Immunization-induced AMI and CMI against malaria

免疫诱导的 AMI 和 CMI 对抗疟疾

• 批准号: 6698824
• 负责人: James Matthew Burns
• 金额: $ 31.57万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6698824
• 关键词: B lymphocyte; Plasmodium; T lymphocyte; active immunization; antibody specificity; apical membrane; cellular immunity; disease /disorder model; drug screening /evaluation; genetically modified animals; humoral immunity; immunomodulators; laboratory mouse; malaria; malaria vaccines; membrane proteins; microarray technology; passive immunization; protozoal antigen; recombinant proteins

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.

描述（由申请人提供）：通过疫苗接种控制恶性疟原虫疟疾需要使用有效组合配制的多种寄生虫抗原进行免疫。在这方面，血液阶段裂殖子表面表达的蛋白质作为疫苗靶点很有吸引力，因为它们在红细胞侵袭和血清抗体可及性方面具有重要功能。然而，由于对保护性反应了解不足以及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。本申请的目的是确定用两种裂殖子表面蛋白（顶膜抗原 1 (AMA-1) 和裂殖子表面蛋白 1 (MSP-1)）疫苗接种所针对的保护性免疫参数。由于单独使用 AMA-1 或 MSP-1 进行免疫的最佳制剂可能有所不同，因此我们的重点将放在对联合抗原免疫有效的制剂上。我们有一个简单、可行的系统，使用重组 AMA-1 和 MSP-1 的组合来对小鼠进行免疫，以抵抗恰鲍迪疟原虫疟疾。良好的 B 细胞反应和显着的抗体产生对于保护是必要的，并且可以使用 Alum 或 Quil A 作为佐剂来实现。然而，攻击前抗体滴度本身并不能预测保护功效。此外，对 B 细胞缺陷小鼠的研究揭示了 Pc MSP-1 诱导的保护作用中存在一种独立于抗体的细胞介导成分。我们将检查抗体特异性、浓度、同种型和亲合力，以确定预测保护功效的可测量参数。通过大规模 DNA 微阵列分析，我们将确定 Pc AMA-1 + Pc MSP-1 免疫和受保护动物的 CD4+ T 细胞的基因表达谱，与完全易感染 P. chabaudi 疟疾的小鼠的 CD4+ T 细胞的基因表达谱进行比较。体外定义的 Pc AMA-1 + Pc MSP-1 诱导的保护性 T 细胞和 B 细胞反应的相关性将通过被动免疫研究和通过选定的免疫敲除小鼠的免疫在体内得到验证。我们预计，随着 AMA-1 和 MSP-1 的组合制剂进入临床试验，所获得的信息可用于评估 Aotus 猴和人类的免疫反应。