Immunization-induced AMI and CMI against malaria

描述（由申请方提供）：通过疫苗接种控制恶性疟原虫疟疾需要使用有效配制的多种寄生虫抗原进行免疫接种。在这方面，表达在血液期裂殖子表面上的蛋白质作为疫苗靶标是有吸引力的，因为它们在红细胞侵入和血清抗体可及性中具有重要功能。然而，由于对保护性应答的理解不足和缺乏可测量的免疫相关性，基于裂殖子抗原的疫苗的人体试验进展受到阻碍。本申请的目的是定义通过用两种裂殖子表面蛋白，顶端膜抗原-1（AMA-1）和裂殖子表面蛋白-1（MSP-1）接种而靶向的保护性免疫的参数。由于AMA-1或MSP-1单独免疫的最佳制剂可能不同，我们的重点将是对联合抗原免疫有效的制剂。我们有一个简单的，可行的系统，使用重组AMA-1和MSP-1的组合免疫小鼠抗夏氏疟原虫疟疾。良好的B细胞应答和显著的抗体产生是保护所必需的，并且可以利用明矾或Quil A作为佐剂来实现。然而，单独的攻击前抗体滴度不能预测保护效力。此外，在B细胞缺陷小鼠中的研究揭示了对Pc MSP-1诱导的保护的抗体非依赖性细胞介导的组分。我们将检查抗体特异性、浓度、同种型和亲合力，以确定预测保护效力的可测量参数。通过大规模DNA微阵列分析，我们将确定来自Pc AMA-1 + Pc MSP-1免疫和保护动物的CD 4 + T细胞的基因表达谱，并与来自完全易感夏氏疟原虫疟疾的小鼠的基因表达谱进行比较。将通过被动免疫研究和通过免疫选定的免疫敲除小鼠在体内验证体外定义的Pc AMA-1 + Pc MSP-1诱导的保护性T细胞和B细胞应答的相关性。我们期望所获得的信息可以应用于评估AMA-1和MSP-1的组合制剂进入临床试验时Aotus猴和人类的免疫应答。

DESCRIPTION (provided by applicant): The control of Plasmodium falciparum malaria by vaccination will require immunization with multiple parasite antigens effectively formulated in combination. In this regard, proteins expressed on the surface of blood-stage merozoites are attractive as vaccine targets given their functional importance in the invasion of erythrocytes and accessibility to serum antibodies. However, progress toward human trials of merozoite antigen based vaccines has been hampered by an inadequate understanding of protective responses and a lack of measurable correlates of that immunity. The objective of this application is to define parameters of protective immunity targeted by vaccination with two merozoite surface proteins, apical membrane antigen-1 (AMA-1) and merozoite surface protein-1 (MSP-1). Since optimal formulations for immunizations with AMA-1 or MSP-1 alone may differ, our focus will be on formulations that are effective for combined antigen immunizations. We have a simple, workable system using combinations of recombinant AMA-1 and MSP-1 to immunize mice against Plasmodium chabaudi malaria. A good B cell response and significant antibody production are necessary for protection and can be achieved utilizing Alum or Quil A as adjuvant. However, prechallenge antibody titers alone are not predictive of protective efficacy. Furthermore, studies in B cell deficient mice revealed an antibody independent, cell mediated component to Pc MSP-1 induced protection. We will examine antibody specificity, concentration, isotype and avidity to define measurable parameters that predict protective efficacy. By large-scale DNA microarray analyses, we will determine gene expression profiles of CD4+ T cells from Pc AMA-1 + Pc MSP-1 immunized and protected animals compared to those from mice fully susceptible to P. chabaudi malaria. Correlates of Pc AMA-1 + Pc MSP-1 induced protective T cell and B cell responses defined in vitro will be validated in vivo by passive immunization studies and through the immunization of selected immunological knockout mice. We expect that the information gained can be applied to the evaluation of immune responses in Aotus monkeys and humans as combined formulations of AMA-1 and MSP-1 move into clinical trials.