A genetically modified Plasmodium falciparum sporozoite vaccine attenuated at the late-liver stage

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ABSTRACT In 2020 malaria caused 241M clinical cases and 627,000 deaths, the greatest numbers of annual deaths since 2012. There were more deaths in Africa from malaria than from COVID-19. There is an urgent unmet medical need for a malaria vaccine that prevents infection and disease in individuals and can be deployed in mass vaccination programs for malaria elimination. The RTS,S malaria vaccine was shown in a pilot implementation program in >900,000 African infants to significantly reduced hospital admissions for malaria by 21% and severe malaria by 30%. In late 2021 it was recommended by WHO for immunization of 5-month-olds. However, it did not significantly reduce cerebral malaria, severe malaria anemia, or overall mortality, or prevent Plasmodium falciparum (Pf) infection. Of vaccines under development, only Sanaria’s PfSPZ vaccines have the efficacy against Pf infection to be considered for prevention of Pf infection in individuals or geographically focused Pf malaria elimination campaigns. Sanaria’s 1st generation vaccine, PfSPZ Vaccine, is composed of radiation-attenuated Pf sporozoites (SPZ), which arrest early in the liver stage. Sanaria’s 2nd generation vaccine is PfSPZ-CVac (Chemoprophylaxis Vaccine). In PfSPZ-CVac, the parasites replicate in the liver, biologically amplifying the immunogen load by up to 50,000-fold and then are killed by an anti-malarial drug. PfSPZ-CVac co-administered with chloroquine (CQ), gave 100% vaccine efficacy (VE) against heterologous controlled human malaria infection (CHMI) 12 weeks after vaccination using 22% the dose of PfSPZ needed to achieve 80% VE at 9-10 weeks against heterologous CHMI with PfSPZ Vaccine. PfSPZ-CVac (CQ) is therefore more protective than PfSPZ Vaccine at ~1/5 the dose. However, transient symptoms of malaria can occur after 1st dose of PfSPZ, and if CQ is not administered appropriately, parasite multiplication in the blood could cause severe malaria. In our Phase I grant, to retain the enhanced potency of PfSPZ-CVac and eliminate its drawbacks, we genetically altered Pf to be able to fully replicate, but arrest prior to entering the blood by deleting first one and then a 2nd gene to produce PfSPZ-LARC2 Vaccine and produced a master cell bank (MCB). This vaccine is now being manufactured in compliance with cGMPs to produce PfSPZ-LARC2 Vaccine and will be assessed for safety and efficacy in a clinical trial in the 2nd half of 2022. In this Phase II grant, we propose to 1) manufacture 2 lots of this late arresting, replication competent (LARC) vaccine (PfSPZ-LARC2), which is based on an African Pf parasite, for assessment in expanded clinical trials, 2) manufacture a Thai strain of Pf (NHP4026) containing Asian variant antigens for regulatory agency directed vaccine assessment, and 3) produce a PfSPZ-LARC2 vaccine based on NHP4026 that can be combined with African LARC2 as a pan-global vaccine if needed. The project is intended to produce a potent, cost effective PfSPZ vaccine that protects against highly variant Pf parasites worldwide.