Immunization with a polyprotein vaccine consisting of the T-cell antigens thiol-specific antioxidant, Leishmania major stress-inducible protein 1, and Leishmania elongation initiation factor protects against leishmaniasis
Immunization with a polyprotein vaccine consisting of the T-cell antigens thiol-specific antioxidant, Leishmania major stress-inducible protein 1, and Leishmania elongation initiation factor protects against leishmaniasis
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DOI：
10.1128/iai.70.8.4215-4225.2002
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发表时间：
2002-08-01
影响因子：
3.1
通讯作者：
Reed, SG
中科院分区：
文献类型：
--
作者：
Coler, RN;Skeiky, YAW;Reed, SG
开发针对利什曼原虫感染的有效疫苗是热带病研究的首要任务。我们最近在小鼠和非人灵长类动物模型中证明了对利什曼原虫的保护作用，其中纯化的利什曼原虫重组抗原单独或组合以质粒 DNA 构建体形式提供或用重组白细胞介素 12 (IL-12) 作为佐剂配制。在本研究中，我们用重组多蛋白对 BALB/c 小鼠进行免疫接种，该重组多蛋白包含利什曼原虫抗原硫醇特异性抗氧化剂、主要利什曼原虫应激诱导蛋白 1 (LmST11) 和利什曼原虫伸长起始因子 (LeIF) 的串联融合，并与适合人类使用的佐剂一起递送。通过使用 BALB/c 小鼠的重大利斯特氏菌攻击模型，评估了含有每种成分的制剂以及称为 Leish-111f 的多聚蛋白的安全性、免疫原性和疫苗功效。当给 BALB/c 小鼠皮下注射 3 次由 MPL-角鲨烯 (SE) 或 Ribi 529-SE 配制的 Leish-111f 多蛋白时，没有观察到不良反应。观察到以体外淋巴细胞增殖、γ干扰素产生和免疫球蛋白 G2A 抗体为特征的主要 Th1 免疫反应，且几乎没有（如果有的话）IL-4。此外，采用 MPL-SE 配制的 Leish-111f 赋予利什曼病免疫力至少 3 个月。这些数据证明了设计和开发预防性利什曼病疫苗的成功，该疫苗在临床前模型中被证明是有效的，该疫苗使用多种利什曼原虫抗原作为单一蛋白质产生，并与适合人类使用的强效 Th1 佐剂一起递送。
Development of an effective vaccine against Leishmania infection is a priority of tropical disease research. We have recently demonstrated protection against Leishmania major in the murine and nonhuman primate models with individual or combinations of purified leishmanial recombinant antigens delivered as plasmid DNA constructs or formulated with recombinant interleukin-12 (IL-12) as adjuvant. In the present study, we immunized BALB/c mice with a recombinant polyprotein comprising a tandem fusion of the leishmanial antigens thiol-specific antioxidant, L. major stress-inducible protein 1 (LmST11), and Leishmania elongation initiation factor (LeIF) delivered with adjuvants suitable for human use. Aspects of the safety, immunogenicity, and vaccine efficacy of formulations with each individual component, as well as the pollyprotein referred to as Leish-111f, were assessed by using the L. major challenge model with BALB/c mice. No adverse reactions were observed when three subcutaneous injections of the Leish-111f polyprotein formulated with either MPL-squalene (SE) or Ribi 529-SE were given to BALB/c mice. A predominant Th1 immune response characterized by in vitro lymphocyte proliferation, gamma interferon production, and immunoglobulin G2A antibodies was observed with little, if any, IL-4. Moreover, Leish-111f formulated with MPL-SE conferred immunity to leishmaniasis for at least 3 months. These data demonstrate success at designing and developing a prophylactic leishmaniasis vaccine that proved effective in a preclinical model using multiple leishmanial antigens produced as a single protein delivered with a powerful Th1 adjuvant suitable for human use.