Abstract
Genetically attenuated sporozoite vaccines can elicit long-lasting protection against malaria but pose risks of breakthrough infection. Chemoprophylaxis vaccination (CVac) has proven to be the most effective vaccine strategy against malaria. Here, we demonstrate that a liver stage-specific autophagy mutant of Plasmodium berghei (ATG8 overexpressor), when used as a live vaccine under a CVac regimen, provides superior long-lasting protection, in both inbred and outbred mice, as compared to WT-CVac. Uniquely, the protection elicited by this mutant is predominantly dependent on a CD8+ T-cell response through an IFN-γ-independent mechanism and is associated with a stable population of antigen-experienced CD8+ T cells. Jointly, our findings support the exploitation of liver-stage mutants as vaccines under a CVac protocol. This vaccination strategy is also a powerful model to study the mechanisms of protective immunity and discover new protective antigens.
Highlights
Malaria caused by Plasmodium parasites remains an infectious disease of major public health importance
Vaccination using WT sporozoites in conjunction with an antimalarial drug administered as prophylaxis (CVac) has shown enhanced efficacy as a whole organism vaccine because the parasite progresses through all liver developmental stages, a potent immune response is triggered against significant biomass of immunogens and the risk of acute blood-stage infection is eliminated with drug treatment
A live sporozoite-Chemoprophylaxis vaccination (CVac) vaccine protocol remains difficult to control in the human population as it crucially relies on the drug regimen and proper use by individuals, and could lead to sporadic development of malaria symptoms in case of failure
Summary
Malaria caused by Plasmodium parasites remains an infectious disease of major public health importance. Malaria vaccine development is a continuously evolving field of research, which aims towards a vaccine with long-lasting stages, strain, and species transcending sterile immunity. Such an ideal vaccine is more essential than ever in the face of increasing resistance to frontline drugs by malaria parasites. Among whole sporozoite vaccines (WSV), radiation-attenuated sporozoites (RAS) have been considered the “gold standard” model for induction of full and sterilizing immunity against malaria[5,10]. A GAP with a late liver stage arresting phenotype would induce stronger and broader protective immune responses. Published in partnership with the Sealy Institute for Vaccine Sciences erythrocytic parasites and the potential use of GAP under a CVac and late (55 h p.i.) liver stage development (Fig. 1e). Difference in the number of EEF per well was observed between the two strains at 24 and 48 h p.i., a significantly higher
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