Modifications in the Polymerase Genes of a Swine-Like Triple-Reassortant Influenza Virus To Generate Live Attenuated Vaccines against 2009 Pandemic H1N1 Viruses
Modifications in the Polymerase Genes of a Swine-Like Triple-Reassortant Influenza Virus To Generate Live Attenuated Vaccines against 2009 Pandemic H1N1 Viruses
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DOI：
10.1128/jvi.01503-10
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发表时间：
2011-01-01
影响因子：
5.4
通讯作者：
Perez, Daniel R.
中科院分区：
文献类型：
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作者：
Pena, Lindomar;Vincent, Amy L.;Perez, Daniel R.
2009年6月11日，世界卫生组织（世卫组织）宣布，新型猪源甲型H1N1流感病毒引起的疫情已达到大流行程度。大流行性H1N1（H1N1 pdm）病毒是人群中的主要流感病毒株。它还跨越了物种障碍，感染了几个国家的火鸡和猪。因此，迫切需要开发在多种动物物种中有效的疫苗。我们以前已经证明，引入温度敏感性突变到PB 2和PB 1基因的禽H9 N2病毒，结合插入血凝素（HA）标签的PB 1，导致在减毒（att）疫苗骨干鸡和小鼠。由于新的大流行毒株是三重抗性（TR）病毒，我们选择将双重减毒修饰引入猪样TR病毒分离株A/turkey/OH/313053/04（H3 N2）（ty/04），目的是生产减毒活流感疫苗（LAIV）。这种基因修饰的骨架在高温下损害了聚合酶活性并限制了病毒的生长。使用ty/04 att骨架产生的两种H1N1疫苗候选物的体内表征表明，该疫苗在小鼠中高度减毒，如通过呼吸道中不存在疾病体征、有限复制和最小组织病理学改变所指示的。用ty/04 att-based疫苗进行单次免疫，可在小鼠中提供针对致命H1N1 pdm病毒感染的完全保护。更重要的是，用ty/04 att-H1N1候选疫苗接种猪，在用2009年H1N1大流行病毒进行侵袭性肠道内攻击时产生了杀菌免疫。我们的研究强调了ty/04 att疫苗平台的安全性及其作为主供体菌株用于生产人和牲畜减毒活疫苗的潜力。
On 11 June 2009, the World Health Organization (WHO) declared that the outbreaks caused by novel swine-origin influenza A (H1N1) virus had reached pandemic proportions. The pandemic H1N1 (H1N1pdm) virus is the predominant influenza virus strain in the human population. It has also crossed the species barriers and infected turkeys and swine in several countries. Thus, the development of a vaccine that is effective in multiple animal species is urgently needed. We have previously demonstrated that the introduction of temperature-sensitive mutations into the PB2 and PB1 genes of an avian H9N2 virus, combined with the insertion of a hemagglutinin (HA) tag in PB1, resulted in an attenuated (att) vaccine backbone for both chickens and mice. Because the new pandemic strain is a triple-reassortant (TR) virus, we chose to introduce the double attenuating modifications into a swine-like TR virus isolate, A/turkey/OH/313053/04 (H3N2) (ty/04), with the goal of producing live attenuated influenza vaccines (LAIV). This genetically modified backbone had impaired polymerase activity and restricted virus growth at elevated temperatures. In vivo characterization of two H1N1 vaccine candidates generated using the ty/04 att backbone demonstrated that this vaccine is highly attenuated in mice, as indicated by the absence of signs of disease, limited replication, and minimum histopathological alterations in the respiratory tract. A single immunization with the ty/04 att-based vaccines conferred complete protection against a lethal H1N1pdm virus infection in mice. More importantly, vaccination of pigs with a ty/04 att-H1N1 vaccine candidate resulted in sterilizing immunity upon an aggressive intratracheal challenge with the 2009 H1N1 pandemic virus. Our studies highlight the safety of the ty/04 att vaccine platform and its potential as a master donor strain for the generation of live attenuated vaccines for humans and livestock.