Experimental Molecular Vaccines for Schistosomiasis

血吸虫病实验分子疫苗

基本信息

批准号：
7996553
负责人：
Afzal A Siddiqui
金额：
$ 60.31万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
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/7996553
关键词：
12 year old Adjuvant Adolescent Affect Age Animal Model Antigen Targeting Antigens Area Binding Biological Models Blood Calpain Cessation of life Chemical Vaccines Child Chronic Chronic Disease Clinical Trials Complement Country 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 Infection Interleukin-12 Interleukin-2 International Investigation Laboratories Larva Lead Mediating Medical Modality Modeling Morbidity - disease rate Mus Papio Parasitic Diseases Parasitic infection Paratropomyosin Pathogenesis Pharmaceutical Preparations Philippines Praziquantel Praziquantel resistance Preclinical Testing Principal Investigator Procedures Process Proteins Publishing Recombinants Reporting Research Research Personnel Resistance Resources Risk Rodent Role Safety Schistosoma Schistosoma mansoni Schistosomiasis School-Age Population Severities Sm antigen Snails Sum Surface T-Lymphocyte Subsets Testing Therapeutic Therapeutic Intervention Treatment Efficacy Triose-Phosphate Isomerase Vaccination Vaccines Water World Bank World Health Organization age group animal model development base chemotherapy clinical care clinically relevant comparative cytokine design disability disorder control high risk human disease immunogenic immunogenicity improved insight membrane biogenesis mortality nonhuman primate novel novel therapeutics novel vaccines prevent programs prophylactic protein p80 research study response therapeutic vaccine tool transmission process trend vaccination strategy vaccine candidate vector years of life lost

项目摘要

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类灵长类动物模型中引发体液和细胞免疫反应方面显示出巨大的前景。我们提议开发一种针对血吸虫感染的 DNA 疫苗，该疫苗影响着 74 个国家的 2 亿多人，还有 6 亿人处于危险之中。我们之前使用候选疫苗 Sm-p80 进行的研究表明，通过在 DNA 疫苗配方中添加编码免疫调节细胞因子（IL-2 和 IL-12）的 DNA 可以提高其功效。本申请中提出的实验旨在阐明这一重要抗原在动物模型系统中赋予免疫力的机制；这包括不同 T 细胞亚群和补体的作用。该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方式的潜力，以试图解决小鼠和非人类灵长类动物的慢性寄生虫感染和相关疾病后遗症。血吸虫-狒狒慢性感染模型的发展可能为其他研究提供重要的国际资源。这种特征明确的动物模型的可用性有可能提供见解并直接影响涉及血吸虫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巨大影响，特别是如果它能提供有效、长期的针对感染的免疫力。寄生虫病血吸虫病在死亡率和发病率方面继续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 亿人面临风险。血吸虫感染了超过 2 亿人，其中学龄儿童的感染流行率和严重程度最高。由于这种使人衰弱的慢性疾病而导致的残疾 (DALY) 损失年数估计为 170 万/年。尽管通过消灭蜗牛和使用吡喹酮（一种 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；这种疾病继续传播到新的地理区域。另一个令人担忧的趋势是据报道对当前医学治疗的支柱吡喹酮的耐药性增加。目前，没有疫苗可以控制这种疾病。因此，血吸虫病疫苗将对现有的疾病控制手段产生巨大影响，特别是如果它能提供有效、长期的针对感染的免疫力。根据我们小组过去 17 年发表的研究和最近的初步数据，我们发现了一种新型血吸虫蛋白，该蛋白最初被认为参与表面膜生物发生。这种现象被认为是血液蠕虫用来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，在接受血吸虫尾蚴实验攻击后，用各种 Sm-p80 制剂进行免疫可以使小鼠产生显着水平的保护性免疫力。我们相信 Sm-p80 代表了一个独特的靶标，可以激发针对血吸虫感染的保护性免疫，因此；一种新型候选疫苗。根据我们实验室令人鼓舞的结果，UNDP/世界银行/WHO-TDR 特别小组（菲律宾马尼拉，2003 年 10 月 6-8 日）指定 Sm-p80 为具有既定资质的优先抗原之一，需要进一步开发Sm-p80现已被该领域的国际专家视为一线候选产品之一。我们提议使用多种方法（例如裸 DNA、初免-加强等）开发基于 Sm-p80 的血吸虫病疫苗。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效果。这种疫苗可以给幼儿接种，以预防在随后的高风险年份（3-12 岁）发生严重感染。这个年龄段的儿童和青少年对应于与受感染水接触最多的年龄。可能不需要加强剂量的血吸虫病疫苗，因为随后接触感染性幼虫可能会持续重新刺激免疫力。这种疫苗将大大减少对后勤困难且昂贵的药物项目的需求，并将拯救数百万人的生命。