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Molecular Hallmarks of Experimentally Acquired Immunity to Malaria [Pilot Study]

ABSTRACT: Sterile immunity to Plasmodium falciparum infection can be induced experimentally in humans after few exposures. An example is the induction of immunity using whole parasites by exposure of malaria-naive volunteers to infectious mosquito bites while using chloroquine prophylaxis (CPS immunization). Chloroquine kills blood-stage parasites but leaves liver-stage parasites unaffected, thereby exposing the liver-stage and early blood-stage antigens to the immune system. Upon subsequent challenge, volunteers are completely protected from infection, but protective efficacy decreases when fewer infectious mosquito bites are used for CPS immunization. Efforts to understand the mechanisms of this immunity, and how it differs from naturally-acquired immunity, may provide critical insights that could aid malaria vaccine development. In this pilot study, transcriptomic features are derived from blood samples collected before and after challenge with infectious mosquito bites.

ORGANISM(S): Homo sapiens

PROVIDER: GSE50957 | GEO | 2013/09/18

SECONDARY ACCESSION(S): PRJNA219425

REPOSITORIES: GEO

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Project description:Description: Experimental exposure to malaria parasites can lead to development of protective immunity, providing a foothold for the development of a malaria vaccine. The goal of this study is to investigate immune transcriptional profiles associated with malaria protective immune responses induced by experimental Chemo-Prophylaxis and Sporozoites (CPS) immunization of P. falciparum-naive human volunteers. Samples for this study were obtained from a CPS-immunization study conducted in 2011 (ClinicalTrials.gov Identifier: NCT01218893), where healthy volunteers received CPS-immunization with bites from different numbers of P. falciparum-infected mosquitoes (three times 15 (n=5), 10 (n=9) or 5 (n=10)). Five control subjects received uninfected mosquito bites under chloroquine prophylaxis. Fifteen weeks after discontinuation of chloroquine prophylaxis, all volunteers were challenged by exposure to infected mosquito bites. Study Design: A maximum of 30 volunteers were divided into four groups. All volunteers received weekly chloroquine prophylaxis for a period of 13 weeks (91 days). During these 13 weeks, on days 8, 36 and 64 they were exposed to the bites of 15 mosquitoes. Group 1 (n=5, positive control) received three CPS immunizations by 15 mosquitoes infected with P. falciparum sporozoites. Group 2 (n=10) received three times 10 bites from infected mosquitoes and 5 bites from uninfected mosquitoes. Group 3 (n=10) received three times 5 bites from infected mosquitoes and 10 bites from uninfected mosquitoes. Group 4 (n=5), the negative control, received three placebo immunizations with 15 bites of uninfected mosquitoes. Fifteen weeks after discontinuation of chloroquine prophylaxis, all 30 volunteers were challenged at day 196 by the bites of 5 infectious mosquitoes and followed for 21 days. All subjects were treated with chloroquine 21 days after challenge or whenever they had a positive thick smear during that period.

Project description:Project Description: The Malaria Host-Pathogen Interaction Center (MaHPIC) is a transdisciplinary malaria systems biology research program initially supported by an NIH/NIAID contract (HHSN272201200031C, 2012-2017; see <a href='http://www.systemsbiology.emory.edu' target='_blank'>http://www.systemsbiology.emory.edu</a>). The MaHPIC continues with ongoing support from the Defense Advanced Research Project Agency (DARPA) and others. The MaHPIC generates many data types (e.g., clinical, hematological, parasitological, metabolomics, functional genomics, lipidomics, proteomics, immune response, telemetry) and mathematical models, to iteratively test and develop hypotheses related to the complex host-parasite dynamics in the course of malaria in non-human primates (NHPs), and metabolomics data via collaborations with investigators conducting clinical studies in malaria endemic countries, with the overarching goal of better understanding human disease, pathogenesis, and immunity. Curation and maintenance of all data and metadata are the responsibility of the MaHPIC. MaHPIC Experiment Description: Sixteen healthy volunteers, 7 malaria naïve and 9 semi-immune, aged 18-45 years, were enrolled in this study during October 2012 to November 2013. Malaria-naive volunteers were recruited in Cali, Colombia, a non-endemic city; those with previous malaria experience were recruited in Buenaventura, a malaria-endemic area on the Colombian Pacific Coast. The study was approved by Institutional Review Boards (IRB) of the Malaria Vaccine and Drug Development Center–MVDC (CECIV, Cali) and Centro Médico Imbanaco (Cali). All protocols and documentation were reviewed and samples shipments approved by the Emory IRB. Male and female patients were eligible for inclusion, which included two steps: 1) age between 15-60 years, hemoglobin levels > 9g/dL, presence of current Plasmodium vivax infection, absence of other Plasmodium species determined by thick blood smear and PCR, blood parasite count of 0.1% or more, absence of other acute or chronic diseases, being able to sign an informed consent form; 2) healthy 18 to 45 years old man or non-pregnant women, capacity to sign an informed consent in a free and voluntary way, acceptable understanding of the clinical trial through the approval of a questionnaire regarding the information given in the consent process, obligatory use of adequate contraceptive method from beginning of recruitment and screening time up to three months after last immunization, do not have chronic or acute diseases, accept not traveling to malaria endemic areas during the clinical trial, have telephone at home or mobile phone that permit permanent contact for follow up, being willing to participated during both steps of the clinical trial. Exclusion criteria included pregnancy, abnormal laboratory test values, hemoglobin pathology, glucose-6-phosphate dehydrogenase (G6PDH) deficiency, positive for blood bank infectious diseases (syphilis, HIV, Chagas disease, HTLV 1–2, and hepatitis B and hepatitis C), or have any condition that would increase the risk of an adverse outcome. Volunteers were infected with P. vivax via sporozoite challenge by exposing volunteers to bites of 2–4 mosquitoes (Anopheles albimanus) of the same infected batch. Plasma samples were collected at 4 time points: Baseline, 1 month pre-inoculation; Diagnosis; 3 weeks post-treatment; 4 months post-treatment. As soon as parasites were detected by thick blood smears, participants were treated orally with curative doses of chloroquine (1500 mg chloroquine provided in three doses: 600 mg initially then 450 mg doses at 24 and 48 hours) and primaquine (30 mg dose given once per day for 14 days). Clinical trial registration: NCT01585077. Samples were analyzed with liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS), evaluated in a time course and between naïve and semi-immune volunteers. Within the MaHPIC, this project is known as ‘Experiment HuC’. Samples were obtained in collaboration with Socrates Herrera from the Malaria Vaccine and Drug Development Center, Colombia. Metabolomics results were produced by Dean Jones at Emory University. To access other publicly available results from HuC and other MaHPIC Experiments visit <a href='http://plasmodb.org/plasmo/mahpic.jsp' target='_blank'>http://plasmodb.org/plasmo/mahpic.jsp</a> . This page will be updated as datasets are released to the public. The following contributed to the creation of this dataset: The MaHPIC Consortium, Jeremy D. DeBarry, Mary R. Galinski, Luiz G. Gardinassi, Socrates Herrera, Myriam Arévalo-Herrera, Dean P. Jones, Jessica C. Kissinger, Shuzhao Li, Regina Joice Cordy, Esmeralda VS Meyer, Mustafa V. Nural, Suman B. Pakala, ViLinh Tran, Karan Uppal Linked Studies: <a href='/metabolights/search?freeTextQuery=MaHPIC' target='_blank'>Malaria Host-Pathogen Interaction Center (MaHPIC)</a>

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Molecular Hallmarks of Experimentally Acquired Immunity to Malaria [Pilot Study]

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