Controlled human malaria infections by mosquito bites induce more severe clinical symptoms than asexual blood-stage challenge infections

& nbsp;Background Fever and inflammation are a hallmark of clinical Plasmodium falciparum (Pf) malaria induced by circulating asexual parasites. Although clinical manifestations of inflammation are associated with parasite density, this relationship is influenced by a complex network of immune-modulating factors of both human and parasite origin.& nbsp;Methods In the Controlled Human Malaria infection (CHMI) model, we compared clinical inflammation in healthy malaria-nay & BULL;ve volunteers infected by either Pf-infected mosquito bites (MB, n=12) or intravenous administration of Pf-infected red blood cells (BS, n=12).& nbsp;Findings All volunteers developed patent parasitaemia, but both the incidence and duration of severe adverse events were significantly higher after MB infection. Similarly, clinical laboratory markers of inflammation were significantly increased in the MB-group, as well as serum pro-inflammatory cytokine concentrations including IFN-g, IL 6, MCP1 and IL-8. Parasite load, as reflected by maximum parasite density and area under the curve, was similar, but median duration of parasitaemia until treatment was longer in the BS-group compared to the MB-group (8 days [range 8 8 days] versus 5.5 days [range 3.5 12.5 days]). The in vitro response of subsets of peripheral blood mononuclear cells showed attenuated Pf-specific IFNg production by gd T-cells in the BS-arm. Interpretation In conclusion, irrespective the parasite load, Pf-infections by MB induce stronger signs and symptoms of inflammation compared to CHMI by BS infection. The pathophysiological basis remains speculative but may relate to induced immune tolerance. Copyright (C)& nbsp;2022 The Authors. Published by Elsevier B.V.