Experimental Molecular Vaccines for Schistosomiasis

血吸虫病实验分子疫苗

基本信息

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疫苗在各种啮齿动物和非人类灵长类动物模型中诱导体液和细胞免疫反应方面显示出巨大的前景。我们正在提议开发一种针对血吸虫感染的DNA疫苗,这种疫苗影响着74个国家的2亿多人,另外还有6亿人面临风险。我们之前使用候选疫苗Sm-p80的研究表明,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可以提高其效力。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提供免疫的机制(S);这包括T细胞和补体的不同亚群的作用。这项提议的主要目标是开发一种有效的血吸虫病保护性疫苗。第二个目标是研究保护性预防性疫苗接种策略作为一种治疗方式的潜力,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建立可能为其他研究提供重要的国际资源。这种具有良好特性的动物模型的可用性可能会为血吸虫发病机制和传播的研究提供洞察力和直接影响。它还可能为未来的疫苗和治疗研究提供一个宝贵的研究工具。血吸虫病疫苗将对现有的疾病控制手段产生重大影响,特别是如果它提供对感染的有效、长期免疫的话。作为一种寄生虫病,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害。这种疾病在74个国家流行,7.9亿人处于危险之中。血吸虫感染了2亿多人,感染的流行率和严重程度最高的是学龄儿童。据估计,这种使人衰弱的慢性疾病每年因残疾而损失的总寿命为170万年。 尽管通过消灭钉螺和使用吡喹酮(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,但这种疾病继续蔓延到新的地理区域。另一个令人担忧的趋势是,据报道,对当前治疗的主要药物--吡喹酮--的抗药性有所增加。目前,还没有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,特别是如果它提供对感染的有效、长期免疫的话。 根据我们课题组过去17年来发表的研究和最近的初步数据,我们鉴定了一种新的血吸虫蛋白,最初被鉴定为参与表膜生物发生。这一现象被认为是住血蠕虫逃避保护性宿主免疫反应的机制之一。这种名为calain的蛋白质有两个亚基,其中较大的一个亚基Sm-p80已被证明在给小鼠注射时具有抗原性。此外,用不同配方的Sm-p80免疫小鼠,在对血吸虫尾虫进行实验性攻击后,已经产生了显著水平的保护性免疫。我们认为,Sm-p80代表了一个独特的靶点,可以激发对血吸虫感染的保护性免疫,因此也是一个新的候选疫苗。根据我们实验室取得的可喜成果,开发计划署/世界银行/世卫组织-TDR特别小组(2003年10月6日至8日,菲律宾马尼拉)指定Sm-p80为具有既定资格的优先抗原之一,需要进一步开发,而Sm-p80现在被该领域的国际专家视为第一级候选抗原之一。 我们建议使用多种方法(如裸DNA、Prime-Boost等)开发一种基于Sm-p80的血吸虫病疫苗。我们打算在动物模型(小鼠和非人类灵长类动物)中测试这种疫苗的预防和治疗效果。这种疫苗可以接种给幼儿,以防止在接下来的高危年份(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相对应。可能没有必要加强剂量的血吸虫病疫苗,因为随后暴露在感染幼虫中可以提供持续的免疫刺激。这样的疫苗将极大地减少后勤困难和昂贵的基于药物的计划的需要,并将拯救数百万人的生命。

项目成果

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Afzal A Siddiqui其他文献

Afzal A Siddiqui的其他文献

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{{ truncateString('Afzal A Siddiqui', 18)}}的其他基金

Experimental Molecular Vaccines for Schistosomiasis
血吸虫病实验分子疫苗
  • 批准号:
    8082076
  • 财政年份:
    2010
  • 资助金额:
    $ 30.76万
  • 项目类别:
Experimental Molecular Vaccines for Schistosomiasis
血吸虫病实验分子疫苗
  • 批准号:
    7846681
  • 财政年份:
    2009
  • 资助金额:
    $ 30.76万
  • 项目类别:
Experimental Molecular Vaccines for Schistosomiasis
血吸虫病实验分子疫苗
  • 批准号:
    7743820
  • 财政年份:
    2008
  • 资助金额:
    $ 30.76万
  • 项目类别:
Experimental Molecular Vaccines for Schistosomiasis
血吸虫病实验分子疫苗
  • 批准号:
    7364845
  • 财政年份:
    2008
  • 资助金额:
    $ 30.76万
  • 项目类别:
Experimental Molecular Vaccines for Schistosomiasis
血吸虫病实验分子疫苗
  • 批准号:
    7541807
  • 财政年份:
    2008
  • 资助金额:
    $ 30.76万
  • 项目类别:
Experimental Molecular Vaccines for Schistosomiasis
血吸虫病实验分子疫苗
  • 批准号:
    8207249
  • 财政年份:
    2008
  • 资助金额:
    $ 30.76万
  • 项目类别:
Experimental Molecular Vaccines for Schistosomiasis
血吸虫病实验分子疫苗
  • 批准号:
    8150761
  • 财政年份:
    2008
  • 资助金额:
    $ 30.76万
  • 项目类别:
Experimental Molecular Vaccines for Schistosomiasis
血吸虫病实验分子疫苗
  • 批准号:
    7996553
  • 财政年份:
    2008
  • 资助金额:
    $ 30.76万
  • 项目类别:
Schistosome Calpain as a Vaccine Candidates
血吸虫钙蛋白酶作为候选疫苗
  • 批准号:
    6413303
  • 财政年份:
    2001
  • 资助金额:
    $ 30.76万
  • 项目类别:
Schistosome Calpain as a Vaccine Candidates
血吸虫钙蛋白酶作为候选疫苗
  • 批准号:
    6570481
  • 财政年份:
    2001
  • 资助金额:
    $ 30.76万
  • 项目类别:

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