Nanoparticles decorated with viral antigens are more immunogenic at low surface density
Nanoparticles decorated with viral antigens are more immunogenic at low surface density
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DOI：
10.1016/j.vaccine.2016.12.049
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发表时间：
2017-02-01
期刊：
影响因子：
5.5
通讯作者：
Dewhurst, Stephen
中科院分区：
文献类型：
--
作者：
Brewer, Matthew G.;DiPiazza, Anthony;Dewhurst, Stephen
迫切需要开发针对高优先级病毒病原体的保护性疫苗。一种已知的增强对病毒蛋白的免疫反应的方法是将它们展示在纳米颗粒(NP)支架上。然而，关于蛋白质密度对B细胞对NPs上显示的抗原的反应的影响，人们知之甚少。为了解决这个问题，HIV-1包膜(Env)和流感血凝素(HA)以不同的密度展示在基于聚苯乙烯的NP支架上-对应于跨越自然产生的病毒粒子所遇到的范围的平均抗原距离。我们的研究表明，在体外，显示低密度的Env或HA的NPs比显示较高的抗原密度的NPs更有效地刺激抗原特异性B细胞。同样，显示低密度的Env或HA的NPs也会在免疫的BALB/c小鼠中诱导更高的抗原特异性血清抗体效价(包括血凝抑制抗体效价的升高)，以及在淋巴结、脾和骨髓中抗原特异性抗体分泌细胞的频率增加。重要的是，我们的研究表明，较低密度的NPs引起的增强的B细胞反应可能次要于更有效的卵泡辅助CD4T细胞和生发中心B细胞的发育。这些发现表明，NP支架上的抗原密度是诱发体液免疫反应的关键决定因素，高密度展示并不总是导致最佳反应。(C)2017爱思唯尔有限公司。保留所有权利。
There is an urgent need to develop protective vaccines for high priority viral pathogens. One approach known to enhance immune responses to viral proteins is to display them on a nanoparticle (NP) scaffold. However, little is known about the effect of protein density on the B cell response to antigens displayed on NPs. To address this question HIV-1 Envelope (Env) and influenza hemagglutinin (HA) were displayed on a polystyrene-based NP scaffold at various densities - corresponding to mean antigen distances that span the range encountered on naturally occurring virions. Our studies revealed that NPs displaying lower densities of Env or HA more efficiently stimulated antigen-specific B cells in vitro, as measured by calcium flux, than did NPs displaying higher antigen densities. Similarly, NPs displaying a low density of Env or HA also elicited higher titers of antigen-specific serum IgG in immunized BALB/c mice (including elevated titers of hemagglutination-inhibiting antibodies), as well as an increased frequency of antigen-specific antibody secreting cells in the lymph node, spleen and bone marrow. Importantly, our studies showed that the enhanced B cell response elicited by the lower density NPs is likely secondary to more efficient development of follicular helper CD4 T cells and germinal center B cells. These findings demonstrate that the density of antigen on a NP scaffold is a critical determinant of the humoral immune response elicited, and that high density display does not always result in an optimal response. (C) 2017 Elsevier Ltd. All rights reserved.