Controlled human malaria infection—Maker and breaker of dogma
Authors: Jean-Marc Chavatte, Georges Snounou
Journal: PLoS Medicine (2021)

Experimental human infections have contributed significantly to knowledge about infectious diseases [1].In a recent report in PLOS Medicine, Rebecca Watts and colleagues followed this tradition by describing controlled human infection (CHI) with artemisinin-resistant Plasmodium falciparum [2].Of the short list of pathogens still utilized in CHIs [1], malaria is exceptional because much of our knowledge of its natural course and its parasites' (Plasmodium) biology derives from an extensive series of CHIs that stretches over a century.The trigger to investigate malaria through routine CHIs was provided by Julius Wagner-Jauregg.Convinced of a beneficial effect of fever on psychoses, he infected patients suffering from neurosyphilis with Plasmodium vivax and recorded unprecedented full recoveries or partial remissions in most [3].Consequently, malariotherapy centers flourished worldwide, attracting malariologists who derived unique insights into the nature of malaria from these CHIs [4].CHIs became so important for malaria studies that when malariotherapy was superseded by antibiotics, malariologists initiated ethically sanctioned volunteer programs.While malariotherapy relied primarily on P. vivax, P. falciparum was used mainly in the United States of America on African American patients who were refractory to P. vivax and from the 1940s, on volunteers of all ethnic backgrounds.From the mid-1970s, the majority of CHIs were initiated by P. falciparum sporozoites, principally to serve in the development of a vaccine against the preerythrocytic forms.These investigations have a minimal clinical risk as the volunteers are treated as soon as blood stages are detectable (a parasite (P) burden � 10 P/ μL), a level in initial infection rarely preceded by any clinical sign.BAU : Pleasecheckwhethertheeditstot y contrast, for blood stage-induced P. falciparum infections that were mainly conducted to evaluate drug efficacy, curative drug treatment was to be initiated as parasite levels neared 1,000 P/μL, but in some volunteers, these exceeded 10,000 P/μL because of the unpredictable and often fulminating multiplication of P. falciparum.Thus, by the mid-1980s, blood stage inoculations were abandoned on ethical grounds.Allan Saul and his team at the Queensland Institute of Medical Research (QIMR) broke this moratorium by bringing together 3 elements needed to embark on CHI initiated by blood stage malaria parasites.First, they elaborated a strategy to constitute a stock of infected red blood cells (RBCs) uncontaminated by other pathogens suitable to serve as an inoculum.Second, they devised a sensitive quantitative method of parasite detection (�10 P/mL) allowing the monitoring of parasitemia over a sufficient AU : Anabbreviationlisthasbeencompiledforthoseusedthr number of replication cycles prior to the appearance of any clinical signs.FAU : PleasecheckwhethertheeditstothesentenceFinally; aprotocolensu inally, a protocol ensuring the safety of the volunteers was elaborated, and ethical approval was secured.Thus, a stock of cryopreserved RBCs infected by P. falciparum 3D7 was obtained and validated [5], making it possible to conduct CHIs using a