Envelope variation as a primary determinant of lentiviral vaccine efficacy
Envelope variation as a primary determinant of lentiviral vaccine efficacy
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DOI：
10.1073/pnas.0706449104
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发表时间：
2007-09-18
影响因子：
11.1
通讯作者：
Montelaro, Ronald C.
中科院分区：
文献类型：
--
作者：
Craigo, Jodi K.;Zhang, Baoshan;Montelaro, Ronald C.
慢病毒包膜抗原变异和相关的免疫逃避被认为是有效疫苗开发的主要障碍。尽管科学界普遍认为这一观点，但迄今为止，还没有严格的实验数据评估慢病毒Env变异水平增加对疫苗效力的影响。我们的工作假设是Env实际上是疫苗有效性的主要决定因素。我们以前报道过，一种成功的实验性马传染性贫血病毒减毒疫苗，来自病毒S2辅助基因的突变，提供100%的保护，从疾病后，强毒病毒的挑战。在这里，我们试图全面测试我们的假设，挑战接种疫苗的动物与前病毒株的定义，增加Env的变化，使用变异的包膜SU基因，自然出现在实验感染马传染性贫血病毒的小马。参考减毒疫苗与这些变异Env攻毒株组合有助于评价祖先免疫原赋予的保护，因为减毒疫苗的Env是变异前病毒株Env的直接祖先。结果表明，祖先Env蛋白没有赋予广泛水平的保护对抗攻击。此外，结果显示Env发散和疾病保护的显著负线性相关。这项研究表明了使用单一分离的祖先Env免疫原的潜在障碍。最后，这些发现揭示了相对较小的Env变异可以对慢病毒疫苗免疫性构成实质性挑战，即使使用迄今为止达到最高水平的疫苗保护的减毒疫苗。
Lentiviral envelope antigenic variation and associated immune evasion are believed to present major obstacles to effective vaccine development. Although this perception is widely assumed by the scientific community, there is, to date, no rigorous experimental data assessing the effect of increasing levels of lentiviral Env variation on vaccine efficacy. it is our working hypothesis that Env is, in fact, a primary determinant of vaccine effectiveness. We previously reported that a successful experimental attenuated equine infectious anemia virus vaccine, derived by mutation of the viral S2 accessory gene, provided 100% protection from disease after virulent virus challenge. Here, we sought to comprehensively test our hypothesis by challenging vaccinated animals with proviral strains of defined, increasing Env variation, using variant envelope SU genes that arose naturally during experimental infection of ponies with equine infectious anemia virus. The reference attenuated vaccine combined with these variant Env challenge strains facilitated evaluation of the protection conferred by ancestral immunogens, because the Env of the attenuated vaccine is a direct ancestor to the variant proviral strain Envs. The results demonstrated that ancestral Env proteins did not impart broad levels of protection against challenge. Furthermore, the results displayed a significant inverse linear correlation of Env divergence and protection from disease. This study demonstrates potential obstacles to the use of single isolate ancestral Env immunogens. Finally, these findings reveal that relatively minor Env variation can pose a substantial challenge to lentiviral vaccine immunity, even when attenuated vaccines are used that, to date, achieve the highest levels of vaccine protection.