Attenuation of Liquid Formulation for PfSPZ Vaccine by X-Ray

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.