Department of Immunology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
Laboratory of Viral Infection I, Department of Infection Control and Immunology, Kitasato Institute for Life Sciences, Kitasato University, Tokyo 108-8641, Japan.
J Immunol. 2019 Dec 15;203(12):3282-3292. doi: 10.4049/jimmunol.1900481. Epub 2019 Nov 8.
Virus-like particles (VLPs) provide a well-established vaccine platform; however, the immunogenic properties acquired by VLP structure remain poorly understood. In this study, we showed that systemic vaccination with norovirus VLP recalls human IgA responses at higher magnitudes than IgG responses under a humanized mouse model that was established by introducing human PBMCs in severely immunodeficient mice. The recall responses elicited by VLP vaccines depended on VLP structure and the disruption of VLP attenuated recall responses, with a more profound reduction being observed in IgA responses. The IgA-focusing property was also conserved in a murine norovirus-primed model under which murine IgA responses were recalled in a manner dependent on VLP structure. Importantly, the VLP-driven IgA response preferentially targeted virus-neutralizing epitopes located in the receptor-binding domain. Consequently, VLP-driven IgA responses were qualitatively superior to IgG responses in terms of the virus-neutralizing activity in vitro. Furthermore, the IgA in mucosa obtained remarkable protective function toward orally administrated virus in vivo. Thus, our results indicate the immune-focusing properties of the VLP vaccine that improve the quality/quantity of mucosal IgA responses, a finding with important implications for developing mucosal vaccines.
病毒样颗粒 (VLPs) 提供了一个成熟的疫苗平台；然而，VLPs 结构获得的免疫原性特性仍知之甚少。在这项研究中，我们发现在严重免疫缺陷小鼠中引入人 PBMC 建立的人源化小鼠模型中，诺如病毒 VLP 的全身疫苗接种会引起比 IgG 反应更高幅度的人类 IgA 反应。VLP 疫苗引起的回忆反应取决于 VLP 结构，而 VLP 的破坏减弱了回忆反应，IgA 反应的减少更为明显。在鼠诺如病毒引发的模型中，IgA 聚焦特性也得到了保留，其中以 VLP 结构依赖的方式引发了鼠 IgA 反应。重要的是，VLP 驱动的 IgA 反应优先针对位于受体结合域的病毒中和表位。因此，与 IgG 反应相比，VLP 驱动的 IgA 反应在体外具有更高的病毒中和活性。此外，体内获得的黏膜 IgA 具有显著的保护作用，可抵抗口服给予的病毒。因此，我们的结果表明 VLP 疫苗具有免疫聚焦特性，可以提高黏膜 IgA 反应的质量/数量，这一发现对开发黏膜疫苗具有重要意义。
