Attenuation of Liquid Formulation for PfSPZ Vaccine by X-Ray

项目概要： PfSPZ疫苗由国际PfSPZ联盟支持进行临床开发，有望成为 美国FDA批准的第一种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（相同菌株）和异源（不同菌株）的 在11个国家进行的19项恶性疟原虫（Pf）疟疾临床试验。到目前为止，80-100%的疫苗效力（VE） 已被证明对控制人类疟疾感染（CHMI），VE已被证明为在 抗异源性至少8个月，抗CHMI至少14个月，持续VE至少18个月 在布基纳法索，用3剂方案对抗Pf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的方案，为III期临床试验做准备。 试验将于2021年第一季度开始，这将支持2022年向FDA提出的生物制品许可证申请。PfSPZ 疫苗是由辐射减毒的、无菌的、纯化的、冷冻保存的Pf子孢子（SPZ）组成。的 PfSPZ在蚊子体内产生，并被60 Co源的γ-照射减弱，而在蚊子体内， 唾液腺我们的目标是将提取、纯化的PfSPZ悬浮液转化为辐射， 疫苗散装产品（VBP），并将PfSPZ减毒过程从X射线照射转换为X射线照射。 将采用实时电离室剂量测定法来监测剂量管理， 衰减这三大变化将使工艺衰减，提高制造效率 并通过以下方式降低疫苗成本：1）允许更少的较高PfSPZ数量的辐照事件， 更小的体积，2）将辐照过程引入洁净室设施内; 3）消除昂贵的60 Co- 相关费用、培训和安全问题，以及4）为大规模疫苗接种提供更可扩展的过程 生产它还将建立一种适合于减弱体外产生的PfSPZ的方法， 在未来4年内取代蚊子生产的PfSPZ。X射线照射是1967年证明 主要研究表明减毒啮齿类疟疾SPZ可以保护小鼠免受疟疾。 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准确 并且可以复制。然而，X射线技术已经有了很大的改进，X射线衰减的好处使得 这种方法比直接照射上级得多。随着Sanaria进一步扩大GMP生产规模，计划建立 在非洲和亚洲的生产工厂，旨在将体外生产的PfSPZ整合到PfSPZ疫苗中， 照射最好在PfSPZ作为VBP悬浮液的情况下进行。从本质上讲，X射线辐射 比60 Co辐照更有效、适合放大和成本有效。三个具体目标概述了工作， 执行：1）定义辐照疫苗散装产品液体混悬液的参数; 2）确定 完全衰减PfSPZ所需的最小剂量的X射线照射; 3）开发电离的使用 用于实时监测辐照剂量的腔室剂量测定。

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.