Immunization with a Vaccine Combining Herpes Simplex Virus 2 (HSV-2) Glycoprotein C (gC) and gD Subunits Improves the Protection of Dorsal Root Ganglia in Mice and Reduces the Frequency of Recurrent Vaginal Shedding of HSV-2 DNA in Guinea Pigs Compared to Immunization with gD Alone
Immunization with a Vaccine Combining Herpes Simplex Virus 2 (HSV-2) Glycoprotein C (gC) and gD Subunits Improves the Protection of Dorsal Root Ganglia in Mice and Reduces the Frequency of Recurrent Vaginal Shedding of HSV-2 DNA in Guinea Pigs Compared to Immunization with gD Alone
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DOI：
10.1128/jvi.00849-11
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发表时间：
2011-10-01
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;Lubinski, John M.;Friedman, Harvey M.
研制一种预防生殖器单纯疱疹病毒2型（HSV-2）疾病的疫苗的尝试只取得了微弱的成功，这表明需要新的策略。在小鼠和豚鼠中对单纯疱疹病毒-2糖蛋白C （gC-2）和gD-2免疫进行了评估，以确定将gC-2添加到gD-2亚单位疫苗中是否会通过产生阻断gC-2免疫逃避补体的抗体来提高保护作用。gC-2免疫产生的抗体阻断了gC-2与补体C3b之间的相互作用，并且gC-2抗体的被动转移保护补体完整小鼠而不是C3敲除小鼠对抗HSV-2的攻击，这表明gC-2抗体是有效的，至少在一定程度上，因为它阻止了HSV-2从补体中逃逸。gC-2免疫也能产生在补体缺失时具有活性的中和抗体；然而，当补体存在时，中和滴度更高，用两种抗原免疫的动物滴度最高。用gc -2 + gd -2组合免疫的动物对每种免疫原都有强大的CD4(+) t细胞反应。在单独接种gC-2、单独接种gD-2或同时接种两种抗原的小鼠和豚鼠中评估多种疾病参数。总体而言，gD-2优于gC-2；然而，gc -2 + gD-2组合优于单独gD-2，特别是在保护小鼠背根神经节和减少豚鼠HSV-2 DNA复发性阴道脱落方面。因此，gC-2亚单位抗原通过刺激CD4(+) t细胞应答、产生在补体缺失和存在时都有效的中和抗体以及阻断抑制补体激活的免疫逃避域来增强gD-2亚单位疫苗。
Attempts to develop a vaccine to prevent genital herpes simplex virus 2 (HSV-2) disease have been only marginally successful, suggesting that novel strategies are needed. Immunization with HSV-2 glycoprotein C (gC-2) and gD-2 was evaluated in mice and guinea pigs to determine whether adding gC-2 to a gD-2 subunit vaccine would improve protection by producing antibodies that block gC-2 immune evasion from complement. Antibodies produced by gC-2 immunization blocked the interaction between gC-2 and complement C3b, and passive transfer of gC-2 antibody protected complement-intact mice but not C3 knockout mice against HSV-2 challenge, indicating that gC-2 antibody is effective, at least in part, because it prevents HSV-2 evasion from complement. Immunization with gC-2 also produced neutralizing antibodies that were active in the absence of complement; however, the neutralizing titers were higher when complement was present, with the highest titers in animals immunized with both antigens. Animals immunized with the gC-2-plus-gD-2 combination had robust CD4(+) T-cell responses to each immunogen. Multiple disease parameters were evaluated in mice and guinea pigs immunized with gC-2 alone, gD-2 alone, or both antigens. In general, gD-2 outperformed gC-2; however, the gC-2-plus-gD-2 combination outperformed gD-2 alone, particularly in protecting dorsal root ganglia in mice and reducing recurrent vaginal shedding of HSV-2 DNA in guinea pigs. Therefore, the gC-2 subunit antigen enhances a gD-2 subunit vaccine by stimulating a CD4(+) T-cell response, by producing neutralizing antibodies that are effective in the absence and presence of complement, and by blocking immune evasion domains that inhibit complement activation.