Optimising Controlled Human Malaria Infection Studies Using Cryopreserved P. falciparum Parasites Administered by Needle and Syringe

Susanne H Sheehy,Stephen L Hoffman,Alexandra J Spencer,Alexander D Douglas,Anusha Gunasekera,Nicholas A Anagnostou,Eric R James,Domtila Kimani,Simon Kerridge,Peter F Billingsley,Alison M Lawrie,Nick J Edwards,Rachel Roberts,B Kim Lee Sim,Andrew R Williams,Ian D Poulton,Adrian V S Hill,Merryn Voysey,Rhea J Longley

doi:10.1371/journal.pone.0065960

Abstract

BackgroundControlled human malaria infection (CHMI) studies have become a routine tool to evaluate efficacy of candidate anti-malarial drugs and vaccines. To date, CHMI trials have mostly been conducted using the bite of infected mosquitoes, restricting the number of trial sites that can perform CHMI studies. Aseptic, cryopreserved P. falciparum sporozoites (PfSPZ Challenge) provide a potentially more accurate, reproducible and practical alternative, allowing a known number of sporozoites to be administered simply by injection.MethodologyWe sought to assess the infectivity of PfSPZ Challenge administered in different dosing regimens to malaria-naive healthy adults (n = 18). Six participants received 2,500 sporozoites intradermally (ID), six received 2,500 sporozoites intramuscularly (IM) and six received 25,000 sporozoites IM.FindingsFive out of six participants receiving 2,500 sporozoites ID, 3/6 participants receiving 2,500 sporozoites IM and 6/6 participants receiving 25,000 sporozoites IM were successfully infected. The median time to diagnosis was 13.2, 17.8 and 12.7 days for 2,500 sporozoites ID, 2,500 sporozoites IM and 25,000 sporozoites IM respectively (Kaplan Meier method; p = 0.024 log rank test).Conclusions2,500 sporozoites ID and 25,000 sporozoites IM have similar infectivities. Given the dose response in infectivity seen with IM administration, further work should evaluate increasing doses of PfSPZ Challenge IM to identify a dosing regimen that reliably infects 100% of participants.Trial RegistrationClinicalTrials.gov NCT01465048

Highlights

The deliberate infection of human participants with microorganisms have contributed uniquely to our understanding of the pathogenesis, immune responses, treatment and prevention of numerous microbial diseases. [1] Plasmodium falciparum malaria is a microbe suited to challenge studies as it has a relatively short and predictable asymptomatic period, a well-established diagnostic laboratory test, and no known long-term sequelae or infectious state following appropriate treatment
The majority of Controlled human malaria infection (CHMI) trials to date have been performed using the NF54 stain of P. falciparum [4,5] or 3D7 [6] sporozoites delivered by mosquito bite
The total duration of symptoms in participants with symptomatic malaria infection ranged from 1–12 days, similar to that seen at a recent mosquito bite CHMI trial at our centre, [29] and there appeared no difference in duration of symptoms of malaria between the groups

Summary

Introduction

The deliberate infection of human participants with microorganisms (challenge studies) have contributed uniquely to our understanding of the pathogenesis, immune responses, treatment and prevention of numerous microbial diseases. [1] Plasmodium falciparum malaria is a microbe suited to challenge studies as it has a relatively short and predictable asymptomatic period, a well-established diagnostic laboratory test (thick film microscopy), and no known long-term sequelae or infectious state following appropriate treatment. [7,8,9,10,11] Mosquito bite CHMI studies can only be performed in centres with access to an appropriate insectary and entomology staff This restriction considerably limits the number of sites that can perform such studies and has provided a major obstacle to the conduct of CHMI trials in malaria endemic regions. If PfSPZ Challenge is to provide an alternative to the mosquito bite CHMI, an administration regimen must be identified that reliably infects 100% of participants. [13] Given the potential practical limitations of an IV CHMI model and promising results already seen with ID administration of PfSPZ Challenge, we sought to conduct a trial to assess the infectivity of PfSPZ Challenge administered IM with a view to establishing a dosing regimen that reliably infects 100% of participants. We sought to assess T-cell responses to other novel preerythrocytic antigens in the hope of identifying new antigenic targets for future vaccine development

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Results

Discussion