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

Date Published: February 18, 2018

Publisher: The American Society of Tropical Medicine and Hygiene

Author(s): Bertrand Lell, Benjamin Mordmüller, Jean-Claude Dejon Agobe, Josiane Honkpehedji, Jeannot Zinsou, Juliana Boex Mengue, Marguerite Massinga Loembe, Ayola Akim Adegnika, Jana Held, Albert Lalremruata, The Trong Nguyen, Meral Esen, Natasha KC, Adam J. Ruben, Sumana Chakravarty, B. Kim Lee Sim, Peter F. Billingsley, Eric R. James, Thomas L. Richie, Stephen L. Hoffman, Peter G. Kremsner.


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.

Partial Text

Controlled human malaria infection (CHMI) is a tool that can be used to accelerate the clinical development of antimalarial interventions.1 In addition, it has been used as an immunotherapy for neurosyphilis2 and to study the pathobiology of malaria and antimalarial immunity.3–5 During the past 90 years, techniques to inoculate parasites were performed—mainly by exposure to the bites of infected mosquitoes, injection/transfusion of parasitized blood, and rarely, injection of parasite-infected mosquito salivary glands. In recent decades, techniques to induce CHMI have become safer, more reproducible, and focused on assessing protective efficacy of vaccine and drug candidates. Most recently, the availability of aseptic, purified, cryopreserved Plasmodium falciparum (Pf) sporozoites (SPZ), a product called Sanaria® PfSPZ Challenge has led to further advances in standardization. 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. For more than 100 years,8 it has been known that NAI develops after repeated exposure to Pf.9 Nevertheless, our understanding of the underlying mechanisms is incomplete. We have also known that individuals with sickle cell trait have a reduced chance of developing severe malaria. To systematically investigate these mechanisms and identify critical targets that could be used to develop subunit vaccination approaches, a stringent and reproducible infection model with a well-defined and relevant end point is required. 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.

In this study, 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. The ability to control parasitemia was shown most strikingly by the differences between the time to parasitemia of the five nonimmune volunteers and that of the volunteers with lifelong exposure. Furthermore, all five nonimmunes developed clinical malaria, whereas only seven of 20 malaria-exposed volunteers did (P = 0.015).




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