In 2020 malaria caused 241M clinical episodes and 627,000 deaths, a significant increase from 2019. 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. Based on results of a pilot implementation program in >500,000 infants, RTS,S/AS01 was recommended in late 2021 by WHO for immunization of 5-month-olds with 4 immunizations administered over 21 months. RTS,S significantly reduced hospital admissions for malaria by 21% and severe malaria by 30%. 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 for geographically focused Pf malaria elimination campaigns. Sanaria's 1st generation vaccine, PfSPZ Vaccine, is comprised of radiation-attenuated Plasmodium falciparum (Pf) sporozoites (SPZ), which arrest early in the liver stage. Phase 3 clinical trials will begin in mid 2022, and marketing authorizations in Europe (EMA) and the US (FDA) are planned for 2023/2024. 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 against heterologous CHMI with PfSPZ Vaccine. PfSPZ-CVac (CQ) is 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. 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 a single gene. The first of our late arresting replication competent (LARC) parasites called PfSPZ-LARC1, was completely attenuated in mice with humanized livers and in humans. To increase the potential safety of PfSPZ-LARC vaccines, we created a parasite with two genes deleted, PfSPZ- LARC2, which also arrests late in the liver stage. Sanaria has also achieved in vitro production of PfSPZ, referred to as iPfSPZ, thereby eliminating the need for mosquitoes in manufacturing PfSPZ vaccines and significantly increasing efficiency and decreasing costs of producing PfSPZ vaccines. In this project we will optimize in vitro production and purification of iPfSPZ-LARC2, produce aseptic, purified, cryopreserved iPfSPZ- LARC2 and demonstrate these iPfSPZ-LARC2 are infectious, and can develop into late liver stages but are attenuated. In the next phase, we will manufacture iPfSPZ-LARC2 for assessment in clinical trials.
Public Health Relevance Statement: PROJECT NARRATIVE Malaria afflicts over two billion people, killing over 600,000 individuals each year, mostly children in Africa. A powerful tool is needed for eliminating Plasmodium falciparum malaria from defined geographical areas, ideally a highly effective, long-acting yet low-cost vaccine that prevents infection, disease and parasite transmission. This proposal describes the development, manufacture and quality control release of a Plasmodium falciparum sporozoite vaccine produced entirely in vitro, and genetically attenuated to arrest development in the late liver stage, as the basis for a next-generation, scalable whole sporozoite malaria vaccine that is ready for clinical testing.
Project Terms: Africa; Africa South of the Sahara; Sub-Saharan Africa; Subsaharan Africa; Antigens; immunogen; Antimalarials; Anti-Malarials; Antimalarial Agents; Antimalarial Drugs; anti-malarial agents; anti-malarial drugs; Bite; Blood; Blood Reticuloendothelial System; Child; 0-11 years old; Child Youth; Children (0-21); youngster; Chloroquine; Chlorochin; Khingamin; Clinical Trials; Communities; Cryopreservation; Cryofixation; cold preservation; cold storage; Cessation of life; Death; Disease; Disorder; Dissection; Erythrocytes; Blood erythrocyte; Erythrocytic; Marrow erythrocyte; Red Blood Cells; Red Cell; blood corpuscles; Europe; Female; Genes; Geographic Locations; Geographic Area; Geographic Region; Geographical Location; geographic site; Geography; Goals; Hospitalization; Hospital Admission; Human; Modern Man; Immunization; Immunologic Sensitization; Immunologic Stimulation; Immunological Sensitization; Immunological Stimulation; Immunostimulation; In Vitro; Infant; Infection; Licensure; Liver; hepatic body system; hepatic organ system; Malaria; Paludism; Plasmodium Infections; Cerebral Malaria; Falciparum Malaria; Plasmodium falciparum Malaria; male; Marketing; Methods; mortality; Culicidae; Mosquitoes; Mus; Mice; Mice Mammals; Murine; Persons; Netherlands; Parasites; Pathology; P falciparum; P. falciparum; P.falciparum; Plasmodium falciparum; expectant mother; expecting mother; pregnant mothers; Pregnant Women; Production; Quality Control; Safety; Salivary Glands Head and Neck; Salivary Glands; Vaccination; Vaccines; Generations; base; Vial device; Vial; Procedures; Area; Clinical; Phase; Medical; Immunization Programs; Vaccination Programs; Malaria Vaccines; Malarial Vaccines; vaccines against malaria; Ensure; Fiber; Hepatic Cells; Hepatic Parenchymal Cell; Liver Cells; Hepatocyte; Individual; African; Phase 3 Clinical Trials; phase III protocol; Phase III Clinical Trials; Metabolic; Attenuated; tool; microbioreactor; Bioreactors; programs; Oocysts; Prevent infection; Infection prevention; Sporozoites; Prevention; Radiation; Mass Vaccinations; preventing; prevent; Dose; Symptoms; Detection; Harvest; in vivo; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Vaccine Production; produce vaccines; transmission process; Transmission; Characteristics; Process; Authorization documentation; Authorization; Permission; Development; developmental; cost; vaccine efficacy; next generation; Plasmodium falciparum vaccine; PfSPZ Vaccine; Sporozoite vaccine; Chemoprophylaxis; mouse model; murine model; humanized mouse; humanized mice; malaria infection; malaria-infected; malarial infection; Immunize; human model; model of human; malarial anemia; COVID-19; COVID19; CV-19; CV19; corona virus disease 2019; coronavirus disease 2019; coronavirus disease-19; coronavirus infectious disease-19
