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

Abstract

BackgroundControlled 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.MethodsAll 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.ResultsAll 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.ConclusionThe 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.Trial RegistrationClinicalTrials.gov NCT01058226

Diagnosis and treatment based on quantitative PCR after controlled human malaria infection

“…The current analysis shows that this has made it possible to lower the treatment threshold much further. Likewise, other CHMI study centres have also repeatedly shown that qPCR first becomes positive 2–4 days before thick blood smear when both are determined [ 18 – 21 ]. Similarly, studies assessing blood stage drugs or vaccines have already begun to use qPCR as a primary outcome, and have confirmed its sensitivity and specificity [ 22 ].…”

New developments in anti-malarial target candidate and product profiles

“…Again, empirically, this translates into fully protective doses in murine models with oral administration at <10 mg/kg. Activity can be confirmed in CHMI sporozoite challenge studies [60–62], and this will help put more objective criteria on TCP-4 over the coming years.…”

“…The insights into the development of new medicines for chemoprotection over the last 4 years in this area can be summarized as follows.Confirmation of the activity in humans for activity against hepatic schizonts or newly emerging asexual erythrocytes can now be tested in controlled human malaria infection (CHMI) volunteer studies using either injected cryopreserved sporozoites [60, 61] or infectious mosquitoes [62]. Currently these models involve infection of non-immune volunteers who live in non-endemic regions, and so it will be important to extend this work to include studies of the impact on the immune response, and in an expanded genetic background.…”

Malaria vaccine clinical trials: what's on the horizon

“…In contrast to other pathogens, such as HIV and Mycobacterium tuberculosis , malaria vaccine efficacy can be tested using CHMIs. Although several centers have the technical expertise and logistics in place to run these trials [57–60], anti-malaria chemotherapy is required as soon as parasite are detected in the blood. Thus, CHMIs are unsuitable to characterize the dynamics of the infection, which is needed to understand immune responses resulting in the control and elimination of the parasite and associated disease.…”