A CAF01-adjuvanted whole asexual blood-stage liposomal malaria vaccine induces a CD4 + T-cell-dependent strain-transcending protective immunity in rodent models

Abstract

ABSTRACT Malaria is a leading cause of illness and death in children under 5 years of age in Sub-Saharan Africa. Currently, there is no highly efficacious malaria vaccine capable of inducing long-lasting immunity. This has increased interest in exploring different vaccine development strategies, including whole-parasite vaccines, and utilizing more effective adjuvant delivery systems. Here, we evaluate the immunogenicity and protective efficacy of a whole-parasite Plasmodium yoelii 17X blood-stage vaccine formulated with the clinically tested cationic adjuvant formulation, CAF01. The vaccine protected both inbred and outbred mice, and protected mice from homologous and heterologous challenge infections. Tracking of RBC subsets in vaccinated mice demonstrated that vaccine-induced immunity cleared parasitized normocytes as well as reticulocytes. Infection prior to vaccination led to an augmented level of protection and boosted immunity post vaccination. The vaccine induced parasite-specific IgG, mainly of the IgG1 subclass, and cellular responses, with a mixed Th1/Th2/Th17 cytokine profile. Mechanistic studies demonstrated that CD4 + T-cells (but not CD8 + T-cells), and Th1 and Th2 cytokines (interferon gamma and tumor necrosis factor, IL-10) were critical in controlling parasitemia and survival following challenge. Vaccinated µMT mice were not protected, suggesting that B-cells also play a role in protective immunity. Depletion of splenic macrophages with clodronate did not affect vaccine efficacy. These pre-clinical findings will inform the transition of this vaccine candidate into clinical trials. IMPORTANCE Malaria is a devastating disease that has claimed many lives, especially children <5 years of age in Sub-Saharan Africa, as documented in World Malaria Reports by WHO. Even though vector control and chemoprevention tools have helped with elimination efforts in some, if not all, endemic areas, these efforts have been hampered by serious issues (including drug and insecticide resistance and disruption to social cohesion caused by the COVID-19 pandemic). Development of an effective malaria vaccine is the alternative preventative tool in the fight against malaria. Vaccines save millions of lives each year and have helped in elimination and/or eradication of global diseases. Development of a highly efficacious malaria vaccine that will ensure long-lasting protective immunity will be a “game-changing” prevention strategy to finally eradicate the disease. Such a vaccine will need to counteract the significant obstacles that have been hampering subunit vaccine development to date, including antigenic polymorphism, sub-optimal immunogenicity, and waning vaccine efficacy.