Intranasal delivery of Norwalk virus-like particles formulated in an in situ gelling, dry powder vaccine.
Intranasal delivery of Norwalk virus-like particles formulated in an in situ gelling, dry powder vaccine.
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DOI：
10.1016/j.vaccine.2011.05.027
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发表时间：
2011-07-18
期刊：
影响因子：
5.5
通讯作者：
Herbst-Kralovetz, Melissa M.
中科院分区：
文献类型：
--
作者：
Velasquez, Lissette S.;Shira, Samantha;Berta, Alice N.;Kilbourne, Jacquelyn;Medi, Babu M.;Tizard, Ian;Ni, Yawei;Arntzen, Charles J.;Herbst-Kralovetz, Melissa M.
关键词：
预防诺沃克病毒感染的疫苗的开发一直集中在黏膜表面的免疫接种上，但受到肠道或鼻腔表面自组装诺瓦克病毒样颗粒(NV VLP)低免疫原性的限制。鼻腔免疫提供了易于免疫的优势，但面临着正常的粘液纤毛清除过程施加的障碍，这限制了所应用抗原的停留时间。在此，我们描述了从芦荟中提取的惰性原位凝胶多糖(GelSite)的干粉配方(GelVac)用于NV VLP抗原的鼻腔输送。无论是否含有NV VLP抗原的粉末制剂，在干燥状态下或在模拟鼻液中复水时，结构都是相似的。将干粉VLP制剂与同等的抗原/佐剂液体制剂在动物体内的免疫原性进行了比较。对于GelVac粉末，我们观察到相对于液体制剂，NV特异性血清和粘膜(空气消化和生殖道)抗体反应更好。在干粉制剂中加入TLR7激动剂Gardiquimod并不能增强抗体反应，尽管在液体制剂中加入TLR7激动剂Gardiquimod确实能增强VLP的免疫原性，无论是否有GelSite。我们将这些数据解释为表明基于GelSite的干粉配方1。)稳定VLP和2的免疫原性结构特性。)诱导的全身和粘膜抗体效价等于或高于VLP加佐剂液体制剂的效价。我们的结论是，GelVac干粉制剂在鼻黏膜表面的原位凝胶化延迟了粘液纤毛的清除，从而延长了VLP抗原暴露在免疫效应部位的时间。
The development of a vaccine to prevent norovirus infections has been focused on immunization at a mucosal surface, but has been limited by the low immunogenicity of self-assembling Norwalk virus-like particles (NV VLPs) delivered enterically or at nasal surfaces. Nasal immunization, which offers the advantage of ease of immunization, faces obstacles imposed by the normal process of mucociliary clearance, which limits residence time of applied antigens. Herein, we describe the use of a dry powder formulation (GelVac) of an inert in-situ gelling polysaccharide (GelSite) extracted from Aloe vera for nasal delivery of NV VLP antigen. Powder formulations, with or without NV VLP antigen, were similar in structure in dry form or when rehydrated in simulated nasal fluids. Immunogenicity of the dry powder VLP formulation was compared to equivalent antigen/adjuvant liquid formulations in animals. For the GelVac powder, we observed superior NV-specific serum and mucosal (aerodigestive and reproductive tracts) antibody responses relative to liquid formulations. Incorporation of TLR7 agonist gardiquimod in dry powder formulations did not enhance antibody responses, although its inclusion in liquid formulations did enhance VLP immunogenicity irrespective of the presence or absence of GelSite. We interpret these data as showing that GelSite-based dry powder formulations 1.) stabilize the immunogenic structural properties of VLPs and 2.) induce systemic and mucosal antibody titers which are equal or greater than those achieved by VLPs plus adjuvant in a liquid formulation. We conclude that in-situ gelation of the GelVac dry powder formulation at nasal mucosal surfaces delays mucociliary clearance and thereby prolongs VLP antigen exposure to immune effector sites.
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