Malaria Vaccine: Pfs25-rEPA

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。一种油包水佐剂Montanide ISA 51能够增强Pfs25的免疫原性；然而，该配方的反应性太强，在美国进行的一期人体试验因配方的反应性而不得不在完成前终止。 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)是伤寒Vi多糖疫苗的载体。我们生产了重组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稳健的接合过程，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，以测试安全性、免疫原性和人体外传播阻断活性。

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 Pfs25; however, the formulation was too reactogenic and a Phase 1 human trial in the US to test the formulation had to be terminated before completion due to reactogenicity of the formulation. Thus the major challenge facing Pfs25-based TBV development is to find a formulation to increase immunogenicity and response longevity. ExoProtein A (EPA) has been used as a carrier for the Vi polysaccharide vaccine against typhoid fever. We have produced recombinant EPA (rEPA), and developed a process to conjugate Pfs25 with rEPA. Various conjugation chemistries and methods were evaluated for optimal immunogenicity and a robust conjugation processes. The biochemical properties of 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 safety, immunogenicity, and ex-vivo transmission blocking activity in humans.