The effect of dosage on the protective efficacy of whole-sporozoite formulations for immunization against malaria

Immunization with Plasmodium sporozoites, either attenuated or administered under the cover of an antimalarial drug, can induce strong protection against malaria in pre-clinical murine models, as well as in human trials. Previous studies have suggested that whole-sporozoite (WSpz) formulations based on parasites with longer liver stage development induce higher protection, but a comparative analysis of four different WSpz formulations has not been reported. We employed a rodent model of malaria to analyze the effect of immunization dosage on the protective efficacy of WSpz formulations consisting of (i) early liver arresting genetically attenuated parasites (EA-GAP) or (ii) radiation-attenuated sporozoites (RAS), (iii) late arresting GAP (LA-GAP), and (iv) sporozoites administered under chemoprophylaxis, that are eliminated upon release into the bloodstream (CPS). Our results show that, unlike all other WSpz formulations, EA-GAP fails to confer complete protection against an infectious challenge at any immunization dosage employed, suggesting that a minimum threshold of liver development is required to elicit fully effective immune responses. Moreover, while immunization with RAS, LA-GAP and CPS WSpz yields comparable, dosage-dependent protection, protection by EA-GAP WSpz peaks at an intermediate dosage and markedly decreases thereafter. In-depth immunological analyses suggest that effector CD8+ T cells elicited by EA-GAP WSpz immunization have limited developmental plasticity, with a potential negative impact on the functional versatility of memory cells and, thus, on protective immunity. Our findings point towards dismissing EA-GAP from prioritization for WSpz malaria vaccination and enhance our understanding of the complexity of the protection elicited by these WSpz vaccine candidates, guiding their future optimization.

Automated summary

Immunization with Plasmodium sporozoites, especially whole-sporozoite (WSpz) formulations, can provide strong protection against malaria. However, a comparative analysis of different WSpz formulations showed that early liver arresting genetically attenuated parasites (EA-GAP) formulation failed to confer complete protection at any immunization dosage, suggesting a minimum threshold of liver development is required for effective immune responses. On the other hand, radiation-attenuated sporozoites (RAS), late arresting GAP (LA-GAP), and sporozoites administered under chemoprophylaxis (CPS) formulations yielded comparable and dosage-dependent protection. Immunological analyses suggested that EA-GAP immunization may negatively impact memory cell functionality and protective immunity.