Table 1. Challenges and suggested lines of research for CPS and GAP.
| Challenges | Lines of research |
|---|---|
| CPS | |
| Optimization of the prophylactic drug protocol | - Direct comparison of different drugs (e.g. primaquine, pyrimethamine, artesunate, azithromycin, clindamycin or piperaquine) for CPS in humans - Development of immunization with a single dose drug regimen - Re-assessment of the drug-development pipeline for novel candidates |
| Development of a program of mass administration using live sporozoite immunization and drug cover in malaria endemic areas | - Proof-of-concept of CPS with injectable sporozoites - Assessment of vaccine efficacy in endemic areas, and the effect of pre-existing immunity and/or (sub-clinical) blood infection - Evaluation of the effect of post-vaccination natural exposure on vaccine induced immunity |
| GAP | |
| Ensuring GAPs are completely attenuated | - Generation of multiple gene deletion mutant (each gene governing an independent and essential liver-stage function) - Generation of GAPs encoding proteins (toxins), which when expressed terminate parasite development in the liver |
| Optimizing GAP potency | - Generation of late arresting GAPs - Creating a GAP that re-capitulates the features of CPS (i.e. arrest immediately after parasite entry into the blood); possibly utilizing inducible and/or auxotrophic systems |
| General—whole sporozoite immunization | |
| Elucidation of immune mechanisms of protection | - Development of functional assays to evaluate pre-erythrocytic cellular and humoral immunity in immunized humans |
| Identification of key antigens and immune modulators of protection | - In vitro stimulation of T cells with synthetically produced overlapping peptides - Assessment of IFNγ production by T cells to recombinantly expressed or synthetic Plasmodium proteins (cross-) presented by autologous monocyte-derived DCs - Analysis of antibody specificities by protein microarrays - Sequencing of the B cell receptor repertoire of circulating plasmablasts and memory B cells after immunization |
| Generation of strain transcending immunity and improvement of durability of protection | - Immunization using multiple Plasmodium strains; isolation and characterization of alternative strains for CHMI and immunization - Optimal dose finding |
| Improvement of route of administration and | - Establish a route of administration most effective and suitable for use in large campaigns targeting young children in malaria endemic countries |
| Reduction of costs and improvement of practicality of whole sporozoite vaccination | - Improvement of sporozoite preservation, alteration of sporozoites; maintain viability during transport on ice or at room temperature - Establishment of axenic in vitro culture of sporozoites to eliminate the requirement for mosquito-based production |