An experimental model of clinical immunity for human malaria

Clinical immunity to malaria can reduce fever and lead to asymptomatic infection but the underlying mechanisms remain unclear. To examine the development of clinical immunity, we conducted a multi-cohort, repeat controlled human malaria infection (CHMI) study with Plasmodium vivax, and a heterologous rechallenge with P. falciparum. Malaria-naive adults underwent P. vivax CHMI up to three times, at an interval of 5 to 20 months, by administration of red blood cells infected with the P. vivax PvW1 clone. In the final cohort of the study, a subset of participants underwent heterologous repeat CHMI with the P. falciparum 3D7 clone. Clinical parameters and the host response to infection were measured up to 3 months after each CHMI. Nineteen participants underwent primary CHMI with P. vivax, 12 returned for secondary homologous CHMI and 2 for tertiary homologous CHMI with the same parasite clone. During rechallenge, parasite growth was not attenuated and there was minimal induction of invasion-blocking antibodies. Nonetheless, clinical symptoms including fever and laboratory abnormalities were less frequent and of lower severity during rechallenge and multi-analyte plasma profiling revealed an attenuated inflammatory response. Six participants who had completed P. vivax CHMI, then underwent heterologous rechallenge with P. falciparum. Previous infection with P. vivax did not protect participants against symptoms, fever or inflammation upon exposure to P. falciparum. Clinical immunity to P. vivax developed rapidly after a single CHMI, protecting participants against fever and laboratory abnormalities associated with malaria and was underpinned by the attenuation of inflammation. In contrast, there was no evidence of anti-parasite immunity, suggesting that mechanisms of clinical immunity can operate independently of pathogen load to reduce the damage caused by malaria. Clinical immunity to P. vivax was parasite species-specific and provided no protection against CHMI with P. falciparum.