Debbink Kari, Lindesmith Lisa C, Donaldson Eric F, Swanstrom Jesica, Baric Ralph S
Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.
Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.
J Virol. 2014 Jul;88(13):7256-66. doi: 10.1128/JVI.00785-14. Epub 2014 Apr 16.
There is currently no licensed vaccine for noroviruses, and development is hindered, in part, by an incomplete understanding of the host adaptive immune response to these highly heterogeneous viruses and rapid GII.4 norovirus molecular evolution. Emergence of a new predominant GII.4 norovirus strain occurs every 2 to 4 years. To address the problem of GII.4 antigenic variation, we tested the hypothesis that chimeric virus-like particle (VLP)-based vaccine platforms, which incorporate antigenic determinants from multiple strains into a single genetic background, will elicit a broader immune response against contemporary and emergent strains. Here, we compare the immune response generated by chimeric VLPs to that of parental strains and a multivalent VLP cocktail. Results demonstrate that chimeric VLPs induce a more broadly cross-blocking immune response than single parental VLPs and a similar response to a multivalent GII.4 VLP cocktail. Furthermore, we show that incorporating epitope site A alone from one strain into the background of another is sufficient to induce a blockade response against the strain donating epitope site A. This suggests a mechanism by which population-wide surveillance of mutations in a single epitope could be used to evaluate antigenic changes in order to identify potential emergent strains and quickly reformulate vaccines against future epidemic strains as they emerge in human populations.
Noroviruses are gastrointestinal pathogens that infect an estimated 21 million people per year in the United States alone. GII.4 noroviruses account for >70% of all outbreaks, making them the most clinically important genotype. GII.4 noroviruses undergo a pattern of epochal evolution, resulting in the emergence of new strains with altered antigenicity over time, complicating vaccine design. This work is relevant to norovirus vaccine design as it demonstrates the potential for development of a chimeric VLP-based vaccine platform that may broaden the protective response against multiple GII.4 strains and proposes a potential reformulation strategy to control newly emergent strains in the human population.
目前尚无针对诺如病毒的许可疫苗，其研发受到阻碍，部分原因是对宿主针对这些高度异质性病毒的适应性免疫反应以及GII.4诺如病毒的快速分子进化缺乏全面了解。每2至4年就会出现一种新的主要GII.4诺如病毒株。为了解决GII.4抗原变异问题，我们检验了以下假设：基于嵌合病毒样颗粒（VLP）的疫苗平台，即将来自多个毒株的抗原决定簇整合到单一基因背景中，将引发针对当代和新出现毒株的更广泛免疫反应。在此，我们比较了嵌合VLP产生的免疫反应与亲本毒株和多价VLP混合物产生的免疫反应。结果表明，嵌合VLP诱导的交叉阻断免疫反应比单一亲本VLP更广泛，且与多价GII.4 VLP混合物的反应相似。此外，我们表明，仅将一个毒株的表位位点A整合到另一个毒株的背景中就足以诱导针对提供表位位点A的毒株的阻断反应。这提示了一种机制，通过对单个表位突变进行全人群监测，可用于评估抗原变化，从而识别潜在的新出现毒株，并在其在人群中出现时迅速重新设计针对未来流行毒株的疫苗。
诺如病毒是胃肠道病原体，仅在美国每年就感染约2100万人。GII.4诺如病毒占所有疫情爆发的70%以上，使其成为临床上最重要的基因型。GII.4诺如病毒经历阶段性进化模式，导致随着时间推移出现抗原性改变的新毒株，使疫苗设计复杂化。这项工作与诺如病毒疫苗设计相关，因为它证明了基于嵌合VLP的疫苗平台的开发潜力，该平台可能扩大针对多种GII.4毒株的保护性反应，并提出了一种潜在的重新配方策略来控制人群中新出现的毒株。
