Expanding the breadth, magnitude, and durability of PfSPZ vaccines by creating multi-strain vaccines, designer hybrid and genetically altered parasite vaccines and use of a unique adjuvant.

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Plasmodium falciparum (Pf) sporozoite (SPZ)-based vaccines have shown excellent safety and vaccine efficacy (VE) in more than 25 clinical trials in Africa, Europe, and the US; Phase 3 assessment will begin in mid 2020. Our goal during the next decade is to develop, license, and deploy next generation PfSPZ vaccines with increased breadth, magnitude, and/or durability of VE and decreased cost of goods. The 1st and 2nd generation aseptic, purified, cryopreserved PfSPZ vaccines, whether radiation-, chemo-, or genetically-attenuated are composed of Pf of the West (W.) African strain of Pf, NF54. In general East (E.) African strains of Pf are more distant genetically from NF54 than are W. African strains, and Asian strains are much more distant genetically from NF54 than are any African Pf strains. Thus, it is possible that immunizing with an E. African strain in E. Africa will be more protective than immunizing with the W. African strain, NF54. Likewise, immunizing with an Asian strain of Pf in Asia will likely be more protective than immunizing with a W. African strain like NF54. In this project we will identify, characterize and optimize PfSPZ production from E. African and Asian strains of Pf. One of the problems we have had in the past is the inability to produce large numbers of stage V gametocytes/ culture and PfSPZ/ mosquito from any Pf strain except NF54. We have identified an Asian (Thai) strain, NHP4026, that is a good stage V gametocyte and PfSPZ producer, although not as good as NF54. To achieve parity and ideally exceed stage V gametocyte and PfSPZ production, we will genetically engineer the E. African and Asian Pf by overexpressing PfAP2-G a transcription factor that is a key regulator of sexual stage development. We will use these new strains alone or as has been successfully shown for the Theilera parva (East Coast Fever) vaccine in Africa and Prevnar, the Streptococcus pneumoniae vaccine used worldwide, we will mix the parasites to create a vaccine cocktail. Producing multiple strains of Pf in a vaccine will be more expensive than producing a single strain. Thus, we will produce hybrid parasites by genetic crossing to include the desired genetic/ proteomic diversity in a single Pf parasite. This will provide proof of concept for how to generate PfSPZ immunogens protecting against global Pf diversity. We propose to increase the magnitude/potency of the immune response to any dose of PfSPZ by selecting for PfSPZ that are more infective to hepatocytes and by creating through genetic alteration, late arresting replication component PfSPZ that express many more antigens and more of each antigen than do current early arresting radiation- and genetically-attenuated PfSPZ. Adjuvants have often provided the most direct route to increasing the durability of vaccines. We have identified a glycolipid adjuvant that increases the potency and durability of murine malaria SPZ vaccines. In this project we will determine the impact of this adjuvant on the immunogenicity of the hybrid and late arresting strains we develop by assessing in non-human primates. The goal is to provide PfSPZ vaccine candidate(s) poised for further downstream process development and future clinical evaluation.