PDF(Pubmed)
Abstract：
Efficacy data on two malaria vaccines, RTS,S and R21, targeting Plasmodium falciparum circumsporozoite protein (PfCSP), are encouraging. Efficacy may be improved by induction of additional antibodies to neutralizing epitopes outside of the central immunodominant repeat domain of PfCSP. We designed four rPfCSP-based vaccines in an effort to improve the diversity of the antibody response. We also evaluated P. falciparum merozoite surface protein 8 (PfMSP8) as a malaria-specific carrier protein as an alternative to hepatitis B surface antigen. We measured the magnitude, specificity, subclass, avidity, durability, and efficacy of vaccine-induced antibodies in outbred CD1 mice. In comparison to N-terminal- or C-terminal-focused constructs, immunization with near full-length vaccines, rPfCSP (#1) or the chimeric rPfCSP/8 (#2), markedly increased the breadth of B cell epitopes recognized covering the N-terminal domain, junctional region, and central repeat. Both rPfCSP (#1) and rPfCSP/8 (#2) also elicited a high proportion of antibodies to conformation-dependent epitopes in the C-terminus of PfCSP. Fusion of PfCSP to PfMSP8 shifted the specificity of the T cell response away from PfCSP toward PfMSP8 epitopes. Challenge studies with transgenic Plasmodium yoelii sporozoites expressing PfCSP demonstrated high and consistent sterile protection following rPfCSP/8 (#2) immunization. Of note, antibodies to conformational C-terminal epitopes were not required for protection. These results indicate that inclusion of the N-terminal domain of PfCSP can drive responses to protective, repeat, and non-repeat B cell epitopes and that PfMSP8 is an effective carrier for induction of high-titer, durable anti-PfCSP antibodies.
摘要：
两种疟疾疫苗的功效数据，RTS,S和R21，靶向恶性疟原虫环子孢子蛋白（PfCSP），令人鼓舞。通过诱导另外的抗体来中和PfCSP的中央免疫显性重复结构域之外的表位,可以提高功效。我们设计了四种基于rPfCSP的疫苗，以努力改善抗体反应的多样性。我们还评估了恶性疟原虫裂殖子表面蛋白8（PfMSP8）作为疟疾特异性载体蛋白作为乙型肝炎表面抗原的替代品。我们测量了大小，特异性，子类,贪婪，耐用性,以及疫苗诱导的抗体在近交CD1小鼠中的功效。与N端或C端聚焦的构建体相比，用接近全长的疫苗免疫，rPfCSP（＃1）或嵌合rPfCSP/8（＃2），显着增加了覆盖N末端结构域的B细胞表位的宽度，连接区，中央重复。rPfCSP(#1)和rPfCSP/8(#2)也在PfCSP的C-末端引发高比例的构象依赖性表位的抗体。PfCSP与PfMSP8的融合将T细胞应答的特异性从PfCSP转移到PfMSP8表位。用表达PfCSP的转基因约氏疟原虫子孢子进行的攻击研究显示了rPfCSP/8（＃2）免疫后的高度和一致的无菌保护。值得注意的是，不需要针对构象C末端表位的抗体进行保护.这些结果表明，包含PfCSP的N端结构域可以驱动对保护性，重复,和非重复B细胞表位，并且PfMSP8是诱导高滴度的有效载体，持久的抗PfCSP抗体。
