Immunization by Replication-Competent Controlled Herpesvirus Vectors.
Immunization by Replication-Competent Controlled Herpesvirus Vectors.
复制标题
通过复制能力控制的疱疹病毒载体进行免疫。
DOI：
10.1128/jvi.00616-18
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发表时间：
2018-08-15
影响因子：
5.4
通讯作者：
Voellmy R
中科院分区：
文献类型：
--
作者：
Bloom DC;Tran RK;Feller J;Voellmy R
我们假设病原体的剧烈复制可能对于引发针对它的最有效和平衡的免疫反应至关重要。因此，应避免减毒/失活（如传统疫苗）。相反，应通过将病原体的复制置于严格控制下并通过严格地在病理无法发展的施用区域中激活病原体的限时复制来提供必要的安全性。然后，免疫接种将在高效病原体复制和不受影响的安全性的背景下进行。我们发现，在小鼠中局部激活具有复制能力的受控疱疹病毒载体的有效但有限的复制，导致对病毒或表达的异源抗原的免疫反应大大增强。这一发现支持了上述假设，并表明载体可能是值得探索的有前景的新型药物，用于预防/减轻缺乏有效疫苗接种的传染病，特别是在免疫功能低下的患者中。具有复制能力的受控病毒载体源自强毒力单纯疱疹病毒 1 (HSV-1) 野生型毒株 17syn+，将一或两个复制必需基因置于由热和抗孕激素共同激活的基因开关的严格控制下。基因开关激活后，载体在受感染的细胞中复制，其功效接近其来源的野生型病毒。在没有激活的情况下基本上不会发生复制。当对小鼠给药时，在全身性抗孕激素存在的情况下局部应用瞬时热处理会导致给药部位有效但有限的病毒复制。在小鼠足垫致死攻击模型中测试了这些病毒载体的免疫原性。未活化的病毒载体（可被视为灭活疫苗的等价物）诱导可检测到的保护，以防止野生型病毒攻击引起的致死性。病毒载体在给药部位（后足垫）的单次激活大大增强了保护性免疫反应，第二次免疫产生了完全保护。一旦激活，载体还能诱导比未激活载体更好的中和抗体和 HSV-1 特异性细胞免疫反应。为了查明异源抗原的免疫原性是否在有效的瞬时载体复制的情况下也得到增强，构建了组成型表达马流感病毒血凝素的病毒载体。用这种重组体免疫小鼠诱导了可检测的抗体介导的马流感病毒中和，以及血凝素特异性细胞免疫反应。病毒复制的单次激活导致这些免疫反应数倍增强。重要性我们假设病原体的活跃复制可能对于引发针对它的最有效和平衡的免疫反应至关重要。因此，应避免减毒/失活（如传统疫苗）。相反，应通过将病原体的复制置于严格控制下并通过严格地在病理无法发展的施用区域中激活病原体的限时复制来提供必要的安全性。然后，免疫接种将在高效病原体复制和不受影响的安全性的背景下进行。我们发现，在小鼠中局部激活具有复制能力的受控疱疹病毒载体的有效但有限的复制，导致对病毒或表达的异源抗原的免疫反应大大增强。这一发现支持了上述假设，并表明载体可能是值得探索的有前景的新型药物，用于预防/减轻缺乏有效疫苗接种的传染病，特别是在免疫功能低下的患者中。
We hypothesized that vigorous replication of a pathogen may be critical for eliciting the most potent and balanced immune response against it. Hence, attenuation/inactivation (as in conventional vaccines) should be avoided. Instead, the necessary safety should be provided by placing replication of the pathogen under stringent control and by activating time-limited replication of the pathogen strictly in an administration region in which pathology cannot develop. Immunization will then occur in the context of highly efficient pathogen replication and uncompromised safety. We found that localized activation in mice of efficient but limited replication of a replication-competent controlled herpesvirus vector resulted in a greatly enhanced immune response to the virus or an expressed heterologous antigen. This finding supports the above-mentioned hypothesis and suggests that the vectors may be promising novel agents worth exploring for the prevention/mitigation of infectious diseases for which efficient vaccination is lacking, in particular in immunocompromised patients. Replication-competent controlled virus vectors were derived from the virulent herpes simplex virus 1 (HSV-1) wild-type strain 17syn+ by placing one or two replication-essential genes under the stringent control of a gene switch that is coactivated by heat and an antiprogestin. Upon activation of the gene switch, the vectors replicate in infected cells with an efficacy that approaches that of the wild-type virus from which they were derived. Essentially no replication occurs in the absence of activation. When administered to mice, localized application of a transient heat treatment in the presence of systemic antiprogestin results in efficient but limited virus replication at the site of administration. The immunogenicity of these viral vectors was tested in a mouse footpad lethal challenge model. Unactivated viral vectors—which may be regarded as equivalents of inactivated vaccines—induced detectable protection against lethality caused by wild-type virus challenge. Single activation of the viral vectors at the site of administration (rear footpads) greatly enhanced protective immune responses, and a second immunization resulted in complete protection. Once activated, vectors also induced far better neutralizing antibody and HSV-1-specific cellular immune responses than unactivated vectors. To find out whether the immunogenicity of a heterologous antigen was also enhanced in the context of efficient transient vector replication, a virus vector constitutively expressing an equine influenza virus hemagglutinin was constructed. Immunization of mice with this recombinant induced detectable antibody-mediated neutralization of equine influenza virus, as well as a hemagglutinin-specific cellular immune response. Single activation of viral replication resulted in a severalfold enhancement of these immune responses. IMPORTANCE We hypothesized that vigorous replication of a pathogen may be critical for eliciting the most potent and balanced immune response against it. Hence, attenuation/inactivation (as in conventional vaccines) should be avoided. Instead, the necessary safety should be provided by placing replication of the pathogen under stringent control and by activating time-limited replication of the pathogen strictly in an administration region in which pathology cannot develop. Immunization will then occur in the context of highly efficient pathogen replication and uncompromised safety. We found that localized activation in mice of efficient but limited replication of a replication-competent controlled herpesvirus vector resulted in a greatly enhanced immune response to the virus or an expressed heterologous antigen. This finding supports the above-mentioned hypothesis and suggests that the vectors may be promising novel agents worth exploring for the prevention/mitigation of infectious diseases for which efficient vaccination is lacking, in particular in immunocompromised patients.