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: 10388090
• 负责人: B. KIM LEE SIM
• 金额: $ 127.92万
• 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/10388090
• 关键词: Address; 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; GTP-Binding Protein alpha Subunits, Gs; 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; Mosaicism; 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; base; cost; immunogenicity; improved; in vivo; 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.

恶性疟原虫（PF）Sporozoite（SPZ）的疫苗表现出极好的安全性和疫苗功效 （VE）在非洲，欧洲和美国进行的25多次临床试验中；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 VE的宽度，大小和/或耐用性增加，商品成本降低。第一代和第二代 无菌，纯化，冷冻保存的PFSPZ疫苗，无论是辐射，化学剂还是遗传销售的疫苗 由西方（W.）非洲PF的PF组成，NF54。在东部东部（E.）非洲PF菌株更多 与非洲菌株相比，远离NF54的遗传学距离，亚洲菌株在遗传上要远得多 来自NF54的任何非洲PF菌株。因此，有可能在E.非洲的E.非洲菌株中免疫。 非洲将比通过W.非洲菌株（NF54）免疫更具保护性。同样，可以免疫 亚洲的亚洲PF菌株可能比使用NF54这样的非洲菌株免疫更具保护性。 在这个项目中，我们将确定，表征和优化来自E.非洲和亚洲菌株的PFSPZ生产 pf。我们过去遇到的问题之一是无法产生大量阶段V 除NF54以外的任何PF菌株中，配子细胞/培养物和PFSPZ/蚊子。我们已经确定了一个亚洲人（泰语） 菌株，NHP4026，这是一个很好的V级配子细胞和PFSPZ生产者，尽管不如NF54好。到 达到奇偶校验，并超过V阶段的Gametocyte和PFSPZ的生产，我们将在基因上设计E. E. 非洲和亚洲PF通过过表达PFAP2-G的转录因子是性阶段的关键调节因子 发展。我们将单独使用这些新菌株，或者正如Theilera Parva成功显示的那样 （东海岸热）非洲和Prevnar的疫苗，全球使用的肺炎链球菌疫苗，我们 将混合寄生虫创建疫苗鸡尾酒。在疫苗中产生多种PF菌株将更多 比产生单个压力昂贵。因此，我们将通过遗传交叉产生杂种寄生虫以包括 单个PF寄生虫中所需的遗传/蛋白质组学多样性。这将为如何提供概念证明 产生PFSPZ免疫原子，以防止全球PF多样性。我们建议增加 通过选择更感染的PFSPZ，免疫反应对任何剂量PFSPZ的幅度/效力 到肝细胞并通过遗传改变来创建，以后逮捕复制部分PFSPZ 与当前捕捉辐射 - 和 遗传衰减的PFSPZ。佐剂通常提供了提高耐用性的最直接途径 疫苗。我们已经确定了一种糖脂佐剂，可提高鼠的效力和耐用性 疟疾SPZ疫苗。在这个项目中，我们将确定该佐剂对 我们通过在非人类灵长类动物中评估杂种和晚期逮捕菌株。目标是提供 PFSPZ候选疫苗候选者有望进一步下游过程开发和未来的临床评估。