Fernández Laura, Solana Jose Carlos, Sánchez Carmen, Jiménez Mª Ángeles, Requena Jose M, Coler Rhea, Reed Steven G, Valenzuela Jesus G, Kamhawi Shaden, Oliveira Fabiano, Fichera Epifanio, Glueck Reinhard, Bottazzi Maria Elena, Gupta Gaurav, Cecilio Pedro, Pérez-Cabezas Begoña, Cordeiro-da-Silva Anabela, Gradoni Luigi, Carrillo Eugenia, Moreno Javier
WHO Collaborating Centre for Leishmaniasis, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Madrid, Spain.
Facultad de Veterinaria, Departamento de Medicina y Cirugía Animal, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Microorganisms. 2021 Oct 29;9(11):2253. doi: 10.3390/microorganisms9112253.
Visceral leishmaniasis (VL) is the most severe clinical form of leishmaniasis, fatal if untreated. Vaccination is the most cost-effective approach to disease control; however, to date, no vaccines against human VL have been made available. This work examines the efficacy of a novel vaccine consisting of the membrane protein KMP11, LEISH-F3+ (a recombinant fusion protein, composed of epitopes of the parasite proteins nucleoside hydrolase, sterol-24-c-methyltransferase, and cysteine protease B), and the sand fly salivary protein LJL143, in two dose ratios. The inclusion of the TLR4 agonist GLA-SE as an adjuvant, and the use of virosomes (VS) as a delivery system, are also examined. In a hamster model of VL, the vaccine elicited antigen-specific immune responses prior to infection with . Of note, the responses were greater when higher doses of KMP11 and LEISH-F3+ proteins were administered along with the GLA-SE adjuvant and/or when delivered within VS. Remarkably, hamsters immunized with the complete combination (i.e., all antigens in VS + GLA-SE) showed significantly lower parasite burdens in the spleen compared to those in control animals. This protection was underpinned by a more intense, specific humoral response against the KMP11, LEISH-F3+, and LJL143 antigens in vaccinated animals, but a significantly less intense antibody response to the pool of soluble antigens (SLA). Overall, these results indicate that this innovative vaccine formulation confers protection against infection, supporting the advancement of the vaccine formulation into process development and manufacturing and the conduction of toxicity studies towards future phase I human clinical trials.
内脏利什曼病（VL）是利什曼病最严重的临床形式，若不治疗会致命。疫苗接种是疾病控制最具成本效益的方法；然而，迄今为止，尚无针对人类VL的疫苗可供使用。这项研究考察了一种新型疫苗的疗效，该疫苗由膜蛋白KMP11、LEISH-F3 +（一种重组融合蛋白，由寄生虫蛋白核苷水解酶、固醇-24-甲基转移酶和半胱氨酸蛋白酶B的表位组成）以及白蛉唾液蛋白LJL143按两种剂量比例组成。还考察了包含TLR4激动剂GLA-SE作为佐剂以及使用病毒体（VS）作为递送系统的情况。在VL的仓鼠模型中，该疫苗在感染[病原体名称未给出]之前引发了抗原特异性免疫反应。值得注意的是，当与GLA-SE佐剂一起施用更高剂量的KMP11和LEISH-F3 +蛋白时，以及/或者当在VS内递送时，免疫反应更强。值得注意的是，与对照动物相比，用完整组合（即VS + GLA-SE中的所有抗原）免疫的仓鼠脾脏中的寄生虫负荷显著降低。这种保护作用的基础是接种疫苗的动物对KMP11、LEISH-F3 +和LJL143抗原产生了更强烈、特异性的体液反应，但对可溶性抗原池（SLA）的抗体反应强度明显较低。总体而言，这些结果表明这种创新的疫苗配方可提供针对[病原体名称未给出]感染的保护，支持将该疫苗配方推进到工艺开发和生产阶段，并开展毒性研究以进行未来的I期人体临床试验。
