Blocking Herpes Simplex Virus 2 Glycoprotein E Immune Evasion as an Approach To Enhance Efficacy of a Trivalent Subunit Antigen Vaccine for Genital Herpes
Blocking Herpes Simplex Virus 2 Glycoprotein E Immune Evasion as an Approach To Enhance Efficacy of a Trivalent Subunit Antigen Vaccine for Genital Herpes
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DOI：
10.1128/jvi.01130-14
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发表时间：
2014-08-01
影响因子：
5.4
通讯作者：
Friedman, Harvey M.
中科院分区：
文献类型：
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作者：
Awasthi, Sita;Huang, Jialing;Friedman, Harvey M.
针对病毒进入分子的单纯疱疹病毒2 （HSV-2）亚单位抗原疫苗在人体试验中未能预防生殖器疱疹。我们的方法是包含一个病毒进入分子，并添加阻止HSV-2免疫逃避的抗原。HSV-2糖蛋白C （gC2）是一种抑制补体的免疫逃避分子。我们以前报道过，在小鼠和豚鼠中，与单独使用任何一种抗原相比，将gC2加入gD2可以提高疫苗的效力。在这里，我们证明了HSV-2糖蛋白E （gE2）通过结合IgG Fc结构域作为免疫逃避分子。HSV-2 gE2与gC2协同保护病毒免受抗体和补体中和。用gE2免疫产生的抗体阻断了gE2介导的IgG Fc结合和细胞间扩散。gE2免疫小鼠对HSV-2阴道攻击仅部分保护；然而，当将gE2加入gC2/gD2中形成三价疫苗时，有补体和没有补体的中和抗体滴度明显高于单独由gD2产生的中和抗体滴度。重要的是，三价疫苗在攻击后第2天至第7天保护了32/33（97%）小鼠的背根神经节（DRG），而gD2组为27/33（82%）。三价疫苗免疫小鼠的HSV-2 DNA拷贝数明显低于单纯gD2免疫小鼠。使用三价疫苗对DRG的保护程度优于我们先前报道的gC2/gD2免疫。因此，gE2是一种候选抗原，可用于试图阻断HSV-2免疫逃逸的多价亚单位疫苗。在世界范围内，单纯疱疹病毒是引起生殖器溃疡的最常见原因。感染会给感染者及其伴侣带来情绪困扰，对分娩期间接触疱疹的婴儿构成生命威胁，并大大增加个人感染和传播艾滋病毒的风险。预防生殖器疱疹感染的疫苗将对公共卫生产生重大益处。我们的疫苗方法包括防止病毒逃避免疫攻击的策略。小鼠接种了三价疫苗，其中含有一种抗原，可诱导抗体阻止病毒进入，两种抗原可诱导抗体阻止抗体和补体的免疫逃逸。经免疫的小鼠未出现生殖器疾病，32/33（97%）的动物未出现背根神经节感染的证据，这表明疫苗可预防潜伏性和复发性感染的建立。
Herpes simplex virus 2 (HSV-2) subunit antigen vaccines targeting virus entry molecules have failed to prevent genital herpes in human trials. Our approach is to include a virus entry molecule and add antigens that block HSV-2 immune evasion. HSV-2 glycoprotein C (gC2) is an immune evasion molecule that inhibits complement. We previously reported that adding gC2 to gD2 improved vaccine efficacy compared to the efficacy of either antigen alone in mice and guinea pigs. Here we demonstrate that HSV-2 glycoprotein E (gE2) functions as an immune evasion molecule by binding the IgG Fc domain. HSV-2 gE2 is synergistic with gC2 in protecting the virus from antibody and complement neutralization. Antibodies produced by immunization with gE2 blocked gE2-mediated IgG Fc binding and cell-to-cell spread. Mice immunized with gE2 were only partially protected against HSV-2 vaginal challenge in mice; however, when gE2 was added to gC2/gD2 to form a trivalent vaccine, neutralizing antibody titers with and without complement were significantly higher than those produced by gD2 alone. Importantly, the trivalent vaccine protected the dorsal root ganglia (DRG) of 32/33 (97%) mice between days 2 and 7 postchallenge, compared with 27/33 (82%) in the gD2 group. The HSV-2 DNA copy number was significantly lower in mice immunized with the trivalent vaccine than in those immunized with gD2 alone. The extent of DRG protection using the trivalent vaccine was better than what we previously reported for gC2/gD2 immunization. Therefore, gE2 is a candidate antigen for inclusion in a multivalent subunit vaccine that attempts to block HSV-2 immune evasion.IMPORTANCEHerpes simplex virus is the most common cause of genital ulcer disease worldwide. Infection results in emotional distress for infected individuals and their partners, is life threatening for infants exposed to herpes during childbirth, and greatly increases the risk of individuals acquiring and transmitting HIV infection. A vaccine that prevents genital herpes infection will have major public health benefits. Our vaccine approach includes strategies to prevent the virus from evading immune attack. Mice were immunized with a trivalent vaccine containing an antigen that induces antibodies to block virus entry and two antigens that induce antibodies that block immune evasion from antibody and complement. Immunized mice demonstrated no genital disease, and 32/33 (97%) animals had no evidence of infection of dorsal root ganglia, suggesting that the vaccine may prevent the establishment of latency and recurrent infections.