Experimental Molecular Vaccines for Schistosomiasis

血吸虫病实验分子疫苗

• 批准号: 7364845
• 负责人: Afzal A Siddiqui
• 金额: $ 32.75万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7364845
• 关键词: Adjuvant; Adolescent; Affect; Age; Age-Years; Agonist; Animal Model; Antibodies; Antibody Formation; Antigens; Area; B-Lymphocytes; Binding; Biological Models; Blood; CD4 Positive T Lymphocytes; Calpain; Caring; Cellular Immunity; Cessation of life; Chemical Vaccines; Child; Chronic; Chronic Disease; Clinical; Clinical Trials; Complement; Country; Credentialing; DNA; DNA Vaccines; Data; Development; Disease; Dose; Drug Formulations; Enhancers; Evaluation; Exposure to; Fatty Acids; Foundations; Future; Geographic Locations; Glutathione S-Transferase; Goals; Health; Helminths; High Prevalence; Human; Immune response; Immunity; Immunization; Immunologics; Inbred BALB C Mice; Infection; Interferons; Interleukin-12; Interleukin-2; International; Investigation; Laboratories; Larva; Lead; Life; Measures; Mediating; Medical; Modality; Modeling; Morbidity - disease rate; Mus; Oligonucleotides; Other Resources; Papio; Parasitic Diseases; Parasitic infection; Paratropomyosin; Passive Immunization; Pathogenesis; Pharmaceutical Preparations; Philippines; Plasmids; Play; Praziquantel; Praziquantel resistance; Procedures; Process; Proteins; Protocols documentation; Publishing; Quil A; Recombinants; Reporting; Research; Research Personnel; Resistance; Risk; Rodent; Role; Safety; Schistosoma; Schistosoma mansoni; Schistosomiasis; School-Age Population; Secondary Immunization; Serum; Severities; Snails; Standards of Weights and Measures; Sum; Surface; System; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; Triose-Phosphate Isomerase; Vaccinated; Vaccination; Vaccines; Water; World Bank; World Health Organization; age group; base; chemotherapy; clinically relevant; cobra venom factor; comparative; cytokine; design; disability; disorder control; human disease; immunogenic; immunogenicity; improved; in vivo; insight; membrane biogenesis; mortality; nonhuman primate; novel; novel therapeutics; novel vaccines; plasmid DNA; prevent; programs; prophylactic; protein p80; research study; resiquimod; response; therapeutic vaccine; tool; transmission process; trend; vaccination strategy; vaccine efficacy; vaccine evaluation; vector; years of life lost

DESCRIPTION (provided by applicant): DNA vaccines have shown great promise in eliciting both humoral and cellular immune responses in a variety of rodent and non-human primate models. We are proposing to develop a DNA vaccine against schistosome infection which affects over 200 million people with an additional 600 million at risk in 74 countries. Our previous studies using the vaccine candidate Sm-p80 has shown that its efficacy can be improved by the addition of DNA encoding immunomodulatory cytokines (IL-2 and IL-12) in a DNA vaccine formulation. The experiments proposed in this application are designed to elucidate the mechanism(s) by which this important antigen confers immunity in an animal model system; this includes the role of different subsets of T cells and complement. The major objective of this proposal is to develop an effective protective vaccine against schistosomiasis. Second objective will be to examine the potential of a protective prophylactic vaccination strategy as a therapeutic treatment modality in an attempt to resolve a chronic parasitic infection and associated disease sequelae in mice and non-human primates. The development of schistosome-baboon chronic infection model may result in an important international resource for other investigations. The potential exists that the availability of such a well characterized animal model could provide insight and directly impact studies involving schistosome pathogenesis and transmission. It may also provide an invaluable research tool for future vaccine and therapeutic investigations. A schistosomiasis vaccine would make a great impact to existing means of disease control, especially if it provides an effective, long-term immunity against the infection. Parasitic disease, schistosomiasis continues to take an enormous toll on the human health in terms of both mortality and morbidity. This disease is endemic in 74 countries with 790 million people at risk. Schistosomes infect more than 200 million people with the highest prevalence and severity of infection occurring among school-age children. The sum of years of life lost through disability (DALYs) because of this debilitating and chronic disease has been estimated to be 1.7 million/year. In spite of advances in control via snail eradication and large-scale chemotherapy using praziquantel (a drug developed 30 years ago); this disease continues to spread to new geographic areas. Another alarming trend is the reported increase in resistance to praziquantel, the mainstay of current medical treatment. Presently, there is no vaccine for controlling this disease. Therefore a schistosomiasis vaccine would make a great impact on the existing means of disease control, especially if it provides an effective, long-term immunity against the infection. Based on published studies from our group for the past 17 years and recent preliminary data, we have identified a novel schistosome protein that was originally identified to be involved in the surface membrane biogenesis. This phenomenon has been considered to be one of the mechanisms utilized by blood-dwelling worms to evade the protective host immune response. This protein designated calpain, has two subunits, the larger of which, designated Sm-p80 has been demonstrated to be antigenic when administered to mice. Furthermore, immunization with various formulations of Sm-p80 has resulted in a significant level of protective immunity in mice following an experimental challenge with schistosome cercariae. We believe that Sm-p80 represents a unique target to invoke protective immunity against schistosome infection and, as such; a novel vaccine candidate. Based on promising results from our laboratory, the UNDP/World Bank/WHO-TDR special panel (Manila, Philippines, October 6-8, 2003), designated, Sm-p80 as one of the priority antigens with established credentials, needing further development and Sm-p80 is now considered as one of the first-tier candidates by international experts in the field. We are proposing to develop a Sm-p80-based schistosomiasis vaccine using a wide variety of approaches (e.g., naked DNA, prime-boost etc.). We intend to the test the prophylactic and therapeutic efficacy of this vaccine in animal models (mice and nonhuman primates). This vaccine can be administered to small children in order to prevent severe infection in the following years of high risk (3-12 years of age). This age group of children and young adolescents correspond to those ages in which contact with infected water is maximal. Booster doses of schistosomiasis vaccine may not be necessary since subsequent exposure to infective larvae could provide continuous re- stimulation to immunity. Such a vaccine would greatly reduce the need for logistically difficult and expensive drug-based programs and will save millions of lives.

