Tharakaraman Kannan, Subramanian Vidya, Viswanathan Karthik, Sloan Susan, Yen Hui-Ling, Barnard Dale L, Leung Y H Connie, Szretter Kristy J, Koch Tyree J, Delaney James C, Babcock Gregory J, Wogan Gerald N, Sasisekharan Ram, Shriver Zachary
Department of Biological Engineering, Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
Visterra, Inc., Cambridge, MA 02139;
Proc Natl Acad Sci U S A. 2015 Sep 1;112(35):10890-5. doi: 10.1073/pnas.1502374112. Epub 2015 Aug 17.
Emerging strains of influenza represent a significant public health threat with potential pandemic consequences. Of particular concern are the recently emerged H7N9 strains which cause pneumonia with acute respiratory distress syndrome. Estimates are that nearly 80% of hospitalized patients with H7N9 have received intensive care unit support. VIS410, a human antibody, targets a unique conserved epitope on influenza A. We evaluated the efficacy of VIS410 for neutralization of group 2 influenza strains, including H3N2 and H7N9 strains in vitro and in vivo. VIS410, administered at 50 mg/kg, protected DBA mice infected with A/Anhui/2013 (H7N9), resulting in significant survival benefit upon single-dose (-24 h) or double-dose (-12 h, +48 h) administration (P < 0.001). A single dose of VIS410 at 50 mg/kg (-12 h) combined with oseltamivir at 50 mg/kg (-12 h, twice daily for 7 d) in C57BL/6 mice infected with A/Shanghai 2/2013 (H7N9) resulted in significant decreased lung viral load (P = 0.002) and decreased lung cytokine responses for nine of the 11 cytokines measured. Based on these results, we find that VIS410 may be effective either as monotherapy or combined with antivirals in treating H7N9 disease, as well as disease from other influenza strains.
新出现的流感毒株对公众健康构成重大威胁,可能引发大流行。特别令人担忧的是最近出现的H7N9毒株,它会导致伴有急性呼吸窘迫综合征的肺炎。据估计,近80%的H7N9住院患者接受了重症监护病房的支持。VIS410是一种人源抗体,靶向甲型流感病毒上一个独特的保守表位。我们评估了VIS410在体外和体内对包括H3N2和H7N9毒株在内的2组流感毒株的中和效果。以50mg/kg的剂量给药VIS410,可保护感染A/安徽/2013(H7N9)的DBA小鼠,单剂量(-24小时)或双剂量(-12小时,+48小时)给药后均有显著的生存获益(P<0.001)。在感染A/上海2/2013(H7N9)的C57BL/6小鼠中,50mg/kg(-12小时)的单剂量VIS410与50mg/kg(-12小时,每日两次,共7天)的奥司他韦联合使用,可显著降低肺部病毒载量(P = 0.002),并使所检测的11种细胞因子中的9种细胞因子的肺部细胞因子反应降低。基于这些结果,我们发现VIS410作为单一疗法或与抗病毒药物联合使用,在治疗H7N9疾病以及其他流感毒株引起的疾病方面可能是有效的。