studies. Using a panel of monoclonal antibodies (mAbs) we confirm that parasite growth-inhibitory epitopes on each antigen are exposed on the surface of the RCR-complex and that mAb pairs binding to different antigens can function additively or synergistically to mediate parasite growth inhibition activity (GIA) in vitro. However, immunisation of rats with the RCR-complex consistently fails to outperform RH5.1 alone. We show this is due to immuno-dominance of RIPR coupled with the inferior potency of anti-full length RIPR polyclonal IgG antibodies as compared to the anti-RH5 and anti-CyRPA response. To address this, we identified the growth-inhibitory antibody epitopes of RIPR are clustered within C-terminal EGF-like domains of RIPR. A fusion of these EGF domains to CyRPA, called “R78C”, combined with RH5.1, provided a new vaccination strategy that improves upon the levels of in vitro GIA seen with RH5.1 alone. Superiority of the combination antigen vaccine candidate was achieved by the induction of a quantitatively higher, but qualitatively similar, polyclonal antibody response that demonstrated additive GIA across the three antigen targets. These preclinical data justified the advancement of the RH5.1+R78C/Matrix-M™ combination vaccine to a Phase 1 clinical trial.
影响因子：
5.5
作者：
Miura, Kazutoyo;Orcutt, Andrew C.;Long, Carole A.
通讯作者：
Long, Carole A.