Vaccine-Derived Neutralizing Antibodies to the Human Cytomegalovirus gH/gL Pentamer Potently Block Primary Cytotrophoblast Infection
Vaccine-Derived Neutralizing Antibodies to the Human Cytomegalovirus gH/gL Pentamer Potently Block Primary Cytotrophoblast Infection
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DOI：
10.1128/jvi.01701-15
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发表时间：
2015-12-01
影响因子：
5.4
通讯作者：
Diamond, Don J.
中科院分区：
文献类型：
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作者：
Chiuppesi, Flavia;Wussow, Felix;Diamond, Don J.
人巨细胞病毒(HCMV)可诱导不同效价和细胞类型特异性的中和抗体(NAB)，以阻止HCMV进入成纤维细胞(FB)和上皮/内皮细胞(EPC/ENC)。针对主要的基本包膜糖蛋白复合体Gb和Gh/gl的NAB抑制Fb和EPC/ENC的进入。与FB感染不同的是，HCMV进入EPC/ENC还被Gh/G1/UL128/130/131A五聚体复合体(PC)构象表位的极强的NAB所阻止。我们最近开发了一种疫苗概念，称为MVA-PC，它是基于单个修改的痘苗病毒安卡拉(MVA)载体共表达所有五个PC亚基。用MVA-PC免疫小鼠和恒河猴，可产生高滴度和持续的NAB，可阻断EPC/ENC感染，而低滴度NAB可抑制FB进入。然而，MVA-PC疫苗诱导中和活性的抗体功能尚未确定。在这里，我们证明了MVA-PC诱导的NAB具有细胞类型特异性的中和效力和抗原识别模式，类似于针对UL128/130/131a亚单位或Gh的构象和线性表位的人NAB。此外，我们还发现，疫苗来源的PC特异性NAB比抗Gh NAB显著更有效地防止HCMV在EPC中的传播和人胎盘细胞滋养层细胞的感染，这两种细胞类型被认为是将HCMV传播到胎儿的关键。这些发现进一步证实了MVA-PC是一种临床候选疫苗，可以诱导类似于HCMV感染期间诱导的NAB，并为PC特异性NAB干扰HCMV细胞相关传播和关键胎盘细胞感染的效力提供了有价值的见解。由于人类巨细胞病毒(HCMV)在导致永久性出生缺陷中的主导作用，开发一种针对HCMV的疫苗已被指定为主要的公共卫生优先事项。我们最近推出了一种疫苗策略，该疫苗基于广泛使用的、安全的和特征良好的痘病毒载体平台，以诱导针对HCMV包膜五聚体复合体(PC)的强大和持久的中和抗体(NAB)反应，PC被认为是预防先天性HCMV感染的疫苗的关键组成部分。通过这项工作，我们证实了疫苗载体诱导的NAB具有与从慢性感染HCMV的个体分离的人NAB相似的特性。此外，我们发现针对PC的NAB具有很强的防止感染关键胎盘细胞的能力，HCMV利用这些细胞穿过胎儿-母体界面，提示针对PC的NAB可能是防止HCMV垂直传播的关键。
Human cytomegalovirus (HCMV) elicits neutralizing antibodies (NAb) of various potencies and cell type specificities to prevent HCMV entry into fibroblasts (FB) and epithelial/endothelial cells (EpC/EnC). NAb targeting the major essential envelope glycoprotein complexes gB and gH/gL inhibit both FB and EpC/EnC entry. In contrast to FB infection, HCMV entry into EpC/EnC is additionally blocked by extremely potent NAb to conformational epitopes of the gH/gL/UL128/130/131A pentamer complex (PC). We recently developed a vaccine concept based on coexpression of all five PC subunits by a single modified vaccinia virus Ankara (MVA) vector, termed MVA-PC. Vaccination of mice and rhesus macaques with MVA-PC resulted in a high titer and sustained NAb that blocked EpC/EnC infection and lower-titer NAb that inhibited FB entry. However, antibody function responsible for the neutralizing activity induced by the MVA-PC vaccine is uncharacterized. Here, we demonstrate that MVA-PC elicits NAb with cell type-specific neutralization potency and antigen recognition pattern similar to human NAb targeting conformational and linear epitopes of the UL128/130/131A subunits or gH. In addition, we show that the vaccine-derived PC-specific NAb are significantly more potent than the anti-gH NAb to prevent HCMV spread in EpC and infection of human placental cytotrophoblasts, cell types thought to be of critical importance for HCMV transmission to the fetus. These findings further validate MVA-PC as a clinical vaccine candidate to elicit NAb that resembles those induced during HCMV infection and provide valuable insights into the potency of PC-specific NAb to interfere with HCMV cell-associated spread and infection of key placental cells.IMPORTANCEAs a consequence of the leading role of human cytomegalovirus (HCMV) in causing permanent birth defects, developing a vaccine against HCMV has been assigned a major public health priority. We have recently introduced a vaccine strategy based on a widely used, safe, and well-characterized poxvirus vector platform to elicit potent and durable neutralizing antibody (NAb) responses targeting the HCMV envelope pentamer complex (PC), which has been suggested as a critical component for a vaccine to prevent congenital HCMV infection. With this work, we confirm that the NAb elicited by the vaccine vector have properties that are similar to those of human NAb isolated from individuals chronically infected with HCMV. In addition, we show that PC-specific NAb have potent ability to prevent infection of key placental cells that HCMV utilizes to cross the fetal-maternal interface, suggesting that NAb targeting the PC may be essential to prevent HCMV vertical transmission.