Heterosubtypic, cross-reactive immunity to human Cytomegalovirus glycoprotein B.
Heterosubtypic, cross-reactive immunity to human Cytomegalovirus glycoprotein B.
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对人巨细胞病毒糖蛋白 B 的异亚型交叉反应免疫。
DOI：
10.1093/cei/uxac031
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发表时间：
2022
影响因子：
4.6
通讯作者：
Steininger,Christoph
中科院分区：
文献类型：
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作者：
Bilgilier,Ceren;Schneider,Martina;Kührer,Kristina;Kilb,Normann;Hartl,Ramona;Topakian,Thais;Kastner,Marie-Theres;Herz,Tobias;Nelson,CodyS;Permar,SallieR;Roth,Günter;Steininger,Christoph
巨细胞病毒（CMV）基因组高度可变，在疫苗开发中应考虑异亚型免疫，因为它可以以交叉反应的方式增强保护。在这里，我们开发了一种蛋白阵列来评估自然感染和疫苗接种中对CMV糖蛋白B（gB）的异亚型免疫。从6株参考毒株和12株临床CMV毒株中扩增gB的4个抗原结构域（AD 1、AD 2、AD 4/5和AD 5）的DNA序列，通过系统发育分析确定最具差异的基因型。体外翻译并固定在蛋白质阵列上。然后，我们用蛋白质原位阵列（比萨）检测了不同血清组（初次感染的患者、再激活的CMV感染者和潜伏CMV感染的健康个体以及gB疫苗接种的兔）的免疫应答。所有患者队列和gB疫苗接种兔的血清抗体识别蛋白阵列上AD的许多遗传变体，包括但不限于感染菌株的亚型。观察到高度交叉反应性。在一些患者中，我们观察到对AD 1和AD 2没有或可忽略的免疫应答，而相同的患者对AD 4/5和AD 5显示出高抗体应答。在初次感染的患者中，抗体应答以AD 5为主。迄今为止最成功的CMV疫苗含有gB，并且仅显示50%的功效。在这项研究中，我们发现，异亚型和交叉反应免疫CMV gB是广泛的。因此，CMV gB疫苗的失败不能用高度株特异性免疫来解释。我们的观察结果表明，其他CMV抗原应在疫苗设计中加以解决。
Cytomegalovirus (CMV) genome is highly variable and heterosubtypic immunity should be considered in vaccine development since it can enhance protection in a cross-reactive manner. Here, we developed a protein array to evaluate heterosubtypic immunity to CMV glycoprotein B (gB) in natural infection and vaccination. DNA sequences of four antigenic domains (AD1, AD2, AD4/5, and AD5) of gB were amplified from six reference and 12 clinical CMV strains, and the most divergent genotypes were determined by phylogenetic analysis. Assigned genotypes werein vitrotranslated and immobilized on protein array. Then, we tested immune response of variable serum groups (primarily infected patients, reactivated CMV infections and healthy individuals with latent CMV infection, as well gB-vaccinated rabbits) with proteinin situarray (PISA). Serum antibodies of all patient cohorts and gB-vaccinated rabbits recognized many genetic variants of ADs on protein array, including but not limited to the subtype of infecting strain. High-grade cross-reactivity was observed. In several patients, we observed none or neglectable immune response to AD1 and AD2, while the same patients showed high antibody response to AD4/5 and AD5. Among the primary infected patients, AD5 was the predominant AD, in antibody response. The most successful CMV vaccine to date contains gB and demonstrates only 50% efficacy. In this study, we showed that heterosubtypic and cross-reactive immunity to CMV gB is extensive. Therefore, the failure of CMV gB vaccines cannot be explained by a highly, strain-specific immunity. Our observations suggest that other CMV antigens should be addressed in vaccine design.