Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
J Virol. 2018 Jul 31;92(16). doi: 10.1128/JVI.00949-18. Print 2018 Aug 15.
Broadly cross-reactive antibodies (Abs) that recognize conserved epitopes within the influenza virus hemagglutinin (HA) stalk domain are of particular interest for their potential use as therapeutic and prophylactic agents against multiple influenza virus subtypes, including zoonotic virus strains. Here, we characterized four human HA stalk-reactive monoclonal antibodies (MAbs) for their binding breadth and affinity, neutralization capacity, and protective potential against an highly pathogenic avian influenza virus. The monoclonal antibodies were isolated from individuals shortly following infection with (70-1F02 and 1009-3B05) or vaccination against (05-2G02 and 09-3A01) A(H1N1)pdm09. Three of the MAbs bound HAs from multiple strains of group 1 viruses, and one MAb, 05-2G02, bound to both group 1 and group 2 influenza A virus HAs. All four antibodies prophylactically protected mice against a lethal challenge with the highly pathogenic A/Vietnam/1203/04 (H5N1) strain. Two MAbs, 70-1F02 and 09-3A01, were further tested for their therapeutic efficacy against the same strain and showed good efficacy in this setting as well. One MAb, 70-1F02, cocrystallized with H5 HA and showed heavy-chain-only interactions similar to those seen with the previously described CR6261 anti-stalk antibody. Finally, we show that antibodies that compete with these MAbs are prevalent in serum from an individual recently infected with the A(H1N1)pdm09 virus. The antibodies described here can be developed into broad-spectrum antiviral therapeutics that could be used to combat infections by zoonotic or emerging pandemic influenza viruses. The rise in zoonotic infections of humans by emerging influenza viruses is a worldwide public health concern. The majority of recent zoonotic human influenza cases were caused by H7N9 and H5Nx viruses and were associated with high morbidity and mortality. In addition, seasonal influenza viruses are estimated to cause up to 650,000 deaths annually worldwide. Currently available antiviral treatment options include only neuraminidase inhibitors, but some influenza viruses are naturally resistant to these drugs, and others quickly develop resistance-conferring mutations. Alternative therapeutics are urgently needed. Broadly protective antibodies that target the conserved "stalk" domain of the hemagglutinin represent potential potent antiviral prophylactic and therapeutic agents that can assist pandemic preparedness. Here, we describe four human monoclonal antibodies that target conserved regions of influenza HA and characterize their binding spectrum as well as their protective capacity in prophylactic and therapeutic settings against a lethal challenge with a zoonotic influenza virus.
广泛交叉反应的抗体（Abs）能够识别流感病毒血凝素（HA）茎部结构域内的保守表位，因此特别适合用作针对多种流感病毒亚型（包括人畜共患病株）的治疗和预防药物。在这里，我们对四种人 HA 茎部反应性单克隆抗体（MAb）进行了鉴定，以评估它们的结合广度和亲和力、中和能力以及针对高致病性禽流感病毒的保护潜力。这些单克隆抗体是从感染（70-1F02 和 1009-3B05）或接种疫苗（05-2G02 和 09-3A01）A（H1N1）pdm09 后不久的个体中分离出来的。其中三种单抗可结合多种 1 组病毒的 HA，而一种单抗（05-2G02）可结合 1 组和 2 组流感 A 病毒的 HA。四种抗体均可预防小鼠受到高致病性 A/Vietnam/1203/04（H5N1）株的致死性攻击。两种单抗（70-1F02 和 09-3A01）进一步用于测试对同一菌株的治疗功效，在这种情况下也显示出良好的疗效。一种单抗（70-1F02）与 H5 HA 共结晶，显示出与先前描述的 CR6261 抗茎部抗体相似的重链单链相互作用。最后，我们表明，与这些单抗竞争的抗体在最近感染 A（H1N1）pdm09 病毒的个体的血清中普遍存在。本文描述的抗体可以开发为广谱抗病毒治疗药物，可用于对抗人畜共患或新发大流行性流感病毒的感染。新兴流感病毒导致人类感染的人畜共患病日益成为全球公共卫生关注的问题。最近的大多数人畜共患人类流感病例是由 H7N9 和 H5Nx 病毒引起的，其发病率和死亡率很高。此外，季节性流感病毒估计每年在全球造成多达 65 万人死亡。目前可用的抗病毒治疗选择仅包括神经氨酸酶抑制剂，但有些流感病毒天然对这些药物具有抗性，而其他病毒则很快产生赋予耐药性的突变。迫切需要替代疗法。针对血凝素“茎”结构域保守区域的广谱保护性抗体代表了具有潜在潜力的强大抗病毒预防和治疗药物，可以帮助大流行的准备。在这里，我们描述了四种针对流感 HA 保守区域的人源单克隆抗体，并对其结合谱以及在预防性和治疗性设置下针对致死性人畜共患流感病毒挑战的保护能力进行了表征。
