First-in-human evaluation of genetically attenuated Plasmodium falciparum sporozoites administered by bite of Anopheles mosquitoes to adult volunteers

Michele Spring, Jittawadee Murphy, Robin Nielsen, Megan Dowler, Jason W. Bennett, Stasya Zarling, Jack Williams, Patricia de la Vega, Lisa Ware, Jack Komisar, Mark Polhemus, Thomas L. Richie, Judy Epstein, Cindy Tamminga, Ilin Chuang, Nancy Richie, Michael O'Neil, D. Gray Heppner, Julie Healer, Matthew O'NeillHannah Smithers, Olivia C. Finney, Sebastian A. Mikolajczak, Ruobing Wang, Alan Cowman, Christian Ockenhouse, Urszula Krzych, Stefan H.I. Kappe*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

Background: Immunization with genetically engineered, attenuated malaria parasites (GAP) that arrest during liver infection confers sterile protection in mouse malaria models. A first generation Plasmodium falciparum GAP (Pf p52-/p36- GAP) was previously generated by deletion of two pre-erythrocytic stage-expressed genes (P52 and P36) in the NF54 strain. Methods: A first-in-human, proof-of-concept, safety and immunogenicity clinical trial in six human volunteers was conducted. Exposure consisted of delivery of Pf p52-/p36- GAP sporozoites via infected Anopheles mosquito bite with a five-bite/volunteer exposure followed by an approximately 200-bite exposure/volunteer one month later. Results: The exposures were well tolerated with mild to moderate local and systemic reactions. All volunteers remained blood stage negative after low dose exposure. Five volunteers remained blood stage negative after high dose exposure. One volunteer developed peripheral