Experimental Molecular Vaccines for Schistosomiasis

血吸虫病实验分子疫苗

基本信息

批准号：
8109778
负责人：
Afzal A Siddiqui
金额：
$ 30.76万
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：
2010
资助国家：
美国
起止时间：
2010-08-02 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8109778
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 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 Infection Interleukin-12 Interleukin-2 International Investigation Laboratories Larva Lead Life 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疫苗在引起各种啮齿动物和非人类灵长类动物模型中引起体液和细胞免疫反应方面表现出了巨大的希望。我们提议开发针对黑斑述感染的DNA疫苗，该疫苗在74个国家 /地区影响超过6亿人口的2亿人中受到影响。我们先前使用疫苗候选SM-P80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。本应用中提出的实验旨在阐明该重要抗原在动物模型系统中赋予免疫力的机制。这包括T细胞不同子集和补体的作用。该提案的主要目的是开发针对血吸虫病的有效保护性疫苗。第二个目标是研究保护性预防性疫苗接种策略作为治疗方法的潜力，以解决小鼠和非人类灵长类动物中的慢性寄生虫感染和相关疾病后遗症的尝试。 Schistosom-Baboon慢性感染模型的发展可能会导致重要的国际资源进行其他调查。潜力是，这种表征良好的动物模型的可用性可以提供洞察力，并直接影响涉及血吸虫发病机理和传播的研究。它还可以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疾病控制手段产生重大影响，尤其是如果它为感染提供了有效的长期免疫力。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个国家处于危险中的74个国家中。阴谋体感染了超过2亿年患者患病率和严重程度最高的人。由于这种使人衰弱和慢性病，由于残疾而丧生（DALYS）的生命总数估计为每年170万。尽管通过消除蜗牛和使用Praziquantel（30年前开发的药物）进行大规模化学疗法的控制取得了进步；这种疾病继续传播到新的地理区域。另一个令人震惊的趋势是，据报道，当前医疗的支柱上的支柱上，对普拉齐甘特尔的抵抗力增加。目前，没有用于控制这种疾病的疫苗。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，尤其是在为感染提供有效的长期免疫力时。基于过去17年中我们小组的已发表研究以及最近的初步数据，我们确定了一种新型的螺旋体蛋白，该蛋白最初被鉴定出与表面膜生物发生有关。这种现象被认为是血液中蠕虫逃避保护性宿主免疫反应的机制之一。该蛋白质指定的钙蛋白酶有两个亚基，其中指定为SM-P80的较大亚基已被证明是抗原时的。此外，在对实验组cercariae进行实验性挑战之后，具有各种SM-P80配方的免疫接种导致了小鼠的保护性免疫力。我们认为，SM-P80代表了一种独特的目标，可以使保护性免疫免受针对黑素感染的影响。一种新颖的疫苗候选者。根据我们实验室的有希望的结果，开发计划署/世界银行/WHO-TDR特别小组（菲律宾马尼拉，2003年10月6日至8日），被指定为SM-P80，是具有既定证书的优先抗原之一，需要进一步开发现在，SM-P80被认为是该领域国际专家的一线候选人之一。我们建议使用多种方法（例如裸体DNA，Prime-Boost等）开发基于SM-P80的血吸虫病疫苗。我们打算测试该疫苗在动物模型（小鼠和非人类灵长类动物）中的预防和治疗功效。该疫苗可以施用给小孩，以防止在接下来的高风险（3-12岁）中发生严重感染。这个年龄段的儿童和年轻青少年对应于与感染水接触的年龄。促进剂量的血吸虫病疫苗可能不需要，因为随后接触感染性幼虫可能会连续刺激免疫。这样的疫苗将大大减少对逻辑上困难和昂贵的药物计划的需求，并挽救数百万的生命。