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

项目摘要/摘要 病毒感染成功的第一步是病毒附着在细胞表面的受体上。最新的发现 组织血型抗原(HBGA)可能是轮状病毒(RV)的潜在受体已显著改善 我们对轮状病毒的流行病学、疾病负担和发病机制的了解。然而，房车表现出显著的 多样性，并能够在许多不同的种群和动物物种中引起疾病，使其 很难开发出针对RV的广泛有效的疫苗。例如，P[6]和P[11]房车识别 HBGA前体或中间产物，并显示独特的年龄特定宿主范围在新生儿和 婴幼儿，进一步使安全有效的疫苗接种战略复杂化。此外，P[6]和 P[11]房车常见于发展中国家，可能是由于人类独特的遗传易感性所致 HBGA类型(Lewis阴性)和这两种基因在农村地区的人畜传播，并可能 需要包括P[6]和/或P[11]房车的鸡尾酒疫苗，以向儿童提供广泛的保护。在这 我们将对南非儿童的轮状病毒感染进行现场监测，以更好地了解 P[6]RV的高流行率，以及其他循环基因型别，并指导改善当前RV 针对RV的疫苗和/或新疫苗的开发。实现两个目标：一是评估 儿童循环轮状病毒毒株及其HBGA结合模式验证HBGA特异性宿主范围 非洲儿童的主要循环RV P类型。新生儿轮状病毒胃肠炎的两年监测 小婴儿将在两个哨所进行表演。将特别注意特定角色的作用 在儿童P[6]RV感染过程中，HBGA，如1型链前体。我们亦会评估 主要循环人轮状病毒的抗原相关性及其与当前轮状病毒疫苗的比较 以确定未来疫苗的其他潜在靶点。第二，我们将研究特定年龄的取向 新生儿和婴幼儿P[6]和P[11]RV。感染特定RV-P类型的年龄窗 将通过AIM 1的RV监测确定。一个队列，每月从新生儿的唾液样本 从出生到一岁的婴儿将被收集起来，以确定表达的年龄窗口 结合P[6]和P[11]RV的特异性HBGA受体。通过这些研究获得的知识对 设计疫苗接种计划，以安全有效地提供这些疫苗株。最后，为了推进 下一代轮状病毒疫苗，我们将研究一种活的、减毒的P[6]的生物学特性和有效性。 RV是我们课题组开发的一种新的RV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.