描述（由申请人提供）：DNA疫苗在多种啮齿动物和非人灵长类动物模型中显示出很大的前景，可引发体液和细胞免疫应答。我们正在提议开发一种DNA疫苗，以防止在74个国家中影响2亿多人的艾滋病毒感染，另有6亿人处于危险之中。我们先前使用候选疫苗Sm-p80的研究表明，通过在DNA疫苗制剂中添加编码免疫调节细胞因子（IL-2和IL-12）的DNA，可以提高其疗效。本申请中提出的实验旨在阐明这种重要抗原在动物模型系统中赋予免疫力的机制;这包括T细胞和补体的不同亚群的作用。本提案的主要目标是开发一种有效的血吸虫病保护性疫苗。第二个目标是检查保护性预防性疫苗接种策略作为治疗性治疗方式的潜力，以解决小鼠和非人灵长类动物的慢性寄生虫感染和相关疾病后遗症。该模型的建立将为其他研究提供重要的国际资源。这种良好表征的动物模型的可用性可能会提供洞察力，并直接影响涉及病毒发病机制和传播的研究。它还可能为未来的疫苗和治疗研究提供宝贵的研究工具。血吸虫病疫苗将对现有的疾病控制手段产生重大影响，特别是如果它能提供有效的长期免疫力。寄生虫病，血吸虫病继续在死亡率和发病率方面对人类健康造成巨大损失。这种疾病在74个国家流行，有7.9亿人面临危险。血吸虫感染了2亿多人，学龄儿童的感染率和严重程度最高。由于这种使人衰弱的慢性疾病而丧失的寿命年数估计为每年170万。 尽管通过消灭蜗牛和使用吡喹酮（30年前开发的药物）进行大规模化疗在控制方面取得了进展，但这种疾病继续向新的地理区域蔓延。另一个令人担忧的趋势是，据报告，对吡喹酮的抗药性增加，吡喹酮是目前医疗的主要药物。目前还没有疫苗来控制这种疾病。因此，血吸虫病疫苗将对现有的疾病控制手段产生重大影响，特别是如果它能提供有效的长期免疫力。 基于我们小组过去17年发表的研究和最近的初步数据，我们已经确定了一种新的核糖体蛋白，该蛋白最初被确定为参与表面膜生物发生。这种现象被认为是血栖蠕虫逃避保护性宿主免疫反应的机制之一。这种被称为钙蛋白酶的蛋白质有两个亚基，其中较大的亚基被称为Sm-p80，已被证明在给予小鼠时具有抗原性。此外，Sm-p80的各种制剂的免疫接种导致在小鼠中的保护性免疫力的显着水平后，实验性挑战与寄生虫尾蚴。我们认为Sm-p80代表了一个独特的靶点，可以引起针对病毒感染的保护性免疫，因此是一种新的疫苗候选物。基于我们实验室的有希望的结果，开发计划署/世界银行/世界卫生组织-TDR特别小组（菲律宾马尼拉，2003年10月6日至8日）指定Sm-p80为具有公认资格的优先抗原之一，需要进一步开发，Sm-p80现在被该领域的国际专家认为是第一级候选抗原之一。 我们建议使用多种方法开发基于Sm-p80的血吸虫病疫苗（例如，裸DNA、初免-加强等）。我们打算在动物模型（小鼠和非人灵长类动物）中测试该疫苗的预防和治疗功效。这种疫苗可用于幼儿，以防止在随后的高风险年份（3-12岁）发生严重感染。这一年龄组的儿童和青少年与接触受感染水最多的年龄组相对应。加强剂量的血吸虫病疫苗可能是不必要的，因为随后暴露于感染性幼虫可以提供持续的免疫再刺激。这种疫苗将大大减少对后勤困难和昂贵的药物为基础的计划的需要，并将挽救数百万人的生命。