EPIDEMIOLOGICAL STUDY FOR DEVELOPING SERA MALARIA VACCINE

恶性疟原虫富含丝氨酸抗原（SERA）是一种很有前途的疟疾疫苗候选抗原。SERA是一种126 kDa的无性血液阶段抗原，特别是在滋养体晚期和滋养体阶段大量产生。我们通过合成适合于在大肠杆菌中表达的具有改变密码子使用的基因，在大肠杆菌中表达了SERA蛋白的N-末端结构域（SE 47 '）和中心结构域（SE 50 A）。SE 47 '蛋白在大鼠和小鼠体内均能诱导抗虫生长抑制抗体产生，而SE 50 A蛋白则不能。在这个项目中，我们检测了Atopi教区（乌干达北方疟疾传播密集的地区）居民中针对SE 47 '和SE 50 A的IgG亚类特异性滴度，以观察针对这些重组分子的天然免疫应答。已经证明IgG 3是Atopi教区居民对SE 47 '的主要应答，并且IgG 3抗体水平的增加与10岁以下儿童的临床免疫相关。然而，对SE 50 A的主要应答是IgG 1亚类，与临床免疫无关。我们进一步发现了以下相关性：1）居民外周血中IgG 3水平的升高与较低的寄生虫密度相关。2)个体血清对培养的寄生虫的生长抑制与血清中抗SE 47 '的IgG 3抗体水平相关。3)总之，我们得出结论，抗SE 47 'IgG 3是人类中主要的抗疟疾免疫应答，这是长期以来未知的。本研究为利用SERA N端结构域重组蛋白研制疟疾疫苗提供了理论依据。

P.falciparum serine rich antigen (SERA) is a promising malaria vaccine candidate antigen. SERA is a 126 kDa asexual blood stage antigen produced in large amounts specifically during late trophozoite and schizont stages. We have expressed N-terminal domain (SE47') and central domain (SE50A) of SERA protein in E.coli by synthesizing the genes with a changed codon usage suitable for expressing in E.coli. SE47'protein but not SE50A protein induced the parasite growth inhibitory antibodies in rat and mouse. In this project, we have examined the IgG subclass specific titers against SE47' and SE50A in residents of Atopi Parish, a region of intense malaria transmission in Northern Uganda, to see the natural immune responses against these recombinant molecules. It has been demonstrated that the IgG3 is the predominant response to SE47' in residents of Atopi Parish and that increased levels of IgG3 antibodies correlated with clinical immunity in children under 10 years old. Predominant response to SE50A was, however, IgG1 subclass and had no correlation with the clinical immunity. We have further found the following correlation ; 1) the increased levels of the IgG3 correlated with the lower parasite density in peripheral blood of the residents. 2) The growth inhibition of the cultured parasites by individual serum correlated with the levels of IgG3 antibodies against SE47' in the serum. 3) The observed parasite growth inhibition was neutralized by adding the recombinant SE47' protein.In summary, we have concluded that the anti-SE47' IgG3 is the major anti-malaria immune response in human that has been long time unknown. The obtained information will accelerate the malaria vaccine development with the recombinant protein of the N-terminal domain of SERA.