Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, Chapel Hill, NC, United States of America.
Department of Pharmacology, University of North Carolina, Chapel Hill, Chapel Hill, NC, United States of America.
PLoS Negl Trop Dis. 2018 Sep 24;12(9):e0006793. doi: 10.1371/journal.pntd.0006793. eCollection 2018 Sep.
Dengue virus (DENV) is the causative agent of dengue fever and dengue hemorrhagic shock syndrome. Dengue vaccine development is challenging because of the need to induce protection against four antigenically distinct DENV serotypes. Recent studies indicate that tetravalent DENV vaccines must induce balanced, serotype-specific neutralizing antibodies to achieve durable protective immunity against all 4 serotypes. With the leading live attenuated tetravalent DENV vaccines, it has been difficult to achieve balanced and type-specific responses to each serotype, most likely because of unbalanced replication of vaccine viral strains. Here we evaluate a tetravalent DENV protein subunit vaccine, based on recombinant envelope protein (rE) adsorbed to the surface of poly (lactic-co-glycolic acid) (PLGA) nanoparticles for immunogenicity in mice. In monovalent and tetravalent formulations, we show that particulate rE induced higher neutralizing antibody titers compared to the soluble rE antigen alone. Importantly, we show the trend that tetravalent rE adsorbed to nanoparticles stimulated a more balanced serotype specific antibody response to each DENV serotype compared to soluble antigens. Our results demonstrate that tetravalent DENV subunit vaccines displayed on nanoparticles have the potential to overcome unbalanced immunity observed for leading live-attenuated vaccine candidates.
登革热病毒(DENV)是登革热和登革出血热休克综合征的病原体。由于需要诱导针对四种具有不同抗原性的登革热血清型的保护作用,因此登革热疫苗的开发具有挑战性。最近的研究表明,四价登革热疫苗必须诱导平衡的、血清型特异性的中和抗体,以实现对所有 4 种血清型的持久保护免疫。对于领先的减毒活四价登革热疫苗,很难对每种血清型实现平衡和特异性反应,这很可能是由于疫苗病毒株的复制不平衡所致。在这里,我们评估了一种基于重组包膜蛋白(rE)吸附到聚(乳酸-共-乙醇酸)(PLGA)纳米颗粒表面的四价登革热蛋白亚单位疫苗,以评估其在小鼠中的免疫原性。在单价和四价制剂中,我们发现与单独的可溶性 rE 抗原相比,颗粒状 rE 诱导了更高的中和抗体滴度。重要的是,我们发现,与可溶性抗原相比,吸附在纳米颗粒上的四价 rE 刺激了对每种 DENV 血清型更平衡的血清型特异性抗体反应的趋势。我们的研究结果表明,在纳米颗粒上展示的四价登革热亚单位疫苗有可能克服对领先的减毒活疫苗候选物观察到的免疫不平衡。