Malaria Vaccines: Pfs25-rEPA/ALHYDROGEL

尽管Pfs25已经被证明可以诱导抗体来阻止蚊子体内寄生虫的发展，但这种蛋白的免疫原性很差。油包水佐剂Montanide ISA 51能够增强Pfs25的免疫原性，然而，该配方具有太强的反应性，在美国进行的第一阶段人体试验在完成之前必须终止该配方。 因此，基于Pfs25的TBV开发面临的主要挑战是寻找一种能够提高免疫原性和反应寿命的配方。外蛋白A(ExoProtein A，EPA)已被用作伤寒Vi多糖疫苗的载体。我们制备了重组EPA(REPA)，并开发了一种将Pfs25与REPA偶联的工艺。为了获得最佳的免疫原性和可靠的接合过程，对各种接合化学方法和方法进行了评估。对Pfs25-Pfs25的生化性质进行了表征，并对其免疫原性进行了动物实验。结合疫苗诱导的免疫血清被测试其阻止蚊子寄生虫发展的能力。已计划进行一项第一阶段试验，以测试其安全性、免疫原性和在人体内的体外传播阻断活性。

Though Pfs25 has been shown to induce antibodies that can block parasite development in mosquitoes, the protein is poorly immunogenic. A water-in-oil adjuvant Montanide ISA 51 was able to enhance the immunogenicity of the Pfs25, however, the formulation was too reactogenic and a Phase 1 human trial in US tested the formulation had to be terminated before completion. Thus the major challenge facing Pfs25-based TBV development is to find a formulation to increase the immunogenicity and response longevity. The ExoProtein A (EPA) has been used as a carrier for the Vi polysaccharide vaccine against typhoid fever. We have produced the recombinant EPA (rEPA), and developed a process to to conjugate Pfs25 with rEPA. Various conjugation chemistries and methods were evaluated for the optimal immunogenicity and the robust conjugation processes. The biochemical properties of the Pfs25-Pfs25 were characterized and the conjugates were evaluated in animals for their immunogenicity. The immune sera induced by the conjugate vaccine were tested for their ability to block parasite development in mosquitoes. A Phase 1 trial has been planned to test the safety, immunogenicity, and ex vivo transmission blocking activity in humans.