DEVELOPMENT OF A LEISHMANIA VACCINES

皮肤利什曼病每年仍影响约1000万人，尽管在病媒控制、根除寄生虫和创造各种疫苗配方方面进行了多次尝试。在人类自然感染所有皮肤物种后，会产生固体免疫力。只有在皮肤利什曼病流行的地区才尝试用活寄生虫接种疫苗来预防这种疾病。由于使用活体寄生虫，导致的损伤往往伴有长期的溃疡和疤痕。使用灭活制剂接种疫苗只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有效。最近使用小鼠模型的观察表明，白介素12可以逆转敏感的BALB/c小鼠的免疫反应，当与粗制利什曼疫苗制剂一起用作佐剂时。在几家制药公司的合作下，我们正在开发一种用于人体临床试验的产品。虽然小鼠模型已经显示出几种抗原与IL-12结合时是有效的，但迫切需要确认细胞因子佐剂在人类中接种的可能性，并确保粗制制剂的安全性和免疫原性。我们已经用小鼠和恒河猴完成了一系列实验，以测试几种制剂的安全性、有效性、有效性和稳定性。疫苗抗原是在我们的实验室里用寄生虫培养物制成的，这些寄生虫经过清洗，然后冷冻和解冻几次，以打破细胞。这些粗制的利什曼制剂被证明在高压灭菌情况下工作良好，高压灭菌制剂在37℃下一个月后仍保持稳定。IND已提交进行I/II期临床试验，目前处于临床搁置状态。已经开始了其他疫苗策略的临床前研究，包括DNA疫苗接种和使用CpG寡核苷酸作为佐剂。

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 several pharmaceutical companies, we are developing a product for use in human clinical trials. 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 and rhesus macaques to test the safety, potency, efficacy, and stability of several preparations. The vaccine antigen was made in our labs 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. An IND has been submitted for the Phase I/II clinical trial, which is currently on clinical hold. Preclinical studies for other vaccine strategies have been initiated including DNA vaccination and the use of CpG oligonucleotides as an adjuvant.