Andersen Tor Kristian, Zhou Fan, Cox Rebecca, Bogen Bjarne, Grødeland Gunnveig
K. G. Jebsen Centre for Influenza Vaccine Research, University of Oslo and Oslo University Hospital, Oslo, Norway.
Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
J Virol. 2017 Nov 14;91(23). doi: 10.1128/JVI.01340-17. Print 2017 Dec 1.
Zoonotic influenza H7 viral infections have a case fatality rate of about 40%. Currently, no or limited human to human spread has occurred, but we may be facing a severe pandemic threat if the virus acquires the ability to transmit between humans. Novel vaccines that can be rapidly produced for global distribution are urgently needed, and DNA vaccines may be the only type of vaccine that allows for the speed necessary to quench an emerging pandemic. Here, we constructed DNA vaccines encoding the hemagglutinin (HA) from influenza A/chicken/Italy/13474/99 (H7N1). In order to increase the efficacy of DNA vaccination, HA was targeted to either major histocompatibility complex class II molecules or chemokine receptors 1, 3, and 5 (CCR1/3/5) that are expressed on antigen-presenting cells (APC). A single DNA vaccination with APC-targeted HA significantly increased antibody levels in sera compared to nontargeted control vaccines. The antibodies were confirmed neutralizing in an H7 pseudotype-based neutralization assay. Furthermore, the APC-targeted vaccines increased the levels of antigen-specific cytotoxic T cells, and a single DNA vaccination could confer protection against a lethal challenge with influenza A/turkey/Italy/3889/1999 (H7N1) in mice. In conclusion, we have developed a vaccine that rapidly could contribute protection against a pandemic threat from avian influenza. Highly pathogenic avian influenza H7 constitute a pandemic threat that can cause severe illness and death in infected individuals. Vaccination is the main method of prophylaxis against influenza, but current vaccine strategies fall short in a pandemic situation due to a prolonged production time and insufficient production capabilities. In contrast, a DNA vaccine can be rapidly produced and deployed to prevent the potential escalation of a highly pathogenic influenza pandemic. We here demonstrate that a single DNA delivery of hemagglutinin from an H7 influenza could mediate full protection against a lethal challenge with H7N1 influenza in mice. Vaccine efficacy was contingent on targeting of the secreted vaccine protein to antigen-presenting cells.
人畜共患的H7型流感病毒感染的病死率约为40%。目前，尚未出现人际传播或人际传播有限，但如果该病毒获得人际传播能力，我们可能面临严重的大流行威胁。迫切需要能够迅速生产并全球分发的新型疫苗，而DNA疫苗可能是唯一能够满足遏制新出现的大流行所需速度的疫苗类型。在此，我们构建了编码来自甲型流感病毒/鸡/意大利/13474/99（H7N1）血凝素（HA）的DNA疫苗。为提高DNA疫苗接种的效力，将HA靶向主要组织相容性复合体II类分子或抗原呈递细胞（APC）上表达的趋化因子受体1、3和5（CCR1/3/5）。与非靶向对照疫苗相比，单次接种靶向APC的HA DNA疫苗可显著提高血清中的抗体水平。在基于H7假型的中和试验中证实这些抗体具有中和作用。此外，靶向APC的疫苗提高了抗原特异性细胞毒性T细胞的水平，单次接种DNA疫苗可使小鼠抵御甲型流感病毒/火鸡/意大利/3889/1999（H7N1）致死性攻击。总之，我们研发出一种能够迅速提供针对禽流感大流行威胁的保护作用的疫苗。高致病性禽流感H7构成大流行威胁，可导致受感染个体出现严重疾病和死亡。接种疫苗是预防流感的主要方法，但由于生产时间长和生产能力不足，当前的疫苗策略在大流行情况下存在不足。相比之下，DNA疫苗能够迅速生产和部署，以防止高致病性流感大流行的潜在升级。我们在此证明，单次递送来自H7流感病毒的血凝素DNA可介导小鼠完全抵御H7N1流感致死性攻击。疫苗效力取决于将分泌的疫苗蛋白靶向抗原呈递细胞。
