Vaccine induced immune responses to plasmodial antigens

描述（由申请人提供）：迫切需要一种有效的疫苗，以减少恶性疟原虫引起的疟疾发病率和死亡率。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进行免疫，诱导抗体来中和细胞外分裂子，防止宿主红细胞的入侵。恶性疟原虫merozoite表面蛋白-1被认为是包含在这种疫苗中的主要候选物，支持数据是大量的。到目前为止，无法诱导高滴度的中和抗体免疫人类对象与PfMSP-1为基础的亚单位疫苗阻碍了努力。认识到存在分裂子侵入的交替和冗余途径，单独接种PfMSP-1也不太可能足够。在yoelii疟原虫啮齿动物模型中，我们已经证明merozoite表面蛋白-8是中和抗体的靶标，可以用来增强MSP-1疫苗的免疫原性和效力。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，这种疫苗可以引发强效的merozoite中和免疫反应，优于目前的PfMSP-142疫苗所诱导的反应。MSP-1/8嵌合抗原被设计为提供强大的、保守的、疟原虫特异性的CD4+ T细胞表位，以促进针对MSP-1和MSP-8保护性B细胞表位的抗体的产生，包括与这两种蛋白中存在的功能相关的表皮生长因子样结构域相关的抗体。具体来说，我们将设计、生产和评估一种PfMSP-1/8嵌合疫苗，这种疫苗能产生高滴度的抗体，从而中和来自不同恶性疟原虫菌株的子宫颈裂殖子。测试将包括详细分析i)与PfMSP-119、PfMSP-142或PfMSP-8单独或MSP-8组分的混合物相比，嵌合PfMSP-1/8免疫诱导的T细胞和B细胞应答，ii)通过寄生虫相关抗原增强疫苗诱导的免疫应答的能力，iii)中和抗体对PfMSP-1和PfMSP-8变异和/或保守表位的特异性。我们已经定义了明确的结果来衡量免疫原性和分裂子体中和能力的“增强”。这些研究将提供数据，支持随后在非人类灵长类动物和人类受试者中测试这种基于msp的恶性疟原虫疫苗。与公共卫生的关系：对于世界上近一半的人口来说，恶性疟原虫造成的疾病和死亡威胁仍然有增无减。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.