Vaccine induced immune responses to plasmodial antigens

描述(由申请人提供)：人们普遍认识到，需要一种有效的疫苗来减少恶性疟原虫引起的疟疾发病率和死亡率，这是非常紧迫的。对于疟疾流行地区，这种疫苗必须针对血液阶段的寄生虫。目前，最可行的方法是用亚单位疫苗免疫，诱导抗体中和胞外裂殖子，防止宿主红细胞的入侵。恶性疟原虫裂殖子表面蛋白-1被认为是包括在这种疫苗中的主要候选蛋白，并且有大量的支持数据。到目前为止，用基于PfMSP-1的亚单位疫苗免疫人类受试者时，无法诱导高滴度的中和抗体，这阻碍了这一努力。认识到存在替代和多余的裂殖子入侵途径，仅用PfMSP-1免疫也不太可能足够。在约氏疟原虫啮齿动物模型中，我们已经证明裂殖子表面蛋白-8是中和抗体的靶标，可以用来增强基于MSP-1的疫苗的免疫原性和有效性。我们的假设是，恶性疟原虫MSP-119与MSP-8的融合将产生一种嵌合疫苗，它能诱导出比目前的PfMSP-142疫苗更好的有效的裂殖子中和免疫反应。MSP-1/8嵌合抗原的设计目的是提供强大的、保守的、疟原虫特异性的CD4+T细胞表位，以促进针对保护性B细胞表位MSP-1和MSP-8的抗体的产生，包括与这两种蛋白质中存在的功能相关的表皮生长因子样结构域相关的抗体。具体地说，我们将设计、生产和评估一种PfMSP-1/8嵌合疫苗，该疫苗能产生高滴度的抗体，中和不同恶性疟原虫株的裂殖子。测试将包括以下方面的详细分析：i)PfMSP-1/8嵌合免疫与PfMSP-119、PfMSP-142或PfMSP-8单独免疫或MSP-1和MSP-8组分混合免疫所诱导的T细胞和B细胞反应；ii)寄生虫相关抗原增强疫苗诱导的免疫反应的能力；以及iii)PfMSP-1和PfMSP-8变异和/或保守表位的中和抗体的特异性。我们已经定义了明确的结果来衡量免疫原性和裂殖子中和能力的“增强”。这些研究将提供数据，以支持这种基于MSP的恶性疟原虫疫苗在非人类灵长类动物和人类受试者中的后续测试。公共卫生相关性：世界上近一半的人口继续受到恶性疟原虫疟疾寄生虫引起的疾病和死亡的威胁。本项目旨在提高恶性疟原虫MSP-1疫苗的免疫原性和保护效果。目前，恶性疟原虫MSP-1是主要的血液期疟疾疫苗候选抗原。

DESCRIPTION (provided by applicant): The need for an efficacious vaccine to reduce malaria morbidity and mortality due to Plasmodium falciparum is widely recognized and urgent. For malaria endemic areas, such a vaccine must target blood- stage parasites. Presently, the most viable approach is to immunize with subunit vaccines to induce antibodies that neutralize extracellular merozoites and prevent the invasion of host erythrocytes. P. falciparum merozoite surface protein -1 is considered the prime candidate for inclusion in such a vaccine and supporting data are substantial. Thus far, the inability to induce high titer of neutralizing antibodies upon immunization of human subjects with PfMSP-1 based subunit vaccine has impeded the effort. Recognizing that alternate and redundant pathways of merozoite invasion exist, it is also very unlikely that immunization with PfMSP-1 alone will be adequate. Working in the Plasmodium yoelii rodent model, we have shown that merozoite surface protein-8 is a target of neutralizing antibodies and can be used to enhance the immunogenicity and efficacy of MSP-1 based vaccines. Our hypothesis is that fusion of P. falciparum MSP-119 to MSP-8 will result in a chimeric vaccine that elicits potent, merozoite neutralizing immune responses that are superior to the responses induced by the current PfMSP-142 vaccines. The MSP-1/8 chimeric antigen is designed to provide strong, conserved, plasmodial-specific CD4+ T cell epitopes to promote the production of antibodies to protective B cell epitopes of MSP-1 and MSP-8, including those associated with the functionally related epidermal growth factor-like domains present in the two proteins. Specifically, we will design, produce and evaluate a PfMSP-1/8 chimeric vaccine that elicits high titers of antibodies that neutralize merozoites from diverse strains of P. falciparum. Testing will include a detailed analysis of i) T cell and B cell responses induced by immunization with the chimeric PfMSP-1/8 in comparison to PfMSP-119, PfMSP-142 or PfMSP-8 alone or an admixture of MSP-1 and MSP-8 components, ii) the ability to boost vaccine-induced immune responses by parasite associated antigen, and iii) the specificity of neutralizing antibodies for variant and/or conserved epitopes of PfMSP-1 and PfMSP-8. We have defined clear outcomes to measure 'enhancement' in immunogenicity and in merozoite neutralizing capacity. These studies will provide data to support the subsequent testing of this MSP-based P. falciparum vaccine in non-human primates and in human subjects. PUBLIC HEALTH RELEVANCE: The threat of disease and death due to Plasmodium falciparum malaria parasites continues unabated for nearly half of the world's population. This project is an effort to improve the immunogenicity and protective efficacy of P. falciparum MSP-1 based vaccines. Currently, P. falciparum MSP-1 is the leading blood-stage malaria vaccine candidate antigen.