Malm M, Heinimäki S, Vesikari T, Blazevic V
Vaccine Research Center, University of Tampere, Tampere, Finland.
Clin Exp Immunol. 2017 Sep;189(3):331-341. doi: 10.1111/cei.12977. Epub 2017 May 16.
A subunit protein vaccine candidate based on norovirus (NoV) virus-like particles (VLPs) and rotavirus (RV) VP6 protein against acute childhood gastroenteritis has been proposed recently. RV VP6 forms different oligomeric nanostructures, including tubes and spheres when expressed in vitro, which are highly immunogenic in different animal models. We have shown recently that recombinant VP6 nanotubes have an adjuvant effect on immunogenicity of NoV VLPs in mice. In this study, we investigated if the adjuvant effect is dependent upon a VP6 dose or different VP6 structural assemblies. In addition, local and systemic adjuvant effects as well as requirements for antigen co-delivery and co-localization were studied. The magnitude and functionality of NoV GII.4-specific antibodies and T cell responses were tested in mice immunized with GII.4 VLPs alone or different combinations of VLPs and VP6. A VP6 dose-dependent adjuvant effect on GII.4-specific antibody responses was observed. The adjuvant effect was found to be strictly dependent upon co-administration of NoV GII.4 VLPs and VP6 at the same anatomic site and at the same time. However, the adjuvant effect was not dependent on the types of oligomers used, as both nanotubes and nanospheres exerted adjuvant effect on GII.4-specific antibody generation and, for the first time, T cell immunity. These findings elucidate the mechanisms of VP6 adjuvant effect in vivo and support its use as an adjuvant in a combination NoV and RV vaccine.
最近有人提出了一种基于诺如病毒（NoV）病毒样颗粒（VLPs）和轮状病毒（RV）VP6蛋白的亚单位蛋白疫苗候选物，用于预防儿童急性肠胃炎。RV VP6在体外表达时会形成不同的寡聚纳米结构，包括管状和球状，这些结构在不同动物模型中具有高度免疫原性。我们最近发现，重组VP6纳米管对小鼠体内NoV VLPs的免疫原性具有佐剂作用。在本研究中，我们调查了这种佐剂作用是否依赖于VP6剂量或不同的VP6结构组装形式。此外，还研究了局部和全身佐剂作用以及抗原共递送和共定位的要求。在用单独的GII.4 VLPs或VLPs与VP6的不同组合免疫的小鼠中，测试了NoV GII.4特异性抗体和T细胞反应的强度和功能。观察到VP6对GII.4特异性抗体反应具有剂量依赖性佐剂作用。发现这种佐剂作用严格依赖于NoV GII.4 VLPs和VP6在同一解剖部位同时共给药。然而，佐剂作用不依赖于所使用的寡聚体类型，因为纳米管和纳米球都对GII.4特异性抗体产生以及首次对T细胞免疫发挥了佐剂作用。这些发现阐明了VP6在体内的佐剂作用机制，并支持其作为佐剂用于NoV和RV联合疫苗。
