Impact of Sickle Cell Trait and Naturally Acquired Immunity on Uncomplicated Malaria after Controlled Human Malaria Infection in Adults in Gabon.

Bertrand Lell,Albert Lalremruata,Eric R James,Natasha Kc,Adam J Ruben,Peter G Kremsner,Peter F Billingsley,B Kim Lee Sim,Meral Esen,Juliana Boex Mengue,Benjamin Mordmüller,Jana Held,Sumana Chakravarty,Stephen L Hoffman,Marguerite Massinga Loembé ,Jean Claude Dejon-Agobé ,Yabo Josiane Honkpéhèdji ,Jeannot Frézus Zinsou ,Ayôla Akim Adegnika

doi:10.4269/ajtmh.17-0343

Abstract

.Controlled human malaria infection (CHMI) by direct venous inoculation (DVI) with 3,200 cryopreserved Plasmodium falciparum sporozoites (PfSPZ) consistently leads to parasitemia and malaria symptoms in malaria-naive adults. We used CHMI by DVI to investigate infection rates, parasite kinetics, and malaria symptoms in lifelong malaria–exposed (semi-immune) Gabonese adults with and without sickle cell trait. Eleven semi-immune Gabonese with normal hemoglobin (IA), nine with sickle cell trait (IS), and five nonimmune European controls with normal hemoglobin (NI) received 3,200 PfSPZ by DVI and were followed 28 days for parasitemia by thick blood smear (TBS) and quantitative polymerase chain reaction (qPCR) and for malaria symptoms. End points were time to parasitemia and parasitemia plus symptoms. PfSPZ Challenge was well tolerated and safe. Five of the five (100%) NI, 7/11 (64%) IA, and 5/9 (56%) IS volunteers developed parasitemia by TBS, and 5/5 (100%) NI, 9/11 (82%) IA, and 7/9 (78%) IS by qPCR, respectively. The time to parasitemia by TBS was longer in IA (geometric mean 16.9 days) and IS (19.1 days) than in NA (12.6 days) volunteers (P = 0.016, 0.021, respectively). Five of the five, 6/9, and 1/7 volunteers with parasitemia developed symptoms (P = 0.003, NI versus IS). Naturally adaptive immunity (NAI) to malaria significantly prolonged the time to parasitemia. Sickle cell trait seemed to prolong it further. NAI plus sickle cell trait, but not NAI alone, significantly reduced symptom rate. Twenty percent (4/20) semi-immunes demonstrated sterile protective immunity. Standardized CHMI with PfSPZ Challenge is a powerful tool for dissecting the impact of innate and naturally acquired adaptive immunity on malaria.

Highlights

Controlled human malaria infection (CHMI) is a tool that can be used to accelerate the clinical development of antimalarial interventions.[1]
We assessed whether standardized CHMI by direct venous inoculation (DVI) of 3,200 PfSPZ in healthy, adult, lifelong malaria–exposed volunteers is a suitable model that 1) is safe and well tolerated, 2) results in parasite dynamics different from CHMI in malaria-naive adults, 3) results in parasite dynamics different between HbAA and HbAS carriers, and 4) can be used to assess acquired immunity against the pre-erythrocytic and erythrocytic stages of the Plasmodium falciparum (Pf) lifecycle
We observed that all malaria-experienced volunteers controlled parasitemia; some manifested sterile protection, others exponential growth but with lower parasite multiplication rates compared with malaria-naive volunteers

Summary

Introduction

Controlled human malaria infection (CHMI) is a tool that can be used to accelerate the clinical development of antimalarial interventions.[1]. After direct venous inoculation (DVI) of 3,200 SPZ with PfSPZ Challenge, all malaria-naive participants have been consistently infected.[6,7] In contrast to previous methods, the dosage, generation, and strain of the parasite are tightly controlled and, due to cryopreservation, clinical studies have fewer requirements for infrastructure and fewer restrictions on timing and design. These advances together with present knowledge and multidimensional techniques to study immunology and metabolism led us, more than five decades following the last experiments,[3] to assess whether CHMI can be used to study innate resistance and naturally adaptive immunity (NAI) to malaria. We assessed whether standardized CHMI by DVI of 3,200 PfSPZ in healthy, adult, lifelong malaria–exposed volunteers is a suitable model that 1) is safe and well tolerated, 2) results in parasite dynamics different from CHMI in malaria-naive adults, 3) results in parasite dynamics different between HbAA and HbAS carriers, and 4) can be used to assess acquired immunity against the pre-erythrocytic and erythrocytic stages of the Pf lifecycle

Methods

Results

Conclusion