Multiepitope circumsporozoite P.falciparum malaria subunit vaccine displayed on v

描述（由申请人提供）：鉴于疟疾给许多发展中国家造成了非常高的负担，本提案的总体目标是开发一种恶性疟原虫疟疾特异性免疫原，这种免疫原可能作为一种可负担得起的有效疫苗用于预防疟疾。目前最有效的疟疾候选疫苗（RTS,S/AS02A）是基于使用与疟疾环孢子子（CS）特异性T和B细胞表位融合的颗粒载体平台（HBsAg）。目前RTS，S疫苗的局限性是需要反应性佐剂和瞬时保护。另一个潜在的并发症是，携带者来自人类病原体乙型肝炎病毒（HBV）。为了避免这些问题，已经开发了一种非人类病原体衍生的载体平台，特别是土拨鼠肝病毒（WHcAg）的核心蛋白。改良的WHcAg颗粒将被用作疫苗平台，原因如下：CS-WHcAg杂交颗粒可引起极高水平的抗cs抗体；使用WHcAg平台可以规避HBV慢性携带者（全球4亿）对HBcAg和HBsAg的免疫耐受；而且由于CS-WHcAg杂交颗粒可以在细菌中制造，疫苗的生产将相对便宜。已经开发出一种初步的CS- whcag杂交颗粒，其中包含插入环区（可提高最高滴度的抗插入抗体的插入位点）的两个中和CS重复表位和融合到c端的两个“通用”疟疾特异性T细胞结构域。这种CS-WHcAg杂交颗粒在小鼠中具有很强的免疫原性，能够激发中和的抗cs重复抗体，防止恶性疟原虫/P。因此，它是开发人用疫苗的理想基础。开发最佳疟疾疫苗的战略分为四个目标：1)纳入额外的cs来源的B细胞和T细胞中和表位；2)检测候选疫苗对恶性疟原虫/疟原虫杂交株的保护效果。berghei孢子体模型，并开发该模型以包含其他恶性疟原虫表位；3)测试重组和化学连接的“分子佐剂”提高疫苗颗粒保护功效的能力；4)确定所选候选疫苗的最佳配方、途径和剂量。whcag载体平台和恶性疟原虫/P。该模型将能够生产多种CS-WHcAg杂交颗粒免疫原，可在恶性疟原虫疟疾特异性体内感染模型系统中测试其保护功效。疟疾是世界上最重要的致命热带寄生虫病（每年造成150万至270万人死亡），估计每年有3亿至5亿临床新病例。天然的恶性疟原虫感染不会产生有效的免疫，而且多重耐药恶性疟原虫的传播和疟蚊媒介对杀虫剂的抗药性正在阻碍疟疾控制工作。因此，迫切需要一种预防性疫苗来防止这种疾病的进一步传播。

DESCRIPTION (provided by applicant): 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. Malaria is the world's most important lethal tropical parasitic disease (1.5 to 2.7 million deaths each year) with an estimated 300-500 million clinical new cases each year. The natural P. falciparum infection does not result in effective immunity, and malaria control efforts are being impeded by the spread of multiple drug resistant P. falciparum and the development of insecticide resistance by the anopheline mosquito vector. Therefore, a prophylactic vaccine is urgently needed to prevent further spread of this disease.