HCMV glycoprotein B subunit vaccine efficacy mediated by nonneutralizing antibody effector functions
HCMV glycoprotein B subunit vaccine efficacy mediated by nonneutralizing antibody effector functions
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DOI：
10.1073/pnas.1800177115
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发表时间：
2018-06-12
影响因子：
11.1
通讯作者：
Permar, Sallie R.
中科院分区：
文献类型：
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作者：
Nelson, Cody S.;Huffman, Tori;Permar, Sallie R.
人类巨细胞病毒（HCMV）是世界上最常见的先天性感染，经常导致患病婴儿的听力损失和脑损伤。预防孕妇在怀孕期间获得HCMV的疫苗对于降低婴儿疾病的发病率是必要的。糖蛋白B（gB）+MF 59佐剂亚单位疫苗平台是迄今为止测试的最成功的HCMV疫苗，在多项2期试验中证明在预防HCMV感染方面有接近50%的功效。然而，疫苗的保护机制仍然未知。对33名产后妇女gB/MF 59疫苗接种者在免疫原性峰值时的血浆进行gB表位特异性以及中和和非中和抗HCMV效应子功能检测，并与HCMV血清阳性队列进行比较。gB/MF 59疫苗接种引发IgG应答，其具有与自然感染相当的gB结合幅度和亲合力。此外，IgG亚类分布与gB疫苗接种和HCMV感染诱导的主要IgG 1和IgG 3应答相似。然而，疫苗引发的抗体表现出对自体病毒的有限中和，对多种异源毒株的可忽略中和，以及对中和抗体靶向的gB结构基序（包括AD-1、AD-2和结构域I）的有限结合应答。疫苗接种者对AD-3线性表位有高幅度的IgG应答，证明了对这种非中和性胞质区域的免疫优势。最后，疫苗引起的IgG强烈结合的转染或HCMV感染的细胞表面上的膜相关的gB和介导的病毒体吞噬作用，虽然是NK细胞活化的不良介质。总之，这些数据表明，非中和抗体功能，包括病毒体吞噬作用，可能在观察到的50%疫苗介导的抗HCMV感染保护中发挥了作用。
Human cytomegalovirus (HCMV) is the most common congenital infection worldwide, frequently causing hearing loss and brain damage in afflicted infants. A vaccine to prevent maternal acquisition of HCMV during pregnancy is necessary to reduce the incidence of infant disease. The glycoprotein B (gB) + MF59 adjuvant subunit vaccine platform is the most successful HCMV vaccine tested to date, demonstrating similar to 50% efficacy in preventing HCMV acquisition in multiple phase 2 trials. However, the mechanism of vaccine protection remains unknown. Plasma from 33 postpartum women gB/MF59 vaccinees at peak immunogenicity was tested for gB epitope specificity as well as neutralizing and nonneutralizing anti-HCMV effector functions and compared with an HCMV-seropositive cohort. gB/MF59 vaccination elicited IgG responses with gB-binding magnitude and avidity comparable to natural infection. Additionally, IgG subclass distribution was similar with predominant IgG1 and IgG3 responses induced by gB vaccination and HCMV infection. However, vaccine-elicited antibodies exhibited limited neutralization of the autologous virus, negligible neutralization of multiple heterologous strains, and limited binding responses against gB structural motifs targeted by neutralizing antibodies including AD-1, AD-2, and domain I. Vaccinees had high-magnitude IgG responses against AD-3 linear epitopes, demonstrating immunodominance against this nonneutralizing, cytosolic region. Finally, vaccine-elicited IgG robustly bound membrane-associated gB on the surface of transfected or HCMV-infected cells and mediated virion phagocytosis, although were poor mediators of NK cell activation. Altogether, these data suggest that nonneutralizing antibody functions, including virion phagocytosis, likely played a role in the observed 50% vaccine-mediated protection against HCMV acquisition.