Department of Tropical Medicine, Medical Microbiology, and Pharmacology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
PLoS One. 2011;6(9):e24782. doi: 10.1371/journal.pone.0024782. Epub 2011 Sep 13.
The C-terminal 42 kDa fragments of the P. falciparum Merozoite Surface Protein 1, MSP1-42 is a leading malaria vaccine candidate. MSP1-33, the N-terminal processed fragment of MSP1-42, is rich in T cell epitopes and it is hypothesized that they enhance antibody response toward MSP1-19. Here, we gave in vivo evidence that T cell epitope regions of MSP1-33 provide functional help in inducing anti-MSP1-19 antibodies. Eleven truncated MSP1-33 segments were expressed in tandem with MSP1-19, and immunogenicity was evaluated in Swiss Webster mice and New Zealand White rabbits. Analyses of anti-MSP1-19 antibody responses revealed striking differences in these segments' helper function despite that they all possess T cell epitopes. Only a few fragments induced a generalized response (100%) in outbred mice. These were comparable to or surpassed the responses observed with the full length MSP1-42. In rabbits, only a subset of truncated antigens induced potent parasite growth inhibitory antibodies. Notably, two constructs were more efficacious than MSP1-42, with one containing only conserved T cell epitopes. Moreover, another T cell epitope region induced high titers of non-inhibitory antibodies and they interfered with the inhibitory activities of anti-MSP1-42 antibodies. In mice, this region also induced a skewed TH2 cellular response. This is the first demonstration that T cell epitope regions of MSP1-33 positively or negatively influenced antibody responses. Differential recognition of these regions by humans may play critical roles in vaccine induced and/or natural immunity to MSP1-42. This study provides the rational basis to re-engineer more efficacious MSP1-42 vaccines by selective inclusion and exclusion of MSP1-33 specific T cell epitopes.
恶性疟原虫裂殖子表面蛋白 1 的 C 端 42kDa 片段，即 MSP1-42，是一种主要的疟疾候选疫苗。MSP1-33 是 MSP1-42 的 N 端加工片段，富含 T 细胞表位，据推测它们增强了对 MSP1-19 的抗体反应。在这里，我们提供了体内证据表明 MSP1-33 的 T 细胞表位区域在诱导抗 MSP1-19 抗体方面提供了功能性帮助。11 个串联表达的 MSP1-33 截断片段与 MSP1-19 一起进行了免疫原性评估，在瑞士 Webster 小鼠和新西兰白兔中进行了评估。抗 MSP1-19 抗体反应的分析显示，尽管它们都具有 T 细胞表位，但这些片段的辅助功能存在显著差异。只有少数片段在杂交小鼠中引起了普遍的反应（100%）。这些反应与全长 MSP1-42 观察到的反应相当或超过。在兔子中，只有一小部分截断抗原诱导了有效的寄生虫生长抑制抗体。值得注意的是，两个构建体比 MSP1-42 更有效，其中一个只包含保守的 T 细胞表位。此外，另一个 T 细胞表位区域诱导了高滴度的非抑制性抗体，它们干扰了抗 MSP1-42 抗体的抑制活性。在小鼠中，该区域还诱导了偏向 TH2 的细胞反应。这是第一个证明 MSP1-33 的 T 细胞表位区域积极或消极地影响抗体反应的证明。这些区域被人类的不同识别可能在 MSP1-42 的疫苗诱导和/或自然免疫中发挥关键作用。这项研究为通过选择性包含和排除 MSP1-33 特异性 T 细胞表位来重新设计更有效的 MSP1-42 疫苗提供了合理的依据。
