Redundancy and plasticity of neutralizing antibody responses are cornerstone attributes of the human immune response to the smallpox vaccine
Redundancy and plasticity of neutralizing antibody responses are cornerstone attributes of the human immune response to the smallpox vaccine
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DOI：
10.1128/jvi.02244-07
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发表时间：
2008-04-01
影响因子：
5.4
通讯作者：
Crotty, Shane
中科院分区：
文献类型：
--
作者：
Benhnia, Mohammed Rafii-El-Idrissi;McCausland, Megan M.;Crotty, Shane
天花疫苗被广泛认为是人类疫苗的黄金标准，但人类的关键抗体靶点仍不清楚。本研究旨在鉴定一种定型的、显性的、成熟的病毒粒子（MV）中和抗体靶点，该靶点可作为诊断天花疫苗（VACV）诱导的保护性不道德免疫的血清学标志物。相反，我们发现多样性是人类抗体对天花疫苗反应的一个决定性特征。我们表明，H3是最免疫显性的VACV中和抗体的目标，确定通过相关性分析的免疫球蛋白G（IgG）特异性MV中和抗体滴度。经测定，纯化的人抗H3 IgG足以中和VACV;然而，抗H3抗体的消耗或阻断显示中和活性无显著降低，表明接种疫苗的人（或小鼠）不需要抗H3 IgG来中和MV。对于人（和小鼠）抗L1 IgG，甚至抗H3和抗L1 IgG的组合，获得了相当的结果。除H3和L1外，对D8、A27、D13和A14的人抗体应答与病毒中和表现出统计学显著相关性。总之，这些数据表明天花疫苗成功地产生了强烈的中和抗体应答，不是通过引发对单一关键抗原的定型应答，而是通过驱动针对多种病毒蛋白的中和抗体的发展，从而产生高度冗余的中和抗体应答的“安全网”，其特异性可能因个体而异。我们认为这是天花疫苗的一个基本属性。
The smallpox vaccine is widely considered the gold standard for human vaccines, yet the key antibody targets in humans remain unclear. We endeavored to identify a stereotypic, dominant, mature virion (MV) neutralizing antibody target in humans which could be used as a diagnostic serological marker of protective Immoral immunity induced by the smallpox vaccine (vaccinia virus [VACV]). We have instead found that diversity is a defining characteristic of the human antibody response to the smallpox vaccine. We show that H3 is the most immunodominant VACV neutralizing antibody target, as determined by correlation analysis of immunoglobulin G (IgG) specificities to MV neutralizing antibody titers. It was determined that purified human anti-H3 IgG is sufficient for neutralization of VACV; however, depletion or blockade of anti-H3 antibodies revealed no significant reduction in neutralization activity, showing anti-H3 IgG is not required in vaccinated humans (or mice) for neutralization of MV. Comparable results were obtained for human (and mouse) anti-L1 IgG and even for anti-H3 and anti-L1 IgG in combination. In addition to H3 and L1, human antibody responses to D8, A27, D13, and A14 exhibited statistically significant correlations with virus neutralization. Altogether, these data indicate the smallpox vaccine succeeds in generating strong neutralizing antibody responses not by eliciting a stereotypic response to a single key antigen but instead by driving development of neutralizing antibodies to multiple viral proteins, resulting in a "safety net" of highly redundant neutralizing antibody responses, the specificities of which can vary from individual to individual. We propose that this is a fundamental attribute of the smallpox vaccine.