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

Moita, D.; Rôla, C.; Nunes-Cabaço, H.; Nogueira, G.; Maia, T.G.; Othman, A.S.; ... ; Prudêncio, M. (2023)

Article / Letter to editor

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.

• All authors: Moita, D.; Rôla, C.; Nunes-Cabaço, H.; Nogueira, G.; Maia, T.G.; Othman, A.S.; Franke-Fayard, B.; Janse, C.J.; Mendes, A.M.; Prudêncio, M.
• Date: 2023-11-24
• Journal: npj Vaccines
• Volume: 8
• Issue: 1
• DOI: doi:10.1038/s41541-023-00778-9
• Link: https://www.nature.com/articles/s41541-023-00778-9