Multiepitope circumsporozoite P.falciparum malaria subunit vaccine displayed on v

摘要报表 鉴于疟疾给许多发展中国家带来的沉重负担，防治疟疾的总体目标是 一项提议是开发一种恶性疟原虫特异性免疫原，它可能是一种负担得起的 预防疟疾的有效疫苗。目前最有效的疟疾候选疫苗(RTS，S/AS02a)是 基于使用融合到疟疾环子孢子(CS)特异性的颗粒载体平台(HBs) T细胞和B细胞表位。目前RTS的局限性，S疫苗已被要求产生反应性 佐剂和暂态保护。另一个潜在的复杂情况是，携带者来自人类 病原体，乙肝病毒(乙肝病毒)。为了绕过这些问题，一种非人类病原体衍生的载体 已经开发了平台，特别是土拨鼠庚型肝炎病毒(WHcAg)的核心蛋白。 修饰后的WHcAg颗粒将被用作疫苗平台，原因有几个：CS-WHcAg杂化颗粒 诱导极高水平的抗CS抗体；慢性乙型肝炎患者对HBcAg和HBs Ag的免疫耐受性 运营商(全球4亿)可以通过使用WHcAg平台来规避；而且因为CS- WHcAg杂化颗粒可以在细菌中制造，生产疫苗将相对便宜。一个 初步研制出含有两个中和CS重复表位的CS-WHcAg杂化颗粒 插入到环区(提高最高滴度的抗插入抗体的插入部位)和两个 “普遍的”疟疾特异性T细胞结构域融合到C-末端。这种CS-WHcAg杂化粒子非常 在小鼠中具有免疫原性，并能够诱导中和抗CS重复抗体，以预防P. 伯氏恶性疟原虫/伯氏疟原虫杂交子孢子肝脏体内感染的研究 开发一种人类使用的疫苗。开发最佳疟疾疫苗的战略分为四个方面 目的：1)加入额外的CS来源的B细胞和T细胞中和表位；2)测试保护性 恶性疟原虫/伯氏疟原虫混合子孢子模型中候选疫苗的效力和发展 包含额外恶性疟原虫表位的模型；3)测试重组和化学连接的“分子” 佐剂“用于提高疫苗颗粒的保护效力的能力；以及4)确定最佳 选定候选疫苗的配方、路线和剂量。这两个强大的组合 技术、WHcAg载体平台和恶性疟原虫/伯氏疟原虫杂交子孢子挑战模型， 将使各种CS-WHcAg杂化颗粒免疫原的生产能够进行测试 针对恶性疟原虫的体内感染模型系统的保护效果。

Summary Statement Given the very high burden malaria imposes on many developing countries, the overall objective of this proposal is to develop a P. falciparum malaria-specific immunogen that may be useful as an affordable and effective vaccine to prevent malaria. The current most effective malaria vaccine candidate (RTS,S/AS02A) is based on the use of a particulate carrier platform (the HBsAg) fused to malaria circumsporozoite (CS)-specific T and B cell epitopes. Current limitations of the RTS,S vaccine have been a requirement for reactogenic adjuvants and transient protection. A further potential complication is that the carrier is derived from a human pathogen, the hepatitis B virus (HBV). To circumvent these problems a non-human pathogen-derived carrier platform has been developed, specifically the core protein from the woodchuck hepadnavirus (WHcAg). Modified WHcAg particles will be used as the vaccine platform for several reasons: CS-WHcAg hybrid particles elicit extremely high levels of anti-CS antibodies; the immune tolerance to HBcAg and HBsAg in HBV chronic carriers (400 million worldwide) can be circumvented by the use of the WHcAg platform; and because CS- WHcAg hybrid particles can be made in bacteria, production of a vaccine will be relatively inexpensive. A preliminary CS-WHcAg hybrid particle has been developed that contains two neutralizing CS repeat epitopes inserted into the loop region (the insertion site that raises the highest titer anti-insert antibodies) and two "universal" malaria-specific T cell domains fused to the C-terminus. This CS-WHcAg hybrid particle is very immunogenic in mice and is capable of eliciting neutralizing anti-CS repeat antibodies that prevent P. falciparum/P. berghei hybrid sporozoite liver infection in vivo, therefore it is an ideal basis from which to develop a vaccine for human use. The strategy for developing an optimal malaria vaccine is divided into four aims: 1) incorporation of additional CS-derived B cell and T cell neutralizing epitopes; 2) testing the protective efficacy of the vaccine candidates in a hybrid P. falciparum/P. berghei sporozoite model and developing the model to encompass additional P. falciparum epitopes; 3) test recombinant and chemically linked "molecular adjuvants" for their ability to improve protective efficacy of the vaccine particles; and 4) determine optimal formulation, route and dosing of the chosen vaccine candidates. The combination of these two powerful technologies, the WHcAg-carrier platform and the P. falciparum/P. berghei hybrid sporozoite challenge model, will enable the production of a variety of CS-WHcAg hybrid particle immunogens that can be tested for protective efficacy in an in vivo infectious model system specific for P. falciparum malaria.