Expanding the breadth, magnitude, and durability of PfSPZ vaccines by creating multi-strain vaccines, designer hybrid and genetically altered parasite vaccines and use of a unique adjuvant.

通过创建多株疫苗、设计混合疫苗和转基因寄生虫疫苗以及使用独特的佐剂，扩大 PfSPZ 疫苗的广度、规模和持久性。

• 批准号: 10598124
• 负责人: B. KIM LEE SIM
• 金额: $ 124.37万
• 依托单位: SANARIA, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-08 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598124
• 关键词: Adjuvant; Affect; Africa; African; Antibodies; Antigens; Area; Asia; Asian; Attenuated; Biological Models; Cellular Immunity; Child; Clinical Trials; Cryopreservation; Culicidae; Development; Disease; Distant; Dose; East Coast Fever; Europe; Exhibits; Falciparum Malaria; Future; Generations; Genetic; Genetic Crosses; Genetic Engineering; Genetic Variation; Geographic Locations; Geography; Glycolipids; Goals; Hepatocyte; Human; Hybrids; Immune response; Immunize; Individual; Infection prevention; Licensing; Liver; Macaca mulatta; Malaria; Monkeys; Mus; Mutation; Parasites; Performance; Persons; Phase; Plasmodium falciparum; Plasmodium falciparum vaccine; Pneumococcal vaccine; Prevnar; Process; Production; Proteomics; Radiation; Route; Safety; Source; Sporozoite vaccine; Sporozoites; Vaccination; Vaccine Production; Vaccines; Vertebral column; cost; immunogenicity; improved; in vivo; manufacture; mosaic; new technology; next generation; nonhuman primate; novel; overexpression; parity; protective efficacy; research clinical testing; response; tool; transcription factor; transmission process; vaccine candidate; vaccine efficacy

Plasmodium falciparum (Pf) sporozoite (SPZ)-based vaccines have shown excellent safety and vaccine efficacy (VE) in more than 25 clinical trials in Africa, Europe, and the US; Phase 3 assessment will begin in mid 2020. Our goal during the next decade is to develop, license, and deploy next generation PfSPZ vaccines with increased breadth, magnitude, and/or durability of VE and decreased cost of goods. The 1st and 2nd generation aseptic, purified, cryopreserved PfSPZ vaccines, whether radiation-, chemo-, or genetically-attenuated are composed of Pf of the West (W.) African strain of Pf, NF54. In general East (E.) African strains of Pf are more distant genetically from NF54 than are W. African strains, and Asian strains are much more distant genetically from NF54 than are any African Pf strains. Thus, it is possible that immunizing with an E. African strain in E. Africa will be more protective than immunizing with the W. African strain, NF54. Likewise, immunizing with an Asian strain of Pf in Asia will likely be more protective than immunizing with a W. African strain like NF54. In this project we will identify, characterize and optimize PfSPZ production from E. African and Asian strains of Pf. One of the problems we have had in the past is the inability to produce large numbers of stage V gametocytes/ culture and PfSPZ/ mosquito from any Pf strain except NF54. We have identified an Asian (Thai) strain, NHP4026, that is a good stage V gametocyte and PfSPZ producer, although not as good as NF54. To achieve parity and ideally exceed stage V gametocyte and PfSPZ production, we will genetically engineer the E. African and Asian Pf by overexpressing PfAP2-G a transcription factor that is a key regulator of sexual stage development. We will use these new strains alone or as has been successfully shown for the Theilera parva (East Coast Fever) vaccine in Africa and Prevnar, the Streptococcus pneumoniae vaccine used worldwide, we will mix the parasites to create a vaccine cocktail. Producing multiple strains of Pf in a vaccine will be more expensive than producing a single strain. Thus, we will produce hybrid parasites by genetic crossing to include the desired genetic/ proteomic diversity in a single Pf parasite. This will provide proof of concept for how to generate PfSPZ immunogens protecting against global Pf diversity. We propose to increase the magnitude/potency of the immune response to any dose of PfSPZ by selecting for PfSPZ that are more infective to hepatocytes and by creating through genetic alteration, late arresting replication component PfSPZ that express many more antigens and more of each antigen than do current early arresting radiation- and genetically-attenuated PfSPZ. Adjuvants have often provided the most direct route to increasing the durability of vaccines. We have identified a glycolipid adjuvant that increases the potency and durability of murine malaria SPZ vaccines. In this project we will determine the impact of this adjuvant on the immunogenicity of the hybrid and late arresting strains we develop by assessing in non-human primates. The goal is to provide PfSPZ vaccine candidate(s) poised for further downstream process development and future clinical evaluation.

