Development of a live attenuated vaccine for visceral leishmaniasis

内脏利什曼病减毒活疫苗的开发

基本信息

  • 批准号:
    9725441
  • 负责人:
  • 金额:
    $ 7.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-03-01 至 2022-02-28
  • 项目状态:
    已结题

项目摘要

Abstract Infections caused by the protozoan parasite Leishmania include cutaneous (CL), mucosal (ML), and visceral leishmaniasis (VL). The WHO classifies leishmaniasis as a neglected tropical disease with over 12 million current infections globally, and approximately 2 million new cases annually. Patients who recover from leishmaniasis develop protective immunity against reinfection, which altogether indicates that a vaccine is feasible. In the past, leishmanization, a process in which deliberate infections with a low dose of Leishmania major, etiologic agent of zoonotic cutaneous leishmaniasis (ZCL) causes a controlled skin lesion and provides > 90% protection against reinfection, was a common practice in ZCL-endemic regions. Under the current regulatory environment such practice is not acceptable due to possibility of complications including non-healing lesions. However, these studies suggest that live-attenuated parasites which don not cause a disease could be an effective vaccine for leishmaniasis. Genetically attenuated L. infantum and L. donovani including LdCen-/- have shown promise as a vaccine in animal models. However, using live-attenuated L. donovani as a vaccine in humans could raise safety concerns due to visceralizing potential of this Leishmania species. Attenuated dermatotrophic Leishmania that cross-protects against VL could be a safer vaccine against Leishmania because adverse events (e.g. development of a lesion as vaccination site) will be easy to monitor and can be treated using approved non-pharmacological interventions such as topical thermotherapy. Several clinical and preclinical animal studies have shown that an infection with dermatotrophic Leishmania such as L. major and L. tropica confers cross-protection against VL caused by L. donovani or L. infantum. Using CRISPR-Cas technology, we have generated antibiotic selection marker free centrin gene deficient L. major (LmCen-/-). Whole genome sequencing of LmCen-/- passed through mice multiple times has confirmed stable deletion of centrin gene without other mutations in the parasite genome. Our preliminary findings show that LmCen-/- are highly attenuated and fail to cause disease in immunocompromised animals. We have also found that immunization with LmCen-/- parasites induces disease protective Th1 response in hamsters and protects them against sand fly transmitted VL caused by L. donovani. Similarly, LmCen-/- immunization also protects against CL caused by L. major. These findings indicate that LmCen-/- is a promising vaccine for leishmaniasis. Our industry partner Gennova Biopharma has already established LmCen-/- production under cGMP conditions at their US-FDA approved facility. In this project, we propose to (Aim 1) perform phenotypic, genetic and biochemical characterization of GMP-LmCen-/-parasites and (Aim 2) determine whether GMP-LmCen-/- induce biomarkers of protection in peripheral blood mononuclear cells (PBMCs) from the patients with active VL, asymptomatics and those who have cured VL. The scientific promise of this project, if successful, could provide foundation for advancing LmCen-/- parasites as a vaccine against leishmaniasis in humans.
抽象的 原生动物寄生虫Leishmania引起的感染包括皮肤(CL),粘膜(ML)和内脏 利什曼病(VL)。世卫组织将利什曼病归类为一种被忽视的热带疾病,超过1200万 当前的全球感染,每年约有200万例新病例。康复的患者 利什曼病的发展保护性免疫免受再感染,这完全表明疫苗是 可行的。过去,利什曼(Leishmanization 人畜共患病利什曼病(ZCL)的专业,病因学剂会引起受控的皮肤病变,并提供 在ZCL流行区域中,> 90%的防止再感染是一种常见的做法。在电流下 监管环境由于可能存在并发症,包括非治疗,这种做法是不可接受的 病变。但是,这些研究表明,没有引起疾病的活体销售寄生虫可能是 利什曼病的有效疫苗。遗传衰减的婴儿乳杆菌和多诺瓦氏乳杆菌,包括ldcen - / - 在动物模型中显示了作为疫苗的承诺。但是,使用活体衰减的多诺瓦尼作为疫苗 在人类中,由于这种利什曼原虫物种的内脏潜力,可能会引起安全问题。衰减 针对VL的交叉保护可能是对利什曼尼亚的更安全的疫苗 因为不良事件(例如,病变作为疫苗接种部位的开发)将很容易监测,并且可以是 使用经认可的非药物干预措施(例如局部热疗)治疗。几个临床和 临床前动物研究表明,具有皮肤营养利什曼原虫的感染,例如乳杆菌和 Tropica L. Tropica赋予了由L. donovani或Infantum L.使用CRISPR-CAS 技术,我们已经产生了抗生素选择标记物基因缺陷L. major(LMCEN - / - )。 LMCEN - / - 多次通过小鼠的整个基因组测序已经证实了稳定的缺失 寄生虫基因组中没有其他突变的中心蛋白基因。我们的初步发现表明lmcen - / - 是 高度减弱,无法引起免疫功能低下的动物。我们还发现 用LMCEN - / - 寄生虫免疫可在仓鼠中诱导疾病保护性TH1反应并保护它们 反对由L. Donovani引起的沙蝇传播的VL。同样,LMCEN - / - 免疫也可以防止 CL由L. Major引起。这些发现表明LMCEN - / - 是利什曼病的有希望的疫苗。我们的 行业伙伴Gennova Biopharma已经在CGMP条件下建立了LMCEN - / - 他们的US-FDA批准了设施。在这个项目中,我们建议(AIM 1)执行表型,遗传和 GMP-LMCEN - / - 寄生虫的生化表征和(AIM 2)确定GMP-LMCEN - / - 是否诱导 活性VL患者的外周血单核细胞(PBMC)保护生物标志物 无疑的人和已经治愈VL的人。如果成功的话,这个项目的科学承诺可以 为在人类中推进LMCEN - / - 寄生虫作为针对利什曼病的疫苗提供了基础。

