Jarmer Johanna, Zlatkovic Jürgen, Tsouchnikas Georgios, Vratskikh Oksana, Strauß Judith, Aberle Judith H, Chmelik Vaclav, Kundi Michael, Stiasny Karin, Heinz Franz X
Department of Virology, Medical University of Vienna, Vienna, Austria.
Hospital Ceske Budejovice, Department of Infectious Diseases, Ceske Budejovice, Czech Republic.
J Virol. 2014 Dec;88(23):13845-57. doi: 10.1128/JVI.02086-14. Epub 2014 Sep 24.
Tick-borne encephalitis (TBE) virus is an important human-pathogenic flavivirus endemic in large parts of Europe and Central and Eastern Asia. Neutralizing antibodies specific for the viral envelope protein E are believed to mediate long-lasting protection after natural infection and vaccination. To study the specificity and individual variation of human antibody responses, we developed immunoassays with recombinant antigens representing viral surface protein domains and domain combinations. These allowed us to dissect and quantify antibody populations of different fine specificities in sera of TBE patients and vaccinees. Postinfection and postvaccination sera both displayed strong individual variation of antibody titers as well as the relative proportions of antibodies to different domains of E, indicating that the immunodominance patterns observed were strongly influenced by individual-specific factors. The contributions of these antibody populations to virus neutralization were quantified by serum depletion analyses and revealed a significantly biased pattern. Antibodies to domain III, in contrast to what was found in mouse immunization studies with TBE and other flaviviruses, did not play any role in the human neutralizing antibody response, which was dominated by antibodies to domains I and II. Importantly, most of the neutralizing activity could be depleted from sera by a dimeric soluble form of the E protein, which is the building block of the icosahedral herringbone-like shell of flaviviruses, suggesting that antibodies to more complex quaternary epitopes involving residues from adjacent dimers play only a minor role in the total response to natural infection and vaccination in humans.
Tick-borne encephalitis (TBE) virus is a close relative of yellow fever, dengue, Japanese encephalitis, and West Nile viruses and distributed in large parts of Europe and Central and Eastern Asia. Antibodies to the viral envelope protein E prevent viral attachment and entry into cells and thus mediate virus neutralization and protection from disease. However, the fine specificity and individual variation of neutralizing antibody responses are currently not known. We have therefore developed new in vitro assays for dissecting the antibody populations present in blood serum and determining their contribution to virus neutralization. In our analysis of human postinfection and postvaccination sera, we found an extensive variation of the antibody populations present in sera, indicating substantial influences of individual-specific factors that control the specificity of the antibody response. Our study provides new insights into the immune response to an important human pathogen that is of relevance for the design of novel vaccines.
蜱传脑炎（TBE）病毒是一种重要的人类致病性黄病毒，在欧洲大部分地区以及中亚和东亚流行。据信，针对病毒包膜蛋白E的中和抗体在自然感染和接种疫苗后介导持久的保护作用。为了研究人类抗体反应的特异性和个体差异，我们开发了免疫测定法，使用代表病毒表面蛋白结构域和结构域组合的重组抗原。这使我们能够剖析和量化TBE患者和疫苗接种者血清中不同精细特异性的抗体群体。感染后和接种疫苗后的血清均显示出抗体滴度以及针对E不同结构域的抗体相对比例的强烈个体差异，表明观察到的免疫优势模式受到个体特异性因素的强烈影响。通过血清去除分析对这些抗体群体对病毒中和的贡献进行了量化，结果显示出明显的偏差模式。与在TBE和其他黄病毒的小鼠免疫研究中发现的情况相反，针对结构域III的抗体在人类中和抗体反应中未发挥任何作用，该反应主要由针对结构域I和II的抗体主导。重要的是，大部分中和活性可以通过E蛋白的二聚体可溶性形式从血清中去除，E蛋白是黄病毒二十面体人字形外壳的构建块，这表明针对涉及相邻二聚体残基的更复杂四级表位的抗体在人类对自然感染和疫苗接种的总体反应中仅起次要作用。
蜱传脑炎（TBE）病毒是黄热病、登革热、日本脑炎和西尼罗河病毒的近亲，分布于欧洲大部分地区以及中亚和东亚。针对病毒包膜蛋白E的抗体可防止病毒附着并进入细胞，从而介导病毒中和并预防疾病。然而，目前尚不清楚中和抗体反应的精细特异性和个体差异。因此，我们开发了新的体外测定法，用于剖析血清中存在的抗体群体并确定它们对病毒中和的贡献。在我们对人类感染后和接种疫苗后血清的分析中，我们发现血清中存在的抗体群体存在广泛差异，表明控制抗体反应特异性的个体特异性因素具有重大影响。我们的研究为针对一种重要人类病原体的免疫反应提供了新见解，这对于新型疫苗的设计具有重要意义。
