Vaccine-Induced Control of Viral Shedding following Rhesus Cytomegalovirus Challenge in Rhesus Macaques
Vaccine-Induced Control of Viral Shedding following Rhesus Cytomegalovirus Challenge in Rhesus Macaques
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DOI：
10.1128/jvi.00883-10
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发表时间：
2011-03-01
影响因子：
5.4
通讯作者：
Barry, Peter A.
中科院分区：
文献类型：
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作者：
Abel, Kristina;Martinez, Joy;Barry, Peter A.
利用人巨细胞病毒(HCMV)感染的动物模型是完善HCMV候选疫苗的关键。已有报道表明，恒河猴对恒河猴巨细胞病毒(RhCMV)的免疫可以减少实验性RhCMV攻击后的局部和系统复制。这些研究使用了单独的DNA表达质粒的PRIME/BOOST组合，或者使用灭活的病毒粒子或表达相同抗原的改良痘苗病毒安卡拉(MVA)的DNA启动和增强。病毒结果包括皮下接种部位的RhCMV复制减少和静脉接种后的RhCMV病毒血症。由于巨细胞病毒从粘膜表面的脱落是病毒水平传播的关键，DNA启动/MVA增强接种被评估了在皮下攻击后减少口腔中巨细胞病毒脱落的能力。在六只单独接种RhCMV糖蛋白B(GB)、磷酸蛋白65(Pp65)和即刻早期1(IE1)的恒河猴中，一半的唾液中的病毒载量比对照猴子低1到3个数量级。此外，在表现出最大程度减少口腔脱落的动物中，攻击后记忆pp65 T细胞反应有很强的相关性。这些结果强调了这样一个事实，即DNA/MVA疫苗接种方案可以显著降低挑战后病毒复制的关键参数。最近完成的GB亚单位疫苗的临床试验表明，在接种疫苗的个体中，人巨细胞病毒感染率降低了50%，这与这项研究的结果一致，表明额外的免疫原可能是最大限度地保护异种繁殖的人类种群所必需的。
The use of animal models of human cytomegalovirus (HCMV) infection is critical to refine HCMV vaccine candidates. Previous reports have demonstrated that immunization of rhesus monkeys against rhesus cytomegalovirus (RhCMV) can reduce both local and systemic replication of RhCMV following experimental RhCMV challenge. These studies used prime/boost combinations of DNA expression plasmids alone or DNA priming and boosting with either inactivated virion particles or modified vaccinia virus Ankara (MVA) expressing the same antigens. Viral outcomes included reduced RhCMV replication at the site of subcutaneous inoculation and RhCMV viremia following intravenous inoculation. Since shedding of cytomegalovirus from mucosal surfaces is critical for horizontal transmission of the virus, DNA priming/MVA boosting was evaluated for the ability to reduce oral shedding of RhCMV following subcutaneous challenge. Of six rhesus monkeys vaccinated exclusively against RhCMV glycoprotein B (gB), phosphoprotein 65 (pp65), and immediate-early 1 (IE1), half showed viral loads in saliva that were lower than those of control monkeys by 1 to 3 orders of magnitude. Further, there was a strong association of memory pp65 T cell responses postchallenge in animals exhibiting the greatest reduction in oral shedding. These results highlight the fact that a DNA/MVA vaccination regimen can achieve a notable reduction in a critical parameter of viral replication postchallenge. The recently completed clinical trial of a gB subunit vaccine in which the rate of HCMV infection was reduced by 50% in the individuals receiving the vaccine is consistent with the results of this study suggesting that additional immunogens are likely essential for maximum protection in an outbred human population.