Controlled Human Malaria Infection (CHMI) Studies: Over 100 Years of Experience with Parasite Injections

Human experimentation by deliberate infection with malarial parasites seems unethical yet has a long history in infectious disease research. After rigorous screening, volunteers are inoculated with Plasmodium sporozoites or blood stages and monitored under strict clinical supervision until they are treated with a licensed malaria drug and the infection is completely resolved. Historically, experimental Plasmodium challenge infections were applied to confirm that Anopheles mosquitoes were the malaria vector and to treat neurosyphilis in Treponema pallidum-infected patients. The lifesaving treatment with reliable parasite inoculation, monitoring, and drug cure was awarded with a Nobel Prize in 1927 and paved the way for human trials for clinical tests of candidate drugs and vaccines. Importantly, controlled human malaria infection (CHMI) studies are indispensable to bridge the major gap between phase I safety and phase II field trials. Here, we describe the biological basis, historical experiences, applications, and ethical considerations for CHMI studies. Acceleration of antimalarial drug and vaccine development remains a priority in medical research and critically depends on capacity building for CHMI studies.