학술논문
Repeat controlled human malaria infection of healthy UK adults with blood-stage Plasmodium falciparum : Safety and parasite growth dynamics.
Document Type
Academic Journal
Author
Salkeld J; Department of Biochemistry, University of Oxford, Oxford, United Kingdom.; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Themistocleous Y; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Barrett JR; Department of Biochemistry, University of Oxford, Oxford, United Kingdom.; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Mitton CH; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Rawlinson TA; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Payne RO; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Hou MM; Department of Biochemistry, University of Oxford, Oxford, United Kingdom.; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Khozoee B; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Edwards NJ; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Nielsen CM; Department of Biochemistry, University of Oxford, Oxford, United Kingdom.; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Sandoval DM; Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.; Bach FA; Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.; Nahrendorf W; Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.; Ramon RL; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Baker M; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Ramos-Lopez F; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Folegatti PM; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Quinkert D; Department of Biochemistry, University of Oxford, Oxford, United Kingdom.; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Ellis KJ; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Poulton ID; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Lawrie AM; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Cho JS; Department of Biochemistry, University of Oxford, Oxford, United Kingdom.; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Nugent FL; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Spence PJ; Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.; Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom.; Silk SE; Department of Biochemistry, University of Oxford, Oxford, United Kingdom.; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Draper SJ; Department of Biochemistry, University of Oxford, Oxford, United Kingdom.; The Jenner Institute, University of Oxford, Oxford, United Kingdom.; Minassian AM; Department of Biochemistry, University of Oxford, Oxford, United Kingdom.; The Jenner Institute, University of Oxford, Oxford, United Kingdom.
Source
Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE
Subject
Language
English
Abstract
In endemic settings it is known that natural malaria immunity is gradually acquired following repeated exposures. Here we sought to assess whether similar acquisition of blood-stage malaria immunity would occur following repeated parasite exposure by controlled human malaria infection (CHMI). We report the findings of repeat homologous blood-stage Plasmodium falciparum (3D7 clone) CHMI studies VAC063C (ClinicalTrials.gov NCT03906474) and VAC063 (ClinicalTrials.gov NCT02927145). In total, 24 healthy, unvaccinated, malaria-naïve UK adult participants underwent primary CHMI followed by drug treatment. Ten of these then underwent secondary CHMI in the same manner, and then six of these underwent a final tertiary CHMI. As with primary CHMI, malaria symptoms were common following secondary and tertiary infection, however, most resolved within a few days of treatment and there were no long term sequelae or serious adverse events related to CHMI. Despite detectable induction and boosting of anti-merozoite serum IgG antibody responses following each round of CHMI, there was no clear evidence of anti-parasite immunity (manifest as reduced parasite growth in vivo ) conferred by repeated challenge with the homologous parasite in the majority of volunteers. However, three volunteers showed some variation in parasite growth dynamics in vivo following repeat CHMI that were either modest or short-lived. We also observed no major differences in clinical symptoms or laboratory markers of infection across the primary, secondary and tertiary challenges. However, there was a trend to more severe pyrexia after primary CHMI and the absence of a detectable transaminitis post-treatment following secondary and tertiary infection. We hypothesize that this could represent the initial induction of clinical immunity. Repeat homologous blood-stage CHMI is thus safe and provides a model with the potential to further the understanding of naturally acquired immunity to blood-stage infection in a highly controlled setting.
Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03906474, NCT02927145.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 Salkeld, Themistocleous, Barrett, Mitton, Rawlinson, Payne, Hou, Khozoee, Edwards, Nielsen, Sandoval, Bach, Nahrendorf, Ramon, Baker, Ramos-Lopez, Folegatti, Quinkert, Ellis, Poulton, Lawrie, Cho, Nugent, Spence, Silk, Draper and Minassian.)
Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03906474, NCT02927145.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 Salkeld, Themistocleous, Barrett, Mitton, Rawlinson, Payne, Hou, Khozoee, Edwards, Nielsen, Sandoval, Bach, Nahrendorf, Ramon, Baker, Ramos-Lopez, Folegatti, Quinkert, Ellis, Poulton, Lawrie, Cho, Nugent, Spence, Silk, Draper and Minassian.)