Attenuation of Liquid Formulation for PfSPZ Vaccine by X-Ray

X 射线法测定 PfSPZ 疫苗液体制剂的减毒效果

• 批准号: 10391482
• 负责人: STEPHEN Lev HOFFMAN
• 金额: $ 30万
• 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: 2021-04-12 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391482
• 关键词: 3-Dimensional; Adopted; Africa; Africa South of the Sahara; Alanine; Asia; Attenuated; Biological Assay; Biological Products; Burkina Faso; COVID-19; COVID-19 pandemic; Characteristics; Child; Clinical Trials; Contracts; Country; Cryopreservation; Culicidae; Cyclic GMP; Disease; Dose; Ensure; Environment; Equatorial Guinea; Event; Falciparum Malaria; Future; Geographic Locations; Germany; Goals; Harvest; Hepatocyte; Human; In Vitro; Infection prevention; International; Interruption; Licensing; Liquid substance; Location; Malaria; Malaria Vaccines; Mali; Maps; Methods; Monitor; Mus; Parasites; Parasitic Diseases; Persons; Phase; Phase III Clinical Trials; Plants; Plasmodium falciparum; Plasmodium falciparum vaccine; Population; Preparation; Process; Radiation; Regimen; Reproducibility; Rodent; Roentgen Rays; Salivary Glands; Sampling; Security; Seminal; Source; Sporozoites; Suspensions; Technology; Time; Training; Tube; Vaccine Production; Vaccines; Visit; Work; attenuation; clinical development; comparative; cost; cost effective; design; dosimetry; humanized mouse; improved; in vivo; ionization; irradiation; liquid formulation; malaria infection; manufacturing process; manufacturing scale-up; novel strategies; operation; prevent; programs; public health relevance; radiation delivery; real time monitoring; scale up; tool; transmission process; vaccine candidate; vaccine efficacy; x-ray irradiation

PROJECT SUMMARY: PfSPZ Vaccine, supported in clinical development by the International PfSPZ Consortium, is on track to be the first US FDA-licensed vaccine against malaria or any human parasitic disease. The vaccine has been safe, well tolerated, and protective against homologous (same strain) and heterologous (different strains) of Plasmodium falciparum (Pf) malaria in 19 clinical trials in 11 countries. To date, 80–100% vaccine efficacy (VE) has been shown against controlled human malaria infection (CHMI), VE that has been demonstrated for at least 8 months against heterologous and 14 months against CHMI, and at least 18 months sustained VE against intense transmission of heterogeneous strains of Pf in Burkina Faso with a 3-dose regimen. Trials in Mali, Equatorial Guinea, and Germany have established optimized regimens in preparation for Phase 3 clinical trials starting in Q1 2021, which will support a Biologics License Application to the FDA in 2022. PfSPZ Vaccine is composed of radiation-attenuated, aseptic, purified, cryopreserved Pf sporozoites (SPZ). The PfSPZ are produced in mosquitoes, and attenuated by -irradiation from a 60Co source while in the mosquitoes’ salivary glands. Our goals are to convert to irradiation of extracted, purified, PfSPZ in a suspension termed vaccine bulk product (VBP) and to convert the PfSPZ attenuation process from -irradiation to X-irradiation. Real-time ionization chamber dosimetry will be introduced to monitor dose administration and to ensure attenuation. These three major changes to the process of attenuation will increase efficiency of manufacturing and decrease the vaccine cost by: 1) allowing for fewer irradiation events of higher numbers of PfSPZ in smaller volumes, 2) bringing the irradiation process inside the clean room facility; 3) eliminating costly 60Co- related expenses, training, and security concerns, and 4) provide a more scalable process for mass vaccine production. It will also establish a method suitable for attenuating in vitro-generated PfSPZ that are planned to replace mosquito-produced PfSPZ in the next 4 years. X-irradiation was the method used in the 1967 proof of principle studies demonstrating that attenuated rodent malaria SPZ could protect mice against malaria. Subsequent studies adopted -irradiation for attenuation because this method was, at the time more accurate and replicable. However, X-ray technology has vastly improved, and the benefits of X-ray attenuation make this approach much superior to -irradiation. As Sanaria further scales up GMP manufacturing, plans to build manufacturing plants in Africa and Asia, and aims to integrate in vitro-produced PfSPZ into PfSPZ Vaccine, irradiation will optimally occur with the PfSPZ in liquid suspension as VBP. Inherently, X-irradiation is far more efficient, amenable to scale up and cost effective than 60Co-irradiation. Three Specific Aims outline the work to be performed: 1) Define the parameters to irradiate Vaccine Bulk Product liquid suspensions; 2) Determine the minimal dose of X-irradiation required to completely attenuate PfSPZ; 3) Develop the use of ionization chamber dosimetry for real-time monitoring of irradiation dose.

项目摘要： 由国际PFSPZ联盟支持的PFSPZ疫苗，在临床开发方面，有望成为 首先是美国FDA许可的疫苗针对疟疾或任何人类寄生虫病。疫苗是安全的， 耐受性良好，并防止同源（相同菌株）和异源（不同菌株） 在11个国家 /地区的19个临床试验中，恶性疟原虫（PF）疟疾。迄今为止，疫苗效率为80–100％ 已经显示出针对受控的人类疟疾感染（CHMI），已证明了AT 至少8个月对异源和针对CHMI的14个月，至少18个月持续 用3剂治疗方案反对布基纳法索中PF的异质菌株的强烈传播。试验 马里，赤道几内亚和德国已经建立了优化方案，以准备3阶段临床 从Q1 2021开始的试验，该试验将在2022年支持FDA的生物制品申请。PFSPZ 疫苗由辐射衰减，无菌性，纯化，冷冻保存的PF孢子岩（SPZ）组成。 PFSPZ是在蚊子中产生的，并在蚊子中从60co来源的辐射减弱。 唾液腺。我们的目标是转换为被称为悬架中提取，纯化的PFSPZ的辐照 疫苗散装产品（VBP），并将PFSPZ衰减过程从辐射转换为X-irradiation。 将引入实时电离室剂量测定法以监测剂量给药并确保 衰减。衰减过程的这三个主要更改将提高制造效率 并通过以下方式降低疫苗成本：1）允许更少的PFSPZ数量的辐照事件 较小的体积，2）将辐照过程带入洁净室设施内； 3）消除昂贵的60co- 相关费用，培训和安全问题，以及4）为大规模疫苗提供更可扩展的过程 生产。它还将建立一种适合衰减体外生成的PFSPZ的方法，该方法计划用于 在接下来的4年中，更换蚊子生产的PFSPZ。 X-radiation是1967年证明的方法 原则研究表明，减弱的啮齿动物疟疾SPZ可以保护小鼠免受疟疾的侵害。 随后的研究采用辐射以进行衰减，因为此方法是更准确的 可复制。但是，X射线技术已大大提高，X射线衰减的好处使得 这种方法优于辐射。随着Sanaria进一步扩大GMP制造，计划建造 非洲和亚洲的制造工厂，旨在将体外生产的PFSPZ整合到PFSPZ疫苗中， PFSPZ将在液体悬浮液中作为VBP最佳地进行辐射。固有地，X射线更大得多 有效，可以扩大比例比60co-radiation。三个特定目标概述了工作 进行：1）定义参数以照射疫苗大量产物液体悬浮液； 2）确定 完全衰减PFSPZ所需的X辐射剂量最小； 3）开发电离的使用 用于实时监测辐射剂量的腔剂量测定法。