基于恶性疟原虫 (Pf) 子孢子 (SPZ) 的疫苗已显示出出色的安全性和疫苗功效 (VE) 在非洲、欧洲和美国进行了超过 25 项临床试验；第三阶段评估将于 2020 年中期开始。 我们未来十年的目标是开发、许可和部署下一代 PfSPZ 疫苗 增加 VE 的广度、规模和/或耐用性并降低商品成本。第一代和第二代 无菌、纯化、冷冻保存的 PfSPZ 疫苗，无论是放射减毒、化学减毒还是基因减毒 由西非 (W.) 非洲 Pf 菌株 NF54 的 Pf 组成。一般来说，东非 Pf 菌株更多 与西非品系相比，NF54 的遗传距离较远，亚洲品系的遗传距离更远 与任何非洲 Pf 菌株相比，来自 NF54 的菌株更多。因此，用大肠杆菌中的非洲大肠杆菌株进行免疫是可能的。 非洲将比使用西非毒株 NF54 进行免疫更具保护性。同样，免疫接种 在亚洲接种 Pf 亚洲毒株可能比使用 NF54 等西非毒株进行免疫更具保护性。 在该项目中，我们将鉴定、表征和优化东非和亚洲菌株的 PfSPZ 生产 的 Pf。我们过去遇到的问题之一是无法大量生产V阶段 来自除 NF54 之外的任何 Pf 菌株的配子细胞/培养物和 PfSPZ/蚊子。我们已经确定了一名亚洲人（泰国人） NHP4026 菌株是良好的 V 期配子体和 PfSPZ 生产者，尽管不如 NF54。到 实现均等并理想地超过 V 阶段配子细胞和 PfSPZ 产量，我们将对大肠杆菌进行基因工程改造。 非洲和亚洲 Pf 通过过度表达 PfAP2-G 来实现，PfAP2-G 是性阶段关键调节因子的转录因子 发展。我们将单独使用这些新菌株，或者像 Theilera parva 已成功展示的那样使用这些新菌株 非洲的（东海岸热）疫苗和全世界使用的肺炎链球菌疫苗 Prevnar，我们 将混合寄生虫以制成疫苗混合物。在疫苗中生产多种 Pf 菌株将更加有效 比生产单一菌株昂贵。因此，我们将通过基因杂交产生杂种寄生虫，包括 单个 Pf 寄生虫中所需的遗传/蛋白质组多样性。这将为如何提供概念证明 产生 PfSPZ 免疫原，防止全球 Pf 多样性。我们建议增加 通过选择更具传染性的 PfSPZ，对任何剂量的 PfSPZ 产生的免疫反应的强度/效力 到肝细胞，并通过基因改变产生晚期抑制复制成分 PfSPZ， 与目前的早期阻止辐射相比，表达更多的抗原以及每种抗原的更多量 基因减毒 PfSPZ。佐剂通常提供了提高耐久性的最直接途径 疫苗。我们已经确定了一种糖脂佐剂，可以提高鼠类药物的效力和持久性 疟疾 SPZ 疫苗。在这个项目中，我们将确定这种佐剂对免疫原性的影响 我们通过在非人类灵长类动物中进行评估来开发杂交菌株和晚期抑制菌株。目标是提供 PfSPZ 候选疫苗已做好进一步下游工艺开发和未来临床评估的准备。