These data suggested that the red cell membranes were required to target the attenuated parasites to dendritic cells in the spleen and liver, which was observed post-vaccination. Although an adjuvant was not required for induction of protective immune responses, vaccine efficacy was ablated if the red cell membrane was disrupted. Similar protection was observed when mice were vaccinated with chemically attenuated Plasmodium yoelii 17X, although three doses of vaccine provided superior protection compared to one dose. To adapt this for a blood-stage vaccine approach, we vaccinated mice with a single dose of ring-stage Plasmodium chabaudi AS parasitised red blood cells (pRBC) that had been treated in vitro with CM or the related compound, TF-A, and demonstrated long-lasting protection from homologous and heterologous blood-stage challenge. Studies in mice involving vaccination with chemically attenuated sporozoites demonstrated induction of protective immunity. These compounds bind covalently to poly-A regions of DNA. Ĭyclopropylpyrolloindole analogues, such as centanamycin (CM) and tafuramycin-A (TF-A) have been used to successfully attenuate both sporozoite and asexual blood-stage malaria parasites. However, there have been no published clinical studies of whole parasite blood-stage malaria vaccines. CHMI with whole blood-stage parasites is also used for the in vivo assessment of malaria vaccine and drug candidate efficacy (reviewed in ). The administration of whole blood-stage parasites in the context of controlled human malaria infection (CHMI) in human volunteers is not new deliberate malaria infection was used as a treatment for neurosyphilis (malariotherapy) in the early 1900s (reviewed in ). There has been considerable progress with injectable whole parasite Plasmodium falciparum sporozoite (PfSPZ) vaccines. The fundamental rationale for a whole parasite vaccine is that by maximising the number of antigens presented to the immune system, including those that are conserved between different parasite strains, the impact of antigenic polymorphism will be diminished. The limited protection induced by sub-unit vaccine candidates has resulted in renewed interest in the whole organism vaccine approach. Disappointing results following the testing of sub-unit vaccines in clinical trials have highlighted some of the limitations of sub-unit vaccines that need to be addressed, including antigenic polymorphism in critical epitopes. An effective vaccine capable of inducing long-lasting immunity is not currently available. parasites cause more than 200 million clinical cases of malaria and 438,000 deaths per year, with the majority of deaths occurring in children < 5 years of age. falciparum 7G8 pRBC treated with 50 nM TF-A (group A). Cytokine production in CD3 + lymphocyte sub-populations in study participants inoculated with a single dose of 3 × 10 7 P. Cytokine production in naïve and memory T lymphocytes in study participants inoculated with a single dose of 3 × 10 7 P. Monofunctional and polyfunctional CD3 + T cells in study participants inoculated with a single dose of 3 × 10 7 P.

falciparum 7G8 pRBC (infectivity study) untreated. falciparum 7G8 pRBC treated with 50 nM TF-A (group A) or (B) 1,800 P. Serum cytokine responses in study participants inoculated with a single dose of (A) 3 × 10 7 P. falciparum 7G8 pRBC treated with 50 nM (group A) or (B) 200 nM (group B) TF-A. falciparum 7G8 in study participants inoculated with a single dose of (A) 3 × 10 7 P. falciparum 7G8 pRBC treated with 200 nM of TF-A. falciparum 7G8 pRBC treated with 50 nM of TF-A or (B) 3 × 10 7 P. falciparum 7G8 IgG responses in study participants inoculated with a single dose of (A) 3 × 10 7 P. falciparum 7G8 following treatment with different doses of tafuramycin-A. Abnormal laboratory values reported in study participants in group A. Adverse events reported in study participants in group A.

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