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: 10156019
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10156019
• 关键词: 3-Dimensional; Adopted; Africa; Africa South of the Sahara; Alanine; Asia; Attenuated; Biological; Biological Assay; 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; 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.

项目概要： PfSPZ 疫苗在国际 PfSPZ 联盟的临床开发支持下，有望成为 第一种获得美国 FDA 许可的针对疟疾或任何人类寄生虫病的疫苗。疫苗是安全的， 耐受性良好，并对同源（同一菌株）和异源（不同菌株）具有保护作用 恶性疟原虫 (Pf) 疟疾在 11 个国家进行的 19 项临床试验。迄今为止，疫苗效力 (VE) 为 80–100% 已被证明可对抗受控人类疟疾感染 (CHMI)，VE 已被证明可用于 至少 8 个月针对异源，14 个月针对 CHMI，以及至少 18 个月持续 VE 在布基纳法索，采用 3 剂量方案来对抗 Pf 异种菌株的强烈传播。试验于 马里、赤道几内亚和德国已制定优化方案，为3期临床做准备 试验将于 2021 年第一季度开始，这将支持 2022 年向 FDA 提交生物制品许可证申请。 疫苗由辐射衰减、无菌、纯化、冷冻保存的 Pf 子孢子 (SPZ) 组成。这 PfSPZ 在蚊子体内产生，并在蚊子体内时通过 60Co 源的 γ 辐射而减弱 唾液腺。我们的目标是将提取、纯化的 PfSPZ 悬浮液中的辐照转化为 疫苗散装产品 (VBP) 并将 PfSPZ 减毒过程从 γ 辐射转换为 X 辐射。 将引入实时电离室剂量测定来监测剂量管理并确保 衰减。衰减过程的这三大变化将提高制造效率 并通过以下方式降低疫苗成本：1) 允许较少数量的 PfSPZ 的照射事件 体积更小，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具可扩展性的流程 生产。它还将建立一种适合减弱体外产生的 PfSPZ 的方法，计划 在未来 4 年内取代蚊子生产的 PfSPZ。 X 射线照射是 1967 年证明中使用的方法 原理研究表明，减毒啮齿动物疟疾 SPZ 可以保护小鼠免受疟疾的侵害。 随后的研究采用了γ-辐照进行衰减，因为这种方法在当时更为准确 且可复制。然而，X射线技术已经有了很大的进步，X射线衰减的好处使得 这种方法比γ-辐照优越得多。随着 Sanaria 进一步扩大 GMP 生产规模，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， 辐照最好使用 PfSPZ 作为 VBP 的液体悬浮液进行。从本质上讲，X 射线照射的作用远大于 与 60Co 辐照相比，效率高、易于扩大规模且具有成本效益。三个具体目标概述了工作 执行： 1) 定义照射疫苗散装产品液体悬浮液的参数； 2）确定 完全减弱 PfSPZ 所需的最小 X 射线剂量； 3) 开发电离的使用 室剂量测定用于实时监测辐照剂量。