Prevalence of P[6] and P[11] rotaviruses in developing countries

项目概要/摘要 成功病毒感染的第一步是病毒附着在细胞表面受体上。最近的发现 组织血型抗原（HBGA）可能是潜在的轮状病毒（RV）受体已显着改善 我们对 RV 流行病学、疾病负担和发病机制的了解。然而，房车表现出显着的 多样性，能够在许多不同的种群和动物物种中引起疾病，使其 开发针对 RV 的广泛有效的疫苗很困难。例如，P[6] 和 P[11] RV 识别 HBGA 前体或中间产物，并揭示了新生儿和儿童中独特的年龄特异性宿主范围 年幼的婴儿，使安全有效的疫苗接种策略进一步复杂化。此外，P[6] 和 P[11] RV 在发展中国家很常见，可能是由于人类具有独特的遗传倾向 HBGA 类型（刘易斯阴性）和这两种基因型在农村地区的人畜共患传播，并且可能 需要包含 P[6] 和/或 P[11] RV 的混合疫苗才能为儿童提供广泛的保护。在这个 应用程序，我们将对南非儿童的 RV 感染进行现场监测，以更好地了解 P[6] RV 以及其他循环基因型的高流行率，并指导当前 RV 的改进 疫苗和/或开发针对 RV 的新疫苗。将实现两个目标：首先，我们将评估 儿童中循环的 RV 菌株及其 HBGA 结合模式，以验证 HBGA 特异性宿主范围 非洲儿童中主要流行的 RV P 型。新生儿和儿童 RV 胃肠炎的两年监测 小婴儿将在两个哨点进行手术。将特别关注特定角色的作用 儿童 P[6] RV 感染期间的 HBGA，例如 1 型链前体。我们还将评估 主要循环人类 RV 之间的抗原相关性，并将其与当前的 RV 疫苗进行比较 菌株以确定未来疫苗的其他潜在目标。其次，我们将研究年龄特异性 新生儿和小婴儿中 P[6] 和 P[11] RV 的变化。特定 RV P 类型感染的年龄窗口 将通过目标 1 中的 RV 监测来确定。每月采集新生儿唾液样本的队列 并且将收集从出生到一岁的婴儿来定义表达的年龄窗口 结合 P[6] 和 P[11] RV 的特定 HBGA 受体。通过这些研究获得的知识对于 设计疫苗接种计划以安全有效地提供这些疫苗株。最后，为推进 下一代 RV 疫苗，我们将研究活的减毒 P[6] 的生物学特性和用途 RV 是我们小组开发的，作为针对 RV 的新型鸡尾酒疫苗的潜在候选者。

Project Summary/Abstract The first step of a successful viral infection is virus attachment to a cell-surface receptor. The recent discovery that histo-blood group antigens (HBGAs) may be potential rotavirus (RV) receptors has significantly improved our understanding of RV epidemiology, disease burden, and pathogenesis. However, RVs exhibit significant diversity and are capable of causing disease in many different populations and animal species, making it difficult to develop broadly effective vaccines against RVs. As examples, the P[6] and P[11] RVs recognize HBGA precursors or intermediate products and revealed unique age-specific host ranges in neonates and young infants, further complicating strategies for safe and effective vaccine delivery. In addition, both P[6] and P[11] RVs are commonly found in developing countries, likely due to a human genetic predisposition for unique HBGA types (Lewis negative) and zoonotic transmission of these two genotypes in rural areas, and may require a cocktail vaccine including P[6] and/or P[11] RVs to confer broad protection to children. In this application, we will perform field surveillance of RV infection in South African children to better understand the high prevalence of P[6] RVs, among other circulating genotypes, and guide improvement of current RV vaccines and/or development of new vaccines against RVs. Two aims will be fulfilled: First, we will evaluate circulating RV strains and their HBGA binding patterns in children to verify the HBGA-specific host ranges of major circulating RV P types in African children. A two-year surveillance of RV gastroenteritis in neonates and young infants will be performed at two sentinel sites. Special attention will be paid to the roles of specific HBGAs, such as the type 1 chain precursors, during P[6] RV infection in children. We will also assess the antigenic relatedness among major circulating human RVs and compare them to the current RV vaccine strains to identify additional potential targets for future vaccines. Second, we will study the age-specific tropism of P[6] and P[11] RVs in neonates and young infants. The age-windows for infection with specific RV P types will be determined through the RV surveillance in Aim 1. A cohort with monthly saliva samples from neonates and young infants from birth to one year of age will be collected to define the age-windows of expression for specific HBGA receptors that bind P[6] and P[11] RVs. Knowledge gained through these studies is valuable to design a vaccination program for safe and effective delivery of these vaccine strains. Finally, to advance the next generation of RV vaccines, we will study the biological properties and usefulness of a live, attenuated P[6] RV, developed in our group, as a potential candidate in a new cocktail vaccine against RVs.