Arthropod-Borne and Infectious Disease Laboratory, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, USA.
J Virol. 2014 Feb;88(3):1771-80. doi: 10.1128/JVI.02297-13. Epub 2013 Nov 20.
Alphaviruses are mosquito-borne viruses that cause significant disease in animals and humans. Western equine encephalitis virus (WEEV) and eastern equine encephalitis virus (EEEV), two New World alphaviruses, can cause fatal encephalitis, and EEEV is a select agent of concern in biodefense. However, we have no antiviral therapies against alphaviral disease, and current vaccine strategies target only a single alphavirus species. In an effort to develop new tools for a broader response to outbreaks, we designed and tested a novel alphavirus vaccine comprised of cationic lipid nucleic acid complexes (CLNCs) and the ectodomain of WEEV E1 protein (E1ecto). Interestingly, we found that the CLNC component, alone, had therapeutic efficacy, as it increased survival of CD-1 mice following lethal WEEV infection. Immunization with the CLNC-WEEV E1ecto mixture (lipid-antigen-nucleic acid complexes [LANACs]) using a prime-boost regimen provided 100% protection in mice challenged with WEEV subcutaneously, intranasally, or via mosquito. Mice immunized with LANACs mounted a strong humoral immune response but did not produce neutralizing antibodies. Passive transfer of serum from LANAC E1ecto-immunized mice to nonimmune CD-1 mice conferred protection against WEEV challenge, indicating that antibody is sufficient for protection. In addition, the LANAC E1ecto immunization protocol significantly increased survival of mice following intranasal or subcutaneous challenge with EEEV. In summary, our LANAC formulation has therapeutic potential and is an effective vaccine strategy that offers protection against two distinct species of alphavirus irrespective of the route of infection. We discuss plausible mechanisms as well the potential utility of our LANAC formulation as a pan-alphavirus vaccine.
甲病毒是通过蚊子传播的病毒，可导致动物和人类发生严重疾病。西马脑炎病毒（WEEV）和东部马脑炎病毒（EEEV）是两种新世界的甲病毒，可引起致命性脑炎，并且 EEEV 是生物防御中值得关注的选定制剂。然而，我们没有针对甲病毒病的抗病毒疗法，并且当前的疫苗策略仅针对单一的甲病毒物种。为了开发针对爆发的更广泛反应的新工具，我们设计并测试了由阳离子脂质核酸复合物（CLNC）和 WEEV E1 蛋白的外域（E1ecto）组成的新型甲病毒疫苗。有趣的是，我们发现单独的 CLNC 成分就具有治疗功效，因为它可以提高 CD-1 小鼠在致死性 WEEV 感染后的存活率。使用初次免疫-加强免疫方案用 CLNC-WEEV E1ecto 混合物（脂质-抗原-核酸复合物 [LANAC]）进行免疫接种，可以在皮下、鼻内或通过蚊子挑战时为小鼠提供 100%的保护。用 LANAC 免疫的小鼠产生了强烈的体液免疫应答，但未产生中和抗体。将来自 LANAC E1ecto 免疫小鼠的血清被动转移给非免疫 CD-1 小鼠可提供针对 WEEV 挑战的保护，表明抗体足以提供保护。此外，LANAC E1ecto 免疫方案可显著提高经鼻内或皮下挑战后 EEEV 感染的小鼠的存活率。总之，我们的 LANAC 配方具有治疗潜力，并且是一种有效的疫苗策略，可提供针对两种不同甲病毒物种的保护，而与感染途径无关。我们讨论了合理的机制以及我们的 LANAC 配方作为泛甲病毒疫苗的潜在用途。
