Human monoclonal antibodies against norovirus.

 描述(申请人提供)：诺如病毒(NOV)是全球急性病毒性胃肠炎的主要原因。目前，还没有专门的疫苗或抗病毒疗法可用于治疗NOV感染。虽然在NOV感染期间患病在健康人中通常是自限性的，但据报道，在缺乏有效免疫功能的人群中，特别是免疫功能低下的个人和5岁以下的儿童，发病率和死亡率更高。针对NOV感染的有效治疗是非常必要的，特别是在这些受试者中临床病例数量不断增加的情况下。基于噬菌体展示的人源抗体基因库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，被广泛用于筛选针对各种微生物或癌症抗原的抗体用于预防策略。为了探索NOV感染的潜在抗病毒治疗方法，我们利用NOV感染者的PBMC构建了一个人抗体基因库，并在鉴定高特异性抗体克隆方面获得了有希望的数据。在这项应用中，我们将重新筛选已建立的人类抗体库，并利用我们之前的筛选实验中确定的最佳条件构建新的抗体库，以提高筛选效率和抗原覆盖率，以发现针对导致重大流行病和散发性胃肠炎的各种NOV基因的潜在交叉反应中和抗体。选定的抗体不仅能够与不同的nov变种结合，而且 还可以阻断参与NOV结合的相关组织血型抗原(HBGA)，从而潜在地抑制人类的NOV感染。此外，一组分离的人类抗体克隆将有利于彻底分析人类抗体识别的nov抗原表位，而使用动物来源的抗体无法完全理解这一表位。成功地分离出针对不同NOV变异体的人类抗体将对脆弱人群中潜在的预防策略具有很高的价值。同时，它们将对了解新城疫病毒的抗原变异非常有帮助，从而为未来新城疫疫苗的设计提供便利。

 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.