BACKGROUND:An effective malaria transmission-blocking vaccine (TBV) would be a major advance in the current efforts to eliminate and, ultimately, eradicate malaria. Antibodies against Plasmodium falciparum surface protein, Pfs25, are known to block parasite development in the mosquito vector. However, in initial clinical trials the limited immunogenicity of recombinant Pfs25 protein-in-adjuvant vaccines has been a challenge. METHODS:Novel human adenovirus type 5 (Ad5) vectors were used in heterologous prime boost vaccination strategies to augment the immune response against Pfs25. Specifically, an Ad5 vector that directs expression of full-length, membrane-bound Pfs25 was used as a priming immunization followed by a boost with Ad5 viral particles displaying only the Pfs25 epitope targeted by transmission-blocking antibodies 4B7 and 1D2 (Pfs25 aa 122-134) in hypervariable region 5 of the hexon capsid protein. RESULTS:This heterologous prime-boost vaccine strategy induced antibodies that significantly inhibit P. falciparum transmission to mosquitoes in a standard membrane-feeding assay. Further, immunized mice generated a robust anti-Pfs25 antibody response characterized by higher titer, higher relative avidity and a broader IgG subclass profile than observed with a homologous prime-boost with recombinant Pfs25/alum. CONCLUSION:The data suggest that focusing the immune response against defined epitopes displayed on the viral capsid is an effective strategy for transmission-blocking vaccine development.

译文

背景:有效的阻断疟疾传播的疫苗(TBV)将是当前消除并最终消除疟疾的努力中的一项重大进展。已知针对恶性疟原虫表面蛋白Pfs25的抗体可阻断蚊媒中的寄生虫发育。然而,在最初的临床试验中,重组Pfs25蛋白佐剂疫苗的有限的免疫原性一直是一个挑战。
方法:将新型人类5型腺病毒(Ad5)载体用于异源初免疫苗接种策略,以增强针对Pfs25的免疫应答。具体而言,将指导全长,与膜结合的Pfs25全长表达的Ad5载体用作初免免疫,然后用Ad5病毒颗粒加强免疫,仅显示被传递阻断抗体4B7和1D2靶向的Pfs25表位(Pfs25 aa 122- 134)在六邻体衣壳蛋白的高变区5中。
结果:这种异源的初免-加强疫苗策略诱导的抗体在标准的膜喂养试验中可显着抑制恶性疟原虫向蚊子的传播。此外,与用重组Pfs25 / alum的同源初免-加强免疫所观察到的相比,免疫的小鼠产生了强大的抗Pfs25抗体应答,其特征在于更高的滴度,更高的相对亲和力和更宽的IgG亚类谱。
结论:数据表明,针对病毒衣壳上展示的确定表位的免疫反应是阻止传播疫苗发展的有效策略。

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