Repeat controlled human malaria infection of healthy UK adults with blood-stage plasmodium falciparum: Safety and parasite growth dynamics

Jo Salkeld, Yrene Themistocleous, Jordan R. Barrett, Celia H. Mitton, Thomas A. Rawlinson, Ruth O. Payne, Mimi M. Hou, Baktash Khozoee, Nick J. Edwards, Carolyn M. Nielsen, Diana Muñoz Sandoval, Florian A. Bach, Wiebke Nahrendorf, Raquel Lopez Ramon, Megan Baker, Fernando Ramos-Lopez, Pedro M. Folegatti, Doris Quinkert, Katherine J Ellis, Ian D. PoultonAlison M. Lawrie, Jee-Sun Cho, Fay L. Nugent, Philip J. Spence, Sarah E. Silk, Simon J. Draper, Angela M. Minassian

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Article number984323
Number of pages15
JournalFrontiers in Immunology
Volume13
Early online date22 Aug 2022
DOIs
Publication statusPublished - 22 Aug 2022

Keywords / Materials (for Non-textual outputs)

  • malaria
  • Plasmodium falciparum
  • controlled human malaria infection (CHMI)
  • malaria immunology
  • human challenge model

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