Malaria Vaccine Based on Self-Assembling Polypeptide Nanoparticles (SAPN)

描述（由申请方提供）：恶性疟原虫疫苗的开发已被证明是一项艰巨的生物工程挑战。全世界有5亿人受疟疾折磨，每年约有300万人死亡，其中大多数是儿童。“RTS，S”是迄今为止最成功的疟疾候选疫苗，在临床和田间攻击研究中仅提供约40%的人类保护效力，并且它需要与佐剂一起配制以实现保护性免疫原性。该申请的广泛的长期目标是开发自组装多肽纳米颗粒（SAPN）作为恶性疟原虫疟疾疫苗的基础，该疫苗可能比目前临床试验中的疫苗更具保护性，显示出优异的热稳定性，并且可以在没有佐剂的情况下递送，这可能与适合在没有冷链的情况下递送的制剂一致。SAPN由线性多肽（LP）结构单元组装而成。每个LP由通过接头分开的五聚体和三聚体卷曲螺旋结构域组成，其中表位抗原在内部以及在N-和C-末端上展示。所提出的工作旨在确定用于在SAPN上展示B细胞和T细胞表位以产生最有效的免疫原性和保护性免疫应答的最佳构型。展示伯氏疟原虫CSP表位（类似于RTS，S中的恶性疟原虫CSP B细胞表位）的SAPN已显示在伯氏疟原虫小鼠疟疾模型中刺激针对致死子孢子攻击的持久保护性免疫应答，而不需要佐剂。SAPN颗粒本身已显示出具有佐剂活性。这表明SAPN平台潜在地上级于迄今为止使用的其他蛋白疫苗技术，因为这些技术都需要添加外来佐剂以具有保护性。我们开发管线中的SAPN疫苗将评估其免疫增强机制（佐剂性）;针对表达来自恶性疟原虫（人疟疾）的CSP转基因的伯氏疟原虫（小鼠疟疾）菌株攻击的保护效力;以及使用人HLA转基因小鼠在人HLA背景中由特异性恶性疟原虫T细胞表位提供的免疫原性/保护性应答。具体目标是：（2）确定通过向具有免疫显性PfCSP B细胞表位的优化密度的SAPN中添加泛等位基因HTL和CTL表位所提供的免疫应答的增强;和（3）在非人灵长类动物（NHP）模型中评价对先导PfCSP SAPN候选疫苗的安全性、反应原性和免疫应答。该研发计划预计将推进创新疫苗平台，并开发基于恶性疟原虫CSP的B细胞和T细胞表位抗原的疟疾疫苗，该疫苗已在临床和田间试验中证明了成功但有限的保护功效，如RTS，S in AS 02 A。成功应该使拟议的研究有资格获得进一步的资金用于人类使用的产品开发和疫苗试验。公共卫生相关性：一种疟疾疫苗将基于一种新技术，自组装肽纳米颗粒，显示疟疾寄生虫免疫原先前显示引发疟疾的保护性免疫。这一新的疫苗平台有望最终为发展中国家生产廉价的疟疾疫苗。

DESCRIPTION (provided by applicant): The development of a vaccine against P. falciparum has proven to be a difficult bioengineering challenge. Malaria afflicts 500 million people worldwide and annually kills about 3 million people, mostly children. "RTS,S", the most successful malaria vaccine candidate to date, provides only about 40% protective efficacy in humans in clinical and field challenge studies, and it requires formulation with an adjuvant to achieve protective immunogenicity. The application's broad, long-term objective is to develop self-assembling polypeptide nanoparticles (SAPN) as the basis for a P. falciparum malaria vaccine that is potentially more protective than those currently in clinical trials, shows excellent heat stability, and can be delivered without an adjuvant, which is likely to be consistent with formulations suited for delivery without a cold chain. SAPN assemble from linear polypeptide (LP) building blocks. Each LP consists of pentameric and trimeric coiled-coil domains separated by a linker, with epitope antigens displayed internally and on the N- and C- termini. The proposed work aims to identify the best configuration for the display of B cell and T cell epitopes on SAPN for producing the most potent immunogenic and protective immune response. SAPN displaying the P. berghei CSP epitope (analogous to the P. falciparum CSP B-cell epitope in RTS,S) have been shown to stimulate a long lasting protective immune response against a lethal sporozoite challenge in the P. berghei mouse malaria model without the need for an adjuvant. The SAPN particles have been shown themselves to have adjuvant activity. This suggests that the SAPN platform is potentially superior to other protein vaccine technologies used to date as these have all required the addition of extraneous adjuvants to be protective. The SAPN vaccines in our development pipeline will be evaluated for their mechanism of immune enhancement (adjuvanticity); protective efficacy against challenge with a strain of P. berghei (mouse malaria) expressing the CSP transgene from P. falciparum (human malaria); and immunogenic/protective response provided by specific P. falciparum T cell epitopes in human HLA backgrounds using human-HLA transgenic mice. The Specific Aims are to: (1) Design and produce SAPN in order to determine the optimal density of the immunodominant PfCSP B-cell epitope to stimulate a potent antibody response; (2) Determine the enhancement to the immune response provided by the addition of pan allelic HTL and CTL epitopes to SAPN with the optimized density of immunodominant PfCSP B cell epitope; and (3) Evaluate the safety, reactogenicity and immune response to the lead PfCSP SAPN vaccine candidate in a non-human primate (NHP) model. This R&D plan is expected to advance an innovative vaccine platform and to develop a malaria vaccine based on B cell and T cell epitope antigens from P. falciparum CSP that have already demonstrated successful, though limited, protective efficacy in clinical and field trials as RTS,S in AS02A. Success should qualify the proposed research for further funding for human- use product development and vaccine trials. PUBLIC HEALTH RELEVANCE: A malaria vaccine will be developed based on a new technology, self-assembling peptide nanoparticles, that display malaria parasite immunogens previously shown to elicit protective immunity to malaria. This new vaccine platform holds promise for ultimately producing an inexpensive malaria vaccine for the developing world.