DEVELOPMENT OF A LEISHMANIA VACCINE USING INTERLEUKIN-12 AS AN ADJUVANT

使用 IL-12 作为佐剂开发利什曼原虫疫苗

• 批准号: 6101100
• 负责人: R T KENNEY
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6101100
• 关键词: Leishmania; Primates; biomaterial development /preparation; clinical research; clinical trial phase I; disease /disorder model; drug screening /evaluation; human subject; immunologic skin test; immunomodulators; interleukin 12; laboratory mouse; microorganism culture; protozoal vaccine; vaccine development; vector vaccine

Cutaneous leishmaniasis still affects about 10 million people a year, despite numerous attempts at vector control, parasite eradication, and creation of various vaccine formulations. Solid immunity develops after natural infection in humans with all cutaneous species. Vaccination against the disease with living parasites, or leishmanization, has only been tried in areas where cutaneous leishmaniasis is endemic. The lesion induced is often complicated by prolonged ulceration and scarring since live parasites are used. Vaccination with killed preparations has only been shown to be immunogenic in small numbers of people, and has never been shown to be effective in large trials. Recent observations using the mouse model have shown that Interleukin-12 can reverse the immune response of susceptible BALB/c mice when used as an adjuvant with a crude leishmania vaccine preparation. With the cooperation of the Genetics Institute (Cambridge, MA), which makes recombinant human and murine IL-12, and B!obras (Montes Claros, Brazil), which makes a leishmania vaccine and skin test antigen, we are developing a product for use in a human Phase I/II trial. While the mouse model has shown several antigens to be efficacious when combined with IL-12, there is an urgent need to confirm the potential for vaccination in humans with the cytokine adjuvant, and to assure the community of the safety and immuno- genicity of a crude preparation. We have completed a series of experiments using mice to test the safety, potency, efficacy, and stability of several preparations. The vaccine antigen is made from cultures of parasites that are washed, then frozen and thawed several times to break the cells. These crude leishmania preps were shown to work well despite autoclaving, and the autoclaved preparation remains stable after one month at 37'C. Monkey experiments to evaluate the safety, immunogenicity, and efficacy of the autoclaved preparation with rHuIL-12 and alum as adjuvants have shown 100% efficacy in 12 animals. Further studies are in progress to refine the antigen preparation. We plan to submit an IND for the combination of the products and begin the clinical trials at NIH by the end of the year.

皮肤利什曼病每年仍影响约1000万人， 尽管在病媒控制、寄生虫根除和 生产各种疫苗。 免疫力增强， 人类所有皮肤物种的自然感染。 疫苗接种 用活的寄生虫或利什曼化来对抗这种疾病， 在皮肤利什曼病流行的地区进行了试验。 病变 诱发的溃疡往往并发长期溃疡和疤痕， 使用活的寄生虫。 用灭活制剂接种疫苗， 已被证明在少数人中具有免疫原性， 在大型试验中被证明是有效的。 最近的观察， 小鼠模型表明白细胞介素-12可以逆转免疫 敏感BALB/c小鼠作为佐剂与粗品 利什曼原虫疫苗制剂。 在遗传学研究所（剑桥，MA）的合作下， 产生重组人和鼠IL-12，和B！obras（Montes Claros， 巴西），该公司生产利什曼原虫疫苗和皮肤测试抗原， 开发用于人类I/II期试验的产品。当老鼠 模型显示，当与以下物质组合时，几种抗原是有效的： IL-12，迫切需要确认疫苗接种的潜力 在人类中使用细胞因子佐剂，并确保 安全性和免疫原性。 我们已经完成了一系列的实验，用老鼠来测试安全性， 几种制剂的效力、功效和稳定性。 疫苗 抗原是由洗涤后冷冻的寄生虫培养物制成的 并解冻数次以破坏细胞。 这些粗糙的利什曼原虫 尽管进行了高压灭菌，但制备物显示出良好的效果，并且高压灭菌的 制剂在37 ℃下一个月后保持稳定。 猴子实验 评价高压灭菌的安全性、免疫原性和有效性， 用rHuIL-12和明矾作为佐剂的制剂显示出100%的功效 12只动物 进一步的研究正在进行中，以完善抗原 准备.我们计划提交产品组合的IND 并在今年年底前开始在NIH进行临床试验。