Safety and Comparability of Controlled Human Plasmodium falciparum Infection by Mosquito Bite in Malaria-Naïve Subjects at a New Facility for Sporozoite Challenge

• Published in: PloS one Vol. 9; no. 11; p. e109654
• Main Authors: Talley, Angela K., Healy, Sara A., Finney, Olivia C., Murphy, Sean C., Kublin, James, Salas, Carola J., Lundebjerg, Susan, Gilbert, Peter, Van Voorhis, Wesley C., Whisler, John, Wang, Ruobing, Ockenhouse, Chris F., Heppner, D. Gray, Kappe, Stefan H., Duffy, Patrick E.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.11.2014; Public Library of Science (PLoS)
• Subjects: Adult; Animals; Anopheles - parasitology; Anopheles - physiology; Antibodies; Antigens; Aquatic insects; Biology and Life Sciences; Biomedical research; Bites and Stings - parasitology; Blood; Chloroquine; Circumsporozoite protein; Clinical trials; Controlled conditions; Culicidae; Diagnosis; Diagnostic systems; Drug development; Drug dosages; Enrollments; Female; Human Experimentation; Humans; Immunology; Infections; Infectious diseases; Insect bites; Laboratories; Liver; Lymphocytes T; Malaria; Malaria, Falciparum - complications; Malaria, Falciparum - diagnosis; Malaria, Falciparum - etiology; Malaria, Falciparum - immunology; Male; Medical research; Medicine and Health Sciences; Merozoite surface protein 1; Microscopy; Mosquitoes; Parasitemia; Parasites; Peripheral blood; Plasmodium falciparum; Plasmodium falciparum - pathogenicity; Plasmodium falciparum - physiology; Polymerase chain reaction; Product development; Reagents; RNA-directed DNA polymerase; Safety; Signs and symptoms; Smear; Sporozoites; Studies; Vaccines; Vector-borne diseases
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0109654

Controlled human malaria infection (CHMI) studies which recapitulate mosquito-borne infection are a critical tool to identify protective vaccine and drug candidates for advancement to field trials. In partnership with the Walter Reed Army Institute of Research, the CHMI model was established at the Seattle Biomedical Research Institute's Malaria Clinical Trials Center (MCTC). Activities and reagents at both centers were aligned to ensure comparability and continued safety of the model. To demonstrate successful implementation, CHMI was performed in six healthy malaria-naïve volunteers. All volunteers received NF54 strain Plasmodium falciparum by the bite of five infected Anopheles stephensi mosquitoes under controlled conditions and were monitored for signs and symptoms of malaria and for parasitemia by peripheral blood smear. Subjects were treated upon diagnosis with chloroquine by directly observed therapy. Immunological (T cell and antibody) and molecular diagnostic (real-time quantitative reverse transcriptase polymerase chain reaction [qRT-PCR]) assessments were also performed. All six volunteers developed patent parasitemia and clinical malaria. No serious adverse events occurred during the study period or for six months post-infection. The mean prepatent period was 11.2 days (range 9-14 days), and geometric mean parasitemia upon diagnosis was 10.8 parasites/µL (range 2-69) by microscopy. qRT-PCR detected parasites an average of 3.7 days (range 2-4 days) earlier than blood smears. All volunteers developed antibodies to the blood-stage antigen merozoite surface protein 1 (MSP-1), which persisted up to six months. Humoral and cellular responses to pre-erythrocytic antigens circumsporozoite protein (CSP) and liver-stage antigen 1 (LSA-1) were limited. The CHMI model was safe, well tolerated and characterized by consistent prepatent periods, pre-symptomatic diagnosis in 3/6 subjects and adverse event profiles as reported at established centers. The MCTC can now evaluate candidates in the increasingly diverse vaccine and drug pipeline using the CHMI model. ClinicalTrials.gov NCT01058226.