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<p>Malaria vaccines consisting of metabolically active <i>Plasmodium falciparum</i> (<i>Pf</i>) sporozoites can offer improved protection compared with currently deployed subunit vaccines. In a previous study, we demonstrated the superior protective efficacy of a three-dose regimen of late-arresting genetically attenuated parasites administered by mosquito bite (GA2-MB) compared with early-arresting counterparts (GA1-MB) against a homologous controlled human malaria infection. Encouraged by these results, we explored the potency of a single GA2-MB immunization in a placebo-controlled randomized trial. Primary outcomes were safety and tolerability, time-to-parasitemia and protective efficacy. Humoral and cellular immunological results were considered secondary outcomes. Here we report the safe administration of GA2-MB with no breakthrough malaria and sterile protection in nine of ten participants at 6 weeks after a single immunization with 50 GA2-infected mosquitoes, compared with none of five mock-immunized participants, against a homologous controlled human malaria infection. Immunization increased circulating <i>Pf</i>-specific polyfunctional effector memory CD4<sup>+</sup> T cells coexpressing tumor necrosis factor and interleukin-2. This unprecedented 90% protective efficacy after a single low-dose immunization holds great promise for the potency of GA2 immunization. Future studies should demonstrate whether GA2 is similarly efficacious in pre-exposed populations and whether the favorable safety profile reported here holds up in larger groups. ClinicalTrials.gov registration: <a href="https://clinicaltrials.gov/ct2/show/NCT05468606">NCT05468606</a>.</p>

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Single immunization with genetically attenuated Pf∆mei2 (GA2) parasites by mosquito bite in controlled human malaria infection: a placebo-controlled randomized trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月3日

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  • Geert V. T. Roozen,
  • Roos van Schuijlenburg,
  • Annefleur D. O. Hensen,
  • Jan Pieter R. Koopman,
  • Olivia A. C. Lamers,
  • Fiona J. A. Geurten,
  • Jeroen C. Sijtsma,
  • Els Baalbergen,
  • Jacqueline J. Janse,
  • Séverine Chevalley-Maurel,
  • Chanel M. Naar,
  • Sascha Bezemer,
  • Hans Kroeze,
  • Huybert J. F. van de Stadt,
  • Bram de Visser,
  • Pauline Meij,
  • Mara S. Tihaya,
  • Emil Colstrup,
  • Eva Iliopoulou,
  • Helena M. de Bes-Roeleveld,
  • Els Wessels,
  • M. Y. Eileen C. van der Stoep,
  • Chris J. Janse,
  • Rajagopal Murugan,
  • Blandine M. D. Franke-Fayard,
  • Meta Roestenberg

摘要

Malaria vaccines consisting of metabolically active Plasmodium falciparum (Pf) sporozoites can offer improved protection compared with currently deployed subunit vaccines. In a previous study, we demonstrated the superior protective efficacy of a three-dose regimen of late-arresting genetically attenuated parasites administered by mosquito bite (GA2-MB) compared with early-arresting counterparts (GA1-MB) against a homologous controlled human malaria infection. Encouraged by these results, we explored the potency of a single GA2-MB immunization in a placebo-controlled randomized trial. Primary outcomes were safety and tolerability, time-to-parasitemia and protective efficacy. Humoral and cellular immunological results were considered secondary outcomes. Here we report the safe administration of GA2-MB with no breakthrough malaria and sterile protection in nine of ten participants at 6 weeks after a single immunization with 50 GA2-infected mosquitoes, compared with none of five mock-immunized participants, against a homologous controlled human malaria infection. Immunization increased circulating Pf-specific polyfunctional effector memory CD4+ T cells coexpressing tumor necrosis factor and interleukin-2. This unprecedented 90% protective efficacy after a single low-dose immunization holds great promise for the potency of GA2 immunization. Future studies should demonstrate whether GA2 is similarly efficacious in pre-exposed populations and whether the favorable safety profile reported here holds up in larger groups. ClinicalTrials.gov registration: NCT05468606.