Vaccine induced immune responses to plasmodial antigens

描述（由申请方提供）：人们广泛认识到迫切需要一种有效的疫苗来降低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免疫，以诱导中和细胞外裂殖子并防止宿主红细胞侵入的抗体。恶性疟原虫裂殖子表面蛋白-1被认为是包含在这种疫苗中的主要候选物，并且支持数据是大量的。迄今为止，在用基于PfMSP-1的亚单位疫苗免疫人类受试者时不能诱导高滴度的中和抗体阻碍了这一努力。认识到存在裂殖子侵入的替代和冗余途径，单独用PfMSP-1免疫也是非常不可能的。在约氏疟原虫啮齿动物模型中，我们已经表明裂殖子表面蛋白-8是中和抗体的靶标，并且可以用于增强基于MSP-1的疫苗的免疫原性和功效。我们的假设是，恶性疟原虫MSP-119与MSP-8的融合将产生嵌合疫苗，该嵌合疫苗产生比目前PfMSP-142疫苗诱导的应答更上级的强效裂殖子中和免疫应答。MSP-1/8嵌合抗原被设计为提供强的、保守的、疟原虫特异性的CD 4 + T细胞表位，以促进针对MSP-1和MSP-8的保护性B细胞表位的抗体的产生，所述保护性B细胞表位包括与存在于两种蛋白质中的功能相关的表皮生长因子样结构域相关的那些。具体地说，我们将设计、生产和评估PfMSP-1/8嵌合疫苗，该疫苗产生高滴度的抗体，中和来自不同恶性疟原虫株的裂殖子。测试将包括详细分析i）与单独的PfMSP-119、PfMSP-142或PfMSP-8或MSP-1和MSP-8组分的混合物相比，用嵌合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加强疫苗诱导的免疫应答的能力，和iii）中和抗体对PfMSP-1和PfMSP-8的变体和/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裂殖子中和能力的“增强”。这些研究将提供数据，以支持该基于MSP的恶性疟原虫疫苗在非人灵长类动物和人类受试者中的后续试验。公共卫生相关性：恶性疟原虫疟疾寄生虫造成的疾病和死亡威胁对世界上近一半的人口继续有增无减。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力。目前，恶性疟原虫MSP-1是主要的血液阶段疟疾疫苗候选抗原。

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.