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: 2456616
• 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/2456616
• 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. These studies are intended to be a proof-of-concept alone. It is anticipated that one of the several recombinant leishmania antigens under development at other laboratories will be ready for human trials within the next year or two. 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 just 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 degrees. Monkey experiments will start next month to evaluate the safety, immunogenicity, and efficacy of the autoclaved preparation with rHuIL-12 as an adjuvant. 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。 在遗传学的合作下， 研究所（剑桥，MA），该研究所制造重组人和鼠 IL-12和B！obras（Montes Claros，巴西），这使得一个利什曼原虫 疫苗和皮肤测试抗原，我们正在开发一种产品，用于 人类I/II期试验。 这些研究旨在成为 仅仅是概念验证 据估计，其中一个 其他实验室正在开发重组利什曼原虫抗原 将在未来一两年内进行人体试验。 而 小鼠模型显示当组合时几种抗原是有效的 对于IL-12，迫切需要确认 用细胞因子佐剂在人中接种，并确保 共同体的安全性和免疫原性的粗制剂。 我们 刚刚完成了一系列用老鼠测试 几种制剂的安全性、效力、功效和稳定性。 的 疫苗抗原是由洗涤后的寄生虫培养物制成的，然后 冷冻和解冻几次以破坏细胞。 的这些土制 尽管高压灭菌，利什曼原虫制剂仍显示出良好的效果， 高压灭菌的制剂在37度下一个月后保持稳定。 猴子实验将于下个月开始，以评估安全性， 免疫原性和具有rHuIL-12的高压灭菌制剂的功效 作为佐剂。 我们计划提交一份IND， 并在年底前在NIH开始临床试验。