Perlmann H, Perlmann P, Berzins K, Wåhlin B, Troye-Blomberg M, Hagstedt M, Andersson I, Högh B, Petersen E, Björkman A
Department of Immunology, University of Stockholm, Sweden.
Immunol Rev. 1989 Dec;112:115-32. doi: 10.1111/j.1600-065x.1989.tb00555.x.
The development of vaccines is presently receiving major attention in malaria research. As it is not possible to base malaria vaccines on the use of killed or attenuated organisms, the vaccines which are being developed are subunit vaccines in which the immunogens consist of defined parasite antigens or antigenic fragments. Since protective immunity to malaria involves both antibody-dependent and antibody-independent mechanisms, the immunogens in a subunit vaccine must have the capacity to induce relevant B- and T-cell responses in the majority of vaccinees. In turn, this requires good knowledge of these responses in humans who have acquired immunity through natural infection. In this paper we have summarized our recent work on the dissection into epitope-specific components of the human antibody response to the Plasmodium falciparum antigen Pf155/RESA, a recognized candidate for a vaccine against the asexual blood stages of this parasite. Epitope mapping of the antigen by means of short synthetic peptides led to the identification in several molecular regions of short amino acid sequences constituting linear and probably immunodominant B-cell epitopes. The antigenically most active region was located in the C-terminus of the molecule. This region, which consists of approximately 40 related, 4- or 8-amino acid long repeats, induced higher antibody concentrations in a larger number of malaria-immune donors than any of the other regions. A large fraction of these antibodies bound to short synthetic peptides representing the major repeat motifs of Pf155/RESA. Although these repeats are made up of closely related amino acid sequences, the antibody response to them was highly polyclonal, indicating the presence of several linear and probably also conformational epitopes which gave rise to a variety of cross-reacting as well as monospecific antibodies. Further analysis revealed that the levels of antibodies differing in specificity and/or avidity for different peptides varied independently of each other in individual donors. In an area (Liberia) where malaria transmission is holoendemic and perennial, these antibody profiles remained constant when individual donors were followed over several years. Since the C-terminal repeat region of Pf155/RESA is conserved in different P. falciparum strains, the results reflect differences in the genetic regulation of epitope-specific host responses rather than antigenic differences between infecting parasites. In donors living in an area with high but seasonal malaria transmission, antibody levels usually drop to lower levels when there is no transmission.(ABSTRACT TRUNCATED AT 400 WORDS)
目前，疟疾研究中疫苗的研发备受关注。由于无法基于灭活或减毒生物体来研发疟疾疫苗，正在研发的疫苗为亚单位疫苗，其中免疫原由特定的寄生虫抗原或抗原片段组成。鉴于对疟疾的保护性免疫涉及抗体依赖和非抗体依赖机制，亚单位疫苗中的免疫原必须有能力在大多数接种者体内诱导相关的B细胞和T细胞反应。相应地，这就需要深入了解那些通过自然感染获得免疫力的人体内的这些反应。在本文中，我们总结了近期的研究工作，即剖析人类针对恶性疟原虫抗原Pf155/RESA的抗体反应中的表位特异性成分，Pf155/RESA是该寄生虫无性血液阶段疫苗的一个公认候选抗原。通过短合成肽对抗原进行表位定位，在几个分子区域鉴定出构成线性且可能为免疫显性B细胞表位的短氨基酸序列。抗原活性最强的区域位于该分子的C末端。该区域由大约40个相关的、4或8个氨基酸长的重复序列组成，与其他任何区域相比，在更多疟疾免疫供体中诱导出更高的抗体浓度。这些抗体中的很大一部分与代表Pf155/RESA主要重复基序的短合成肽结合。尽管这些重复序列由密切相关的氨基酸序列组成，但针对它们的抗体反应是高度多克隆的，表明存在几个线性且可能还有构象表位，这些表位产生了多种交叉反应抗体和单特异性抗体。进一步分析表明，在个体供体中，对不同肽具有不同特异性和/或亲和力的抗体水平相互独立变化。在疟疾传播为高度地方性流行且常年存在的地区（利比里亚），当对个体供体进行数年跟踪时，这些抗体谱保持不变。由于Pf155/RESA的C末端重复区域在不同的恶性疟原虫菌株中是保守的，这些结果反映了表位特异性宿主反应的基因调控差异，而非感染寄生虫之间的抗原差异。在疟疾传播高发但有季节性的地区生活的供体中，当没有传播时，抗体水平通常会降至较低水平。（摘要截选至400字）
