Establishing a blood-stage controlled human malaria infection model with Plasmodium falciparum in healthy semi-immune Tanzanian adults

Controlled human malaria infection (CHMI) studies are a critical tool for the assessment and down-selection of potential malaria interventions, allowing detailed characterisation and understanding of host-parasite responses to inform both malaria vaccine and antimalarial drug development in humans. Blood-stage CHMI offers a specific means for proof-of-concept testing of blood-stage malaria vaccines, bypassing the pre-erythrocytic stages of malaria infection. Here, we establish a blood-stage CHMI model in an endemic region in a clinical study involving 12 healthy semi-immune male adult participants residing in Bagamoyo district, Tanzania. Participants were enrolled into relatively 'low' (n=6) and 'high' (n=6) malaria pre-exposure groups as defined by serum anti-schizont IgG levels. Participants were challenged with approximately 1000 erythrocytes infected with a chloroquine-sensitive Plasmodium falciparum 3D7 clone and closely monitored for 28 days at the Ifakara Health Institute clinical trial facility in Bagamoyo. Blood samples were collected for safety and immunology assessments, with venous blood samples for P. falciparum quantitative polymerase chain reaction (qPCR) taken once on day after challenge (C+1) and twice daily from two to 28 days after challenge (C+2 to C+28). Participants were treated once pre-defined diagnostic criteria were met or at day 28 (if criteria not met). The challenge inoculum was found to be safe with the severity grading of adverse events (AEs) in keeping with previous challenge studies. Overall, fewer AEs were reported as compared to malaria-naive UK adults previously challenged with the same inoculum dose, despite a 50-fold higher treatment threshold being used in Tanzanian adults. Nine of 11 participants developed parasitaemia detectable by qPCR and one participant was retrospectively excluded from parasitaemia endpoint analysis due to non-3D7 type infection. The two participants who remained qPCR negative were both in the 'high' pre-exposure group. Higher anti-schizont baseline serology status was associated with later median time to parasitaemia detection and time to pre-defined treatment criteria. These data demonstrate that blood-stage CHMI is safe and feasible in semi-immune adults in a malaria-endemic setting.