Plasmodium falciparum Malaria Challenge by the Bite of Aseptic Anopheles stephensi Mosquitoes: Results of a Randomized Infectivity Trial

Kirsten E Lyke,Matthew Adams,B Kim Lee Sim,Sumana Chakravarty,Mark Loyevsky,Christopher V Plowe,Matthew Laurens,Peter F Billingsley,Adam Richman,Robert Edelman,Stephen L Hoffman

doi:10.1371/journal.pone.0013490

Abstract

BackgroundExperimental infection of malaria-naïve volunteers by the bite of Plasmodium falciparum-infected mosquitoes is a preferred means to test the protective effect of malaria vaccines and drugs. The standard model relies on the bite of five infected mosquitoes to induce malaria. We examined the efficacy of malaria transmission using mosquitoes raised aseptically in compliance with current Good Manufacturing Practices (cGMPs).Methods and FindingsEighteen adults aged 18–40 years were randomized to receive 1, 3 or 5 bites of Anopheles stephensi mosquitoes infected with the chloroquine-sensitive NF54 strain of P. falciparum.Seventeen participants developed malaria; fourteen occurring on Day 11. The mean prepatent period was 10.9 days (9–12 days). The geometric mean parasitemia was 15.7 parasites/µL (range: 4–70) by microscopy. Polymerase chain reaction (PCR) detected parasites 3.1 (range: 0–4) days prior to microscopy. The geometric mean sporozoite load was 16,753 sporozoites per infected mosquito (range: 1,000–57,500). A 1-bite participant withdrew from the study on Day 13 post-challenge and was PCR and smear negative.ConclusionsThe use of aseptic, cGMP-compliant P. falciparum-infected mosquitoes is safe, is associated with a precise prepatent period compared to the standard model and appears more efficient than the standard approach, as it led to infection in 100% (6/6) of volunteers exposed to three mosquito bites and 83% (5/6) of volunteers exposed to one mosquito bite.Trial RegistrationClinicalTrials.gov NCT00744133

Highlights

The use of aseptic, current Good Manufacturing Practices (cGMPs)-compliant P. falciparum-infected mosquitoes is safe, is associated with a precise prepatent period compared to the standard model and appears more efficient than the standard approach, as it led to infection in 100% (6/6) of volunteers exposed to three mosquito bites and 83% (5/6) of volunteers exposed to one mosquito bite
Experimental infection of malaria-naıve volunteers by the bite of Plasmodium falciparum-infected mosquitoes has been a preferred means to test the protective effect of malaria vaccine and drug candidates in malaria-naıve volunteers
The primary objective of this study was to evaluate the safety and tolerability of a new human malaria challenge model using aseptic A. stephensi mosquitoes infected with the chloroquinesensitive NF54 isolate of P. falciparum and reared in compliance with cGMPs

Summary

Introduction

Experimental infection of malaria-naıve volunteers by the bite of Plasmodium falciparum-infected mosquitoes has been a preferred means to test the protective effect of malaria vaccine and drug candidates in malaria-naıve volunteers. If sporozoites could be manufactured, vialed, and transported to clinical trial centers around the world, and used to infect volunteers by needle and syringe inoculation, this would dramatically increase the capacity to assess new anti-malaria vaccine and drug candidates. Such capacity is of critical importance as the need for malaria challenge facilities is expected to grow with the advent of new malaria vaccine constructs and new antimalarial drugs [3]. Experimental infection of malaria-naıve volunteers by the bite of Plasmodium falciparum-infected mosquitoes is a preferred means to test the protective effect of malaria vaccines and drugs. We examined the efficacy of malaria transmission using mosquitoes raised aseptically in compliance with current Good Manufacturing Practices (cGMPs)

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Conclusion