项目成果

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Abhay R Satoskar其他文献

Molecular characterization and genetic diversity of cutaneous leishmaniasis from North Eastern Pakistan
  • DOI:
    10.1016/j.actatropica.2021.105964
  • 发表时间:
    2021-09-01
  • 期刊:
  • 影响因子:
  • 作者:
    Nargis Shaheen;Chaitenya Verma;Thalia Pacheco-Fernandez;Greta Volpedo;Aneeqa Hamid;Ismail Zeb;Syed Aizaz Ali Shah;Shah Fahad;Attiya Iqbal;Asma Ashraf;Amjad Khan;Misbah Gul;Muhammad Ilyas Khan;Huma Fatima;Muhammad Afzal;Abhay R Satoskar;Naveeda Akhter Qureshi
  • 通讯作者:
    Naveeda Akhter Qureshi

Abhay R Satoskar的其他文献

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{{ truncateString('Abhay R Satoskar', 18)}}的其他基金

Development of a live attenuated vaccine for visceral leishmaniasis
内脏利什曼病减毒活疫苗的开发
  • 批准号:
    10115582
  • 财政年份:
    2020
  • 资助金额:
    $ 7.8万
  • 项目类别:
A live attenuated vaccine for leishmaniasis
利什曼病减毒活疫苗
  • 批准号:
    9753154
  • 财政年份:
    2018
  • 资助金额:
    $ 7.8万
  • 项目类别:
Treating cutaneous leishmaniasis by radio-frequency induced heat (RFH) therapy
通过射频诱导热 (RFH) 疗法治疗皮肤利什曼病
  • 批准号:
    8331827
  • 财政年份:
    2012
  • 资助金额:
    $ 7.8万
  • 项目类别:
Chemopreventition and treatment of non-melanoma skin cancer by targeting MIF
通过靶向 MIF 化学预防和治疗非黑色素瘤皮肤癌
  • 批准号:
    8230915
  • 财政年份:
    2012
  • 资助金额:
    $ 7.8万
  • 项目类别:
Chemopreventition and treatment of non-melanoma skin cancer by targeting MIF
通过靶向 MIF 化学预防和治疗非黑色素瘤皮肤癌
  • 批准号:
    8434824
  • 财政年份:
    2012
  • 资助金额:
    $ 7.8万
  • 项目类别:
Visualization of CXCR3 allelic usage in vivo
CXCR3 等位基因体内使用的可视化
  • 批准号:
    7957584
  • 财政年份:
    2010
  • 资助金额:
    $ 7.8万
  • 项目类别:
Visualization of CXCR3 allelic usage in vivo
CXCR3 等位基因体内使用的可视化
  • 批准号:
    8066661
  • 财政年份:
    2010
  • 资助金额:
    $ 7.8万
  • 项目类别:
Discovery of novel antileishmanial molecules from the plant Pentalinon andreuxii
从植物 Pentalinon andreuxii 中发现新型抗利什曼尼分子
  • 批准号:
    8083173
  • 财政年份:
    2010
  • 资助金额:
    $ 7.8万
  • 项目类别:
Treatment of cutaneous leishmaniasis using Pentalinon andrieuxii root extract
使用 Pentalinon andrieuxii 根提取物治疗皮肤利什曼病
  • 批准号:
    7584697
  • 财政年份:
    2009
  • 资助金额:
    $ 7.8万
  • 项目类别:
Treatment of cutaneous leishmaniasis using Pentalinon andrieuxii root extract
使用 Pentalinon andrieuxii 根提取物治疗皮肤利什曼病
  • 批准号:
    7762723
  • 财政年份:
    2009
  • 资助金额:
    $ 7.8万
  • 项目类别:

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