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

皮肤利什曼病每年仍影响约1000万人， 尽管多次尝试控制病媒，根除寄生虫，以及 创造各种疫苗配方。固体免疫在以下情况下形成 人类对所有皮肤物种的自然感染。接种疫苗 用活的寄生虫对抗疾病，或利什曼，只有 已在皮肤利什曼病流行的地区试用。病变 诱导性溃疡通常因长期溃疡和疤痕形成而复杂化，因为 使用的是活寄生虫。用灭活制剂接种疫苗只有 已被证明在少数人中具有免疫原性，并且从未 在大型试验中被证明是有效的。最近的观察结果使用 小鼠模型表明，白介素12可以逆转免疫 易感BALB/c小鼠作为粗提物佐剂时的免疫应答 利什曼原虫疫苗准备工作。 与遗传研究所(马萨诸塞州剑桥)合作，该研究所 制造重组人和小鼠IL-12，以及B！obras(Montes Claros， 巴西)，生产利什曼疫苗和皮试抗原，我们是 开发一种用于人类I/II期试验的产品。当鼠标 模型显示，当几种抗原与 IL-12，迫切需要确认接种疫苗的潜力 在人类中使用细胞因子佐剂，并向社区保证 粗制制剂的安全性和免疫原性。 我们已经完成了一系列用小鼠来测试安全性的实验， 几种制剂的效力、疗效和稳定性。疫苗 抗原是由寄生虫的培养物制成的，这些寄生虫被清洗，然后冷冻 并解冻了几次以打破细胞。这些粗暴的利什曼狂热 尽管进行了高压灭菌，预备物仍表现良好，而高压灭菌 在37℃恒温一个月后，制剂保持稳定。 评价高压灭菌剂的安全性、免疫原性和有效性 以rHuIL-12和明矾为佐剂的制剂显示100%有效 在12只动物身上。进一步的研究正在进行中，以提炼抗原 准备工作。我们计划提交一份产品组合的IND 并在今年年底前开始在NIH进行临床试验。

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.