TY - JOUR
T1 - Repeat controlled human malaria infection of healthy UK adults with blood-stage plasmodium falciparum
T2 - Safety and parasite growth dynamics
AU - Salkeld, Jo
AU - Themistocleous, Yrene
AU - Barrett, Jordan R.
AU - Mitton, Celia H.
AU - Rawlinson, Thomas A.
AU - Payne, Ruth O.
AU - Hou, Mimi M.
AU - Khozoee, Baktash
AU - Edwards, Nick J.
AU - Nielsen, Carolyn M.
AU - Sandoval, Diana Muñoz
AU - Bach, Florian A.
AU - Nahrendorf, Wiebke
AU - Ramon, Raquel Lopez
AU - Baker, Megan
AU - Ramos-Lopez, Fernando
AU - Folegatti, Pedro M.
AU - Quinkert, Doris
AU - Ellis, Katherine J
AU - Poulton, Ian D.
AU - Lawrie, Alison M.
AU - Cho, Jee-Sun
AU - Nugent, Fay L.
AU - Spence, Philip J.
AU - Silk, Sarah E.
AU - Draper, Simon J.
AU - Minassian, Angela M.
N1 - Funding Information:
The VAC063 clinical trial was funded by the Office of Infectious Diseases, Bureau for Global Health, USAID, under the terms of Malaria Vaccine Development Program (MVDP) contract AID-OAA-C-15-00071, for which Leidos, Inc. was the prime contractor. The opinions expressed here are those of the authors and do not necessarily reflect the views of the USAID. This work was also supported in part by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. TAR held a Wellcome Trust Research Training Fellowship [108734/Z/15/Z] and CMN held a Wellcome Trust Sir Henry Wellcome Postdoctoral Fellowship [209200/Z/17/Z]. SJD is a Jenner Investigator and held a Wellcome Trust Senior Fellowship [106917/Z/15/Z].
Publisher Copyright:
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.
PY - 2022/8/22
Y1 - 2022/8/22
N2 - 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.
AB - 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.
KW - malaria
KW - Plasmodium falciparum
KW - controlled human malaria infection (CHMI)
KW - malaria immunology
KW - human challenge model
UR - https://www.frontiersin.org/articles/10.3389/ fimmu.2022.984323/full#supplementary-material
U2 - 10.3389/fimmu.2022.984323
DO - 10.3389/fimmu.2022.984323
M3 - Article
C2 - 36072606
SN - 1664-3224
VL - 13
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 984323
ER -