Influenza A viruses with truncated NS1 as modified live virus vaccines: pilot studies of safety and efficacy in horses.
Influenza A viruses with truncated NS1 as modified live virus vaccines: pilot studies of safety and efficacy in horses.
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DOI：
10.2746/042516408x371937
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发表时间：
2009-01
影响因子：
2.2
通讯作者：
Palese P
中科院分区：
文献类型：
--
作者：
Chambers TM;Quinlivan M;Sturgill T;Cullinane A;Horohov DW;Zamarin D;Arkins S;García-Sastre A;Palese P
先前已经描述了用于马流感病毒的反向遗传学拯救系统和编码73、99或126个氨基酸的羧基末端截短的NS 1蛋白的三种NS 1突变体病毒的构建（Quinidian等人，J. Virology 79，8431-8439，2005）。这些病毒在体外抑制I型IFN产生的能力受损，并且是复制减毒的，因此是用作马中的改良活流感病毒疫苗的候选者。这些突变病毒中的一种或多种在对马施用时是安全的，并且当用野生型流感病毒攻击时，受体马的疾病的生理学和病毒学相关性降低。在马中进行疫苗接种和攻毒研究，测量发热、临床体征、病毒脱落和全身促炎细胞因子。用病毒对马进行气雾剂或鼻内接种未产生不良反应。接种NS 1 -73和NS 1 -126病毒（但非NS 1 -99病毒）的血清阴性马可检出病毒并产生显著水平的抗体。在用野生型流感病毒攻击后，与未接种疫苗的对照组相比，用NS 1 -126病毒接种疫苗的马没有出现发热（>38.5°C），具有显著更少的疾病临床体征，并且在攻击后较短时间内排泄的病毒量显著减少。通过mRNA定量RT-PCR检测促炎细胞因子IL-1β、IL-6、IFNγ和TNFα的表达。对照组动物的平均IL-1β和IL-6水平显著较高，并且与攻毒后第+2天的病毒散毒峰值和发热呈正相关。这些数据表明，重组NS 1病毒作为马流感的修饰活病毒疫苗是安全有效的。这种基于反向遗传学的疫苗可以很容易地通过交换病毒表面抗原来更新，以解决流感病毒中的抗原漂移问题。
A reverse genetics rescue system for equine influenza virus and the construction of three NS1 mutant viruses encoding carboxy-terminally truncated NS1 proteins of 73, 99 or 126 amino acids, have been previously described (Quinlivan et al., J. Virology 79, 8431–8439, 2005). These viruses are impaired in their ability to inhibit type I IFN production in vitro and are replication attenuated, thus are candidates for use as a modified live influenza virus vaccine in the horse. One or more of these mutant viruses are safe when administered to horses, and recipient horses when challenged with wild-type influenza have reduced physiological and virological correlates of disease. Vaccination and challenge studies were done in horses, with measurement of pyrexia, clinical signs, virus shedding, and systemic pro-inflammatory cytokines. Aerosol or intranasal inoculation of horses with the viruses produced no adverse effects. Seronegative horses inoculated with the NS1-73 and NS1-126 viruses, but not the NS1-99 virus, shed detectable virus and generated significant levels of antibodies. Following challenge with wild-type influenza, horses vaccinated with NS1-126 virus did not develop fever (>38.5°C), had significantly fewer clinical signs of illness, and significantly reduced quantities of virus excreted for a shorter duration post-challenge compared to unvaccinated controls. Expression of pro-inflammatory cytokines IL-1β, IL-6, IFNγ, and TNFα was examined by quantitative RT-PCR of mRNA. Mean IL-1β and IL-6 levels were significantly higher in control animals, and were positively correlated with peak viral shedding and pyrexia on Day +2 post-challenge. These data suggest the recombinant NS1 viruses are safe and effective as modified live virus vaccines against equine influenza. This type of reverse genetics-based vaccine can be easily updated by exchanging viral surface antigens to combat the problem of antigenic drift in influenza viruses.
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影响因子：
15.9
作者：
Palese, P;García-Sastre, A
通讯作者：
García-Sastre, A
影响因子：
5.5
作者：
Park, AW;Wood, JLN;Grenfell, BT
通讯作者：
Grenfell, BT
影响因子：
5.4
作者：
Egorov, A;Brandt, S;Muster, T
通讯作者：
Muster, T
影响因子：
5.5
作者：
Lunn, DP;Soboll, G;Olsen, CW
通讯作者：
Olsen, CW
影响因子：
5.4
作者：
Kochs, Georg;Garcia-Sastre, Adolfo;Martinez-Sobrido, Luis
通讯作者：
Martinez-Sobrido, Luis