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首页> 外文学位 >Linking Humoral Immunity to Protective Herpes Simplex Viral Vaccines: Is Sterilizing Immunity Achievable?.
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Linking Humoral Immunity to Protective Herpes Simplex Viral Vaccines: Is Sterilizing Immunity Achievable?.

机译：将体液免疫与保护性单纯疱疹病毒疫苗相关联：可以实现灭菌免疫吗？

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摘要

Human herpes simplex viruses (HSV) type 1 and type 2 are a continued global burden with worldwide HSV-2 prevalence >500 million. Furthermore, epidemiological studies consistently demonstrate that HSV-2 is associated with an increased risk of acquiring and transmitting HIV-1. Currently, there is no effective cure or vaccine against HSV infection.;Past HSV vaccines focused on subunit formulations designed to elicit neutralizing antibodies targeting the envelope glycoprotein D (gD). While these vaccines elicited high levels of neutralizing antibodies in animals and humans, they failed to protect against HSV-2 infections in clinical trials. This lack of correlation between neutralizing Abs and HSV protection led to the hypothesis that a vaccine that elicits multi-functional antibodies engaging Fcgamma-receptors may provide greater protection than neutralization alone, serving as an immune-correlate. To test this hypothesis we 1) genetically engineered HSV virions as a live single-cycle viral vaccine deleted in gD and assessed this vaccine to generate Fc effector antibodies and efficacy against murine HSV infections, and 2) characterizing the functionality of local HSV antibodies from a cohort of HSV and HSV/HIV infected individuals that can control outbreaks (asymptomatic) vs individuals that cannot (symptomatic).;We first engineered an HSV-2 virus deleted for gD (DeltagD -2). Subcutaneous immunization of mice with DeltagD-2 provided 100% protection against lethal challenges of clinical HSV-1 and HSV-2 isolates as well as prevented the establishment of latency. Notably, mice immunized with HSV-2 DeltagD-2 elicited high HSV-specific antibodies that were weakly neutralizing but possessed antibody-dependent-cellular cytotoxicity and phagocytosis functions. Passive transfer of Deltag D-2 immune serum completely protected wild-type, but not Fcgamma-receptor knock-out mice. Secondly, when measuring mucosal HSV specific antibodies from clinically asymptomatic vs symptomatic individuals, we observed a marked difference in neutralization in asymptomatic individuals compared to symptomatic individuals. When isotyped, asymptomatic individuals had elevated IgG3 HSV specific antibodies which are consistent with antibodies that can engage Fcgamma-receptors.;These studies challenge the dogma that neutralizing antibodies are crucial for HSV containment. We show that non-neutralizing Fc effector activating antibodies can be used as a surrogate marker for immunity as seen in mice via vaccination and in clinical samples.
机译：1型和2型人类单纯疱疹病毒（HSV）是持续的全球负担，全球HSV-2流行率超过5亿。此外，流行病学研究始终表明，HSV-2与增加感染和传播HIV-1的风险有关。目前，尚无针对HSV感染的有效治愈方法或疫苗。过去的HSV疫苗侧重于旨在引发针对包膜糖蛋白D（gD）的中和抗体的亚基制剂。尽管这些疫苗在动物和人类中引起高水平的中和抗体，但它们在临床试验中未能预防HSV-2感染。中和抗体和HSV保护之间缺乏相关性，导致了这样一个假说，即引发与Fcγ受体结合的多功能抗体的疫苗可能比单独的中和提供更大的保护，从而起到免疫相关作用。为了验证这一假设，我们1）将基因工程化的HSV病毒体作为在gD中缺失的活单周期病毒疫苗，并评估了该疫苗以产生Fc效应子抗体和抗鼠HSV感染的功效，以及2）表征来自当地的HSV抗体的功能能够控制暴发（无症状）和无法控制（无症状）的HSV和HSV / HIV感染者的队列。我们首先设计了缺失gD的HSV-2病毒（DeltagD -2）。用DeltagD-2进行的小鼠皮下免疫为临床HSV-1和HSV-2分离株的致命攻击提供了100％的保护，并防止了潜伏期的建立。值得注意的是，用HSV-2 DeltagD-2免疫的小鼠引起了高HSV特异性抗体，该抗体弱中和但具有抗体依赖性细胞毒性和吞噬功能。 Deltag D-2免疫血清的被动转移可以完全保护野生型小鼠，但不能保护Fcγ受体敲除小鼠。其次，当从临床上无症状的人和有症状的人中测量粘膜HSV特异性抗体时，我们观察到无症状的人与有症状的人相比中和作用存在显着差异。同种型时，无症状个体的IgG3 HSV特异性抗体升高，与可与Fcγ受体结合的抗体一致。这些研究挑战教条，即中和抗体对于遏制HSV至关重要。我们显示非中和性Fc效应子激活抗体可以用作免疫的替代标志物，如通过疫苗接种的小鼠和临床样品中所见。

著录项

  • 作者

    Petro, Christopher Daniel.;

  • 作者单位

    Yeshiva University.;

  • 授予单位 Yeshiva University.;
  • 学科 Microbiology.;Virology.;Biology.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 203 p.
  • 总页数 203
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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