Development of a polyvalent chimeric vaccine for Lyme disease

描述(申请人提供)：莱姆病是一个重要的健康问题，也是北美和欧洲主要的节肢动物传播疾病。2003年，在美国，大约有22,000例病例报告给了疾控中心。莱姆病是由人畜共患病原体伯氏疏螺旋体、加里氏疏螺旋体和费氏疏螺旋体引起的，它们通过受感染的硬蜱的叮咬传播给人类。第一种获准用于人类的莱姆病疫苗于1998年进入市场，但于2002年被下架。迫切需要仔细确定新的潜在疫苗来源的特征，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，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蛋白。OspC是一种22 kDa的脂蛋白，在感染早期表达，具有很强的抗原性。最近的研究表明，它在莱姆病的发病机制中起着重要作用。尽管OspC在疏螺旋体的致病机制中具有潜在的重要性，而且其保护功能也得到了很好的证明，但我们对该蛋白及其抗原结构的抗体反应的了解仍然是一个显著的空白。将OspC发展为疫苗原所遇到的困难之一是其广泛的遗传和抗原变异性。OspC序列形成了大约21个不同的系统类群，称为OspC类型(通过字母名称区分)。只有OspC类型的一部分与人类侵袭性感染有关。SpC晶体结构的测定已经确定了莱姆螺旋体在自然感染过程中可能暴露和呈现的特定结构域。因此，我们现在有了促进合理设计和构建有效疫苗的工具和资源。在这一应用中，我们提出了证据表明，OspC内的特定表位在感染、杀菌过程中是免疫优势的，并且是OspC型特异性抗体反应的主要线性决定因素。在目标1中，我们将确定每种OSPC类型的免疫优势表位，并确定每种表位是否都能引起杀菌抗体反应。在目标2中，我们将构建多价嵌合疫苗原，在目标3中，我们将评估其有效性。

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.