Development of a polyvalent chimeric vaccine for Lyme disease

描述（由申请人提供）：莱姆病是一个重要的健康问题和主要的节肢动物传播的疾病在N。美国和欧洲。2003年，美国向CDC报告了大约22，000例病例。莱姆病是由人畜共患病原体伯氏疏螺旋体B引起的。garinii和B.通过感染的硬蜱叮咬传播给人类的阿氏病毒。第一种莱姆病疫苗于1998年进入市场，但于2002年被撤出市场。迫切需要仔细描述新的潜在疫苗原并推进疫苗开发。莱姆病螺旋体的抗原性和遗传复杂性以及我们对疏螺旋体表面蛋白抗原结构的普遍缺乏了解阻碍了开发新一代疫苗的努力。外表面蛋白C（OspC）已成为疫苗开发的潜在候选者。OspC是一种22 kDa的脂蛋白，在早期感染期间表达，具有高度抗原性。最近的分析表明，它在莱姆病的发病机制中起着重要作用。尽管OspC在疏螺旋体发病机制中的潜在重要性及其有据可查的保护能力，但我们对该蛋白质及其抗原结构的Ab应答的理解仍存在显著空白。在开发OspC作为疫苗原时遇到的困难之一是其广泛的遗传和抗原变异性。OspC序列形成大约21个不同的系统群，称为OspC类型（通过字母名称区分）。只有一部分OspC类型与人类的侵袭性感染有关。OspC晶体结构的测定已经确定了可能在自然感染期间由莱姆螺旋体表面暴露和呈现的特定结构域。因此，我们现在有工具和资源来促进合理设计和构建有效的疫苗。在本申请中，我们提出了OspC内的特异性表位在感染期间是免疫显性的、杀菌的并且是OspC类型特异性Ab应答中的主要线性决定簇的证据。在目标1中，我们将鉴定每种OspC类型的免疫显性表位，并确定每种表位是否引起杀菌性Ab应答。在目标2中，我们将构建多价嵌合疫苗原，在目标3中，我们将评估其功效。

DESCRIPTION (provided by applicant): Lyme disease is an important health concern and the leading arthropod-borne disease in N. America and Europe. In the U.S. in 2003, approximately 22,000 cases were reported to the CDC. Lyme disease is caused by the zoonotic pathogens Borrelia burgdorferi, B. garinii and B. afzelii which are transmitted to humans through the bite of infected Ixodid ticks. The first Lyme disease vaccine licensed for use in humans entered the market in 1998 but was removed from the market in 2002. There is a pressing need to carefully characterize new potential vaccinogens and move forward with vaccine development. Efforts to develop a new generation of vaccines have been hampered by the antigenic and genetic complexity of the Lyme disease spirochetes and our general lack of knowledge regarding the antigenic structure of Borrelia surface proteins. Outer surface protein C (OspC) has emerged as a potential candidate for vaccine development. OspC is a 22 kDa lipoprotein that is expressed during early infection and is highly antigenic. Recent analyses indicate that it plays an important role in the pathogenesis of Lyme disease. In spite of the potential importance of OspC in Borrelia pathogenesis and its well documented protective capabilities, a significant void remains in our understanding of the Ab response to this protein and its antigenic structure. One of the difficulties that has been encountered in developing OspC as a vaccinogen is its extensive genetic and antigenic variability. OspC sequences form approximately 21 distinct phyletic groups that are referred to as OspC types (differentiated by letter designations). Only a subset of OspC types are associated with invasive infection in humans. The determination of OspC crystal structures has identified specific domains that are likely to be surface exposed and presented by the Lyme spirochetes during natural infection. Hence, we now have the tools and resources facilitate the rational design and construction of an effective vaccine. In this application, we present evidence that specific epitopes within OspC are immunodominant during infection, bactericidal and are major linear determinants in the OspC type specific Ab response. In aim 1we will identify the immunodominant epitopes of each OspC type and determine if each elicits a bactericidal Ab response. In aim 2 we will construct a polyvalent chimeric vaccinogen and in aim 3 we will assess its efficacy.