Human monoclonal antibodies against norovirus.

 描述（由申请方提供）：诺如病毒（NoV）是全球急性病毒性胃肠炎的主要原因。目前，没有特定的疫苗或抗病毒疗法可用于治疗NoV感染。尽管健康个体在感染NoV期间的疾病通常是自限性的，但在缺乏有效免疫功能的人群中，特别是免疫功能低下的个体和5岁以下的儿童中，报告了较高的发病率和死亡率。针对NoV感染的有效治疗是非常必要的，特别是随着这些受试者中临床病例数量的增加。基于噬菌体展示的人源抗体基因文库已被广泛用于选择针对各种微生物或癌症抗原的抗体用于预防策略，利用噬菌体展示的大容量和多样性，以及其方便和直接的筛选方法。为了探索用于NoV感染的潜在抗病毒治疗剂，我们使用来自参加NoV攻击研究的NoV感染的人类受试者的PBMC构建了人抗体基因文库，并获得了鉴定高度特异性抗体克隆的有希望的数据。在本申请中，我们将重新筛选已建立的人源抗体库并构建新的库，使用我们先前筛选实验中确定的最佳条件，以提高筛选效率和抗原覆盖率，从而发现针对引起重大流行病和散发性胃肠炎的各种NoV基因型的潜在交叉反应性中和抗体。选择的抗体不仅能够结合不同的NoV变体， 还阻断参与NoV结合的相关组织-血型抗原（HBGA），从而潜在地抑制人中的NoV感染。此外，一组分离的人抗体克隆将有利于彻底分析人抗体识别的NoV抗原表位，这不能通过使用动物来源的抗体完全理解。成功分离针对各种NoV变体的人抗体对于脆弱人群中的潜在预防策略将是非常有价值的。同时，它们将非常有助于了解NoV抗原变异，以促进未来的NoV疫苗设计。

 DESCRIPTION (provided by applicant): Noroviruses (NoVs) are the major cause of acute viral gastroenteritis worldwide. Currently, no specific vaccines or antiviral therapies are available to treat NoV infections. Although illness during NoV infection is generally self-limiting in healthy individuals, higher morbidity and mortality rates have been reported among populations lacking effective immune function, especially immunocompromised individuals and children younger than 5 years of age. An effective treatment against NoV infection is of high necessity, especially with the increasing number of clinical cases among these subjects. Phage display-based human antibody gene libraries have been widely used to select antibodies against various microbial or cancer antigens for prophylactic strategies, taking advantage of the large capacity and diversity of phage display, as well as its convenience and straightforward screening approaches. In order to explore potential antiviral therapeutics for NoV infection, we have constructed a human antibody gene library using PBMCs from NoV-infected human subjects enrolled in a NoV-challenge study and obtained promising data towards identifying highly specific antibody clones. In this application, we will re-screen the established human antibody library and construct new libraries, using optimal conditions identified in our previous screening experiments, to increase the screen efficiency and antigenic coverage to discover potential cross-reactive neutralizing antibodies against various NoV genotypes that cause major epidemics and sporadic gastroenteritis. Selected antibodies are not only capable of binding to different NoV variants, but also blocking related histo-blood group antigens (HBGAs) involved in NoV binding, thus, potentially inhibiting NoV infection in humans. Furthermore, a panel of isolated human antibody clones will be favorable for thorough analysis of NoV antigen epitopes recognized by human antibodies, which cannot be fully understood by using animal-origin antibodies. Successfully isolated human antibodies against various NoV variants would be highly valuable for potential prophylactic strategies among vulnerable populations. Meanwhile, they will be extremely helpful in understanding NoV antigenic variation, in order to facilitate future NoV vaccine design.