Combination of three virus-derived nanoparticles as a vaccine against enteric pathogens; enterovirus, norovirus and rotavirus
Combination of three virus-derived nanoparticles as a vaccine against enteric pathogens; enterovirus, norovirus and rotavirus
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DOI：
10.1016/j.vaccine.2019.09.072
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发表时间：
2019-12-03
期刊：
影响因子：
5.5
通讯作者：
Blazevic, Vesna
中科院分区：
文献类型：
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作者：
Heinimaki, Suvi;Hankaniemi, Minna M.;Blazevic, Vesna
肠道病毒在儿童中引起多种感染，发病率和死亡率很高，轮状病毒（RV）和诺如病毒（NoV）是严重儿童胃肠炎的主要病原体。柯萨奇B型病毒（CVB）是一种常见的肠道病毒（EV），与新生儿严重CVB疾病的发病率增加有关，具有潜在的致命后果。为了预防大多数儿童胃肠炎，我们开发了一种由病毒样颗粒（vlp）和病毒寡聚物rVP6蛋白组成的非活病毒-病毒联合疫苗，可诱导小鼠对病毒和病毒的保护性免疫反应。此外，rVP6可作为NoV VLPs的佐剂。在这里，我们研究了通过添加来自EV CVB1的重组纳米颗粒，在候选的NoV-RV疫苗中加入第三种肠道病毒衍生抗原的可能性。为了检验EV-NoV-RV疫苗的免疫原性，我们用10 μ g CVB1 VLPs、GII.4 VLPs和rVP6纳米管分别或联合免疫BALB/c小鼠两次。为了评估rVP6对EV反应的辅助作用，小鼠接受0.3 μ g含或不含10 μ g rVP6的CVB1 VLPs。无论是单独给药还是联合给药，均检测出可比的血清IgG抗体。每种制剂产生IgG1和IgG2a抗体，表明混合Th2/ th1型反应。CVB1 VLPs的同型分布略微偏向IgG1亚型，而EV-NoV-RV联合疫苗诱导了对CVB1的无偏倚Th1/Th2反应。每种抗原还诱导T细胞介导的免疫，通过ifn - γ分泌来测量对体内特定刺激物的免疫。单抗原和联合制剂制备的抗血清对CVB1和NoV - gii也表现出较强的中和能力。此外，rVP6显示出对CVB1应答的辅助作用，节省了VLP剂量并使应答均匀化。最后，研究结果支持在候选的NoV-RV联合疫苗中加入额外的抗原来对抗严重的儿童感染，并证实了rVP6纳米结构的佐剂作用。(C) 2019作者。Elsevier Ltd.出版。
y Enteric viruses cause diverse infections with substantial morbidity and mortality in children, rotavirus (RV) and norovirus (NoV) being the leading agents of severe pediatric gastroenteritis. Coxsackie B viruses (CVB) are common enteroviruses (EV), associated with increased incidence of severe neonatal CVB disease with potentially fatal consequences. To prevent majority of childhood gastroenteritis, we have developed a non-live NoV-RV combination vaccine consisting of NoV virus-like particles (VLPs) and RV oligomeric rVP6 protein that induced protective immune responses to NoV and RV in mice. Moreover, rVP6 acted as an adjuvant for NoV VLPs. Here, we investigated a possibility to include a third enteric virus-derived antigen in the candidate NoV-RV vaccine, by adding recombinant nanoparticles derived from EV CVB1. To examine immunogenicity of EV-NoV-RV vaccine, BALB/c mice were immunized intramuscularly twice with 10 mu g CVB1 VLPs, GII.4 VLPs and rVP6 nanotubes, either separately or combined. To evaluate the adjuvant effect of rVP6 on EV responses, mice received 0.3 mu g CVB1 VLPs with or without 10 mu g rVP6. Comparable serum IgG antibodies were detected whether the antigens were administered separately or in combination. Each formulation generated IgG1 and IgG2a antibodies, indicating a mixed Th2/Th1-type response. CVB1 VLPs skewed the isotype distribution slightly towards IgG1 subtype, while EV-NoV-RV combination vaccine induced unbiased Th1/Th2 responses to CVB1. Each antigen also induced T cell mediated immunity measured by IFN-gamma secretion to specific stimulants ex vivo. Antisera raised by single antigens and combined formulation also exhibited strong neutralizing ability against CVB1 and NoV GII.4. Further, rVP6 showed an adjuvant effect on CVB1 responses, sparing the VLP dose and homogenizing the responses. Finally, the results support inclusion of additional antigens in the candidate NoV-RV combination vaccine to combat severe childhood infections and confirm adjuvant effect of rVP6 nanostructures. (C) 2019 The Authors. Published by Elsevier Ltd.