An experimental model of clinical immunity for human malaria

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Abstract 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-naïve 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 .

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