Brar Gurpreet, Farhat Nisar A, Sukhina Alisa, Lam Alex K, Kim Yong Hoon, Hsu Tiffany, Tong Leming, Lin Wai Wai, Ware Carl F, Blackman Marcia A, Sun Ren, Wu Ting-Ting
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, 90095, USA.
Laboratory of Molecular Immunology, Infectious and Inflammatory Diseases Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
NPJ Vaccines. 2020 Nov 5;5(1):102. doi: 10.1038/s41541-020-00251-x.
Vaccines based on live attenuated viruses often induce broad, multifaceted immune responses. However, they also usually sacrifice immunogenicity for attenuation. It is particularly difficult to elicit an effective vaccine for herpesviruses due to an armament of immune evasion genes and a latent phase. Here, to overcome the limitation of attenuation, we developed a rational herpesvirus vaccine in which viral immune evasion genes were deleted to enhance immunogenicity while also attaining safety. To test this vaccine strategy, we utilized murine gammaherpesvirus-68 (MHV-68) as a proof-of-concept model for the cancer-associated human γ-herpesviruses, Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus. We engineered a recombinant MHV-68 virus by targeted inactivation of viral antagonists of type I interferon (IFN-I) pathway and deletion of the latency locus responsible for persistent infection. This recombinant virus is highly attenuated with no measurable capacity for replication, latency, or persistence in immunocompetent hosts. It stimulates robust innate immunity, differentiates virus-specific memory T cells, and elicits neutralizing antibodies. A single vaccination affords durable protection that blocks the establishment of latency following challenge with the wild type MHV-68 for at least six months post-vaccination. These results provide a framework for effective vaccination against cancer-associated herpesviruses through the elimination of latency and key immune evasion mechanisms from the pathogen.
基于减毒活病毒的疫苗通常能诱导广泛、多方面的免疫反应。然而，它们通常也会为了减毒而牺牲免疫原性。由于存在一系列免疫逃避基因以及潜伏期，要研发出一种有效的疱疹病毒疫苗尤其困难。在此，为克服减毒的局限性，我们开发了一种合理的疱疹病毒疫苗，其中删除了病毒免疫逃避基因以增强免疫原性，同时确保安全性。为测试这种疫苗策略，我们利用鼠γ疱疹病毒68（MHV - 68）作为与癌症相关的人类γ疱疹病毒——爱泼斯坦 - 巴尔病毒和卡波西肉瘤相关疱疹病毒的概念验证模型。我们通过靶向失活I型干扰素（IFN - I）途径的病毒拮抗剂并删除负责持续感染的潜伏位点，构建了一种重组MHV - 68病毒。这种重组病毒高度减毒，在免疫健全的宿主中没有可测量的复制、潜伏或持续感染能力。它能刺激强大的先天免疫，分化出病毒特异性记忆T细胞，并引发中和抗体。单次接种可提供持久的保护，在接种疫苗后至少六个月内，能阻止野生型MHV - 68攻击后潜伏期的建立。这些结果为通过消除病原体的潜伏期和关键免疫逃避机制来有效接种针对与癌症相关的疱疹病毒的疫苗提供了一个框架。
