Department of Virology and Vaccine Vectors, Profectus BioSciences Inc., Pearl River, New York, USA
Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.
J Virol. 2018 Jan 17;92(3). doi: 10.1128/JVI.01190-17. Print 2018 Feb 1.
Previous studies demonstrated that a single intramuscular (i.m.) dose of an attenuated recombinant vesicular stomatitis virus (rVSV) vector (VesiculoVax vector platform; rVSV-N4CT1) expressing the glycoprotein (GP) from the Mayinga strain of (EBOV) protected nonhuman primates (NHPs) from lethal challenge with EBOV strains Kikwit and Makona. Here, we studied the immunogenicities of an expanded range of attenuated rVSV vectors expressing filovirus GP in mice. Based on data from those studies, an optimal attenuated trivalent rVSV vector formulation was identified that included rVSV vectors expressing EBOV, (SUDV), and the Angola strain of (MARV) GPs. NHPs were vaccinated with a single dose of the trivalent formulation, followed by lethal challenge 28 days later with each of the three corresponding filoviruses. At day 14 postvaccination, a serum IgG response specific for all three GPs was detected in all the vaccinated macaques. A modest and balanced cell-mediated immune response specific for each GP was also detected in a majority of the vaccinated macaques. No matter the level of total GP-specific immune response detected postvaccination, all the vaccinated macaques were protected from disease and death following lethal challenge with each of the three filoviruses. These findings indicate that vaccination with a single dose of attenuated rVSV-N4CT1 vectors each expressing a single filovirus GP may provide protection against the filoviruses most commonly responsible for outbreaks of hemorrhagic fever in sub-Saharan Africa. The West African Ebola virus Zaire outbreak in 2013 showed that the disease was not only a regional concern, but a worldwide problem, and highlighted the need for a safe and efficacious vaccine to be administered to the populace. However, other endemic pathogens, like Ebola virus Sudan and Marburg, also pose an important health risk to the public and therefore require development of a vaccine prior to the occurrence of an outbreak. The significance of our research was the development of a blended trivalent filovirus vaccine that elicited a balanced immune response when administered as a single dose and provided complete protection against a lethal challenge with all three filovirus pathogens.
先前的研究表明，单次肌肉内（i.m.）给予减毒重组水疱性口炎病毒（rVSV）载体（VesiculoVax 载体平台；rVSV-N4CT1），该载体表达来自 （EBOV）梅因加株的糖蛋白（GP），可保护非人灵长类动物（NHPs）免受 EBOV 株 Kikwit 和 Makona 的致死性挑战。在这里，我们研究了表达丝状病毒 GP 的一系列范围更广的减毒 rVSV 载体在小鼠中的免疫原性。基于这些研究的数据，确定了一种最佳的减毒三价 rVSV 载体配方，其中包括表达 EBOV、（SUDV）和 （MARV）安哥拉株 GP 的 rVSV 载体。NHPs 接种一剂三价配方，28 天后用三种相应的丝状病毒中的每一种进行致死性挑战。接种后第 14 天，所有接种的猕猴均检测到针对三种 GP 的血清 IgG 应答。在大多数接种的猕猴中，还检测到针对每种 GP 的适度且平衡的细胞介导免疫应答。无论接种后检测到的总 GP 特异性免疫应答水平如何，所有接种的猕猴在用三种丝状病毒中的每一种进行致死性挑战后均免受疾病和死亡的影响。这些发现表明，接种一剂减毒 rVSV-N4CT1 载体，每种载体表达一种丝状病毒 GP，可能为撒哈拉以南非洲地区常见的出血热病毒提供保护。2013 年西非扎伊尔埃博拉病毒爆发表明，该疾病不仅是一个地区性问题，也是一个全球性问题，突显了需要向民众提供安全有效的疫苗。然而，其他地方性病原体，如埃博拉病毒苏丹和马尔堡，也对公众构成重要的健康风险，因此需要在爆发之前开发疫苗。我们研究的意义在于开发了一种混合三价丝状病毒疫苗，当作为一剂给予时，可引起平衡的免疫应答，并对所有三种丝状病毒病原体的致死性挑战提供完全保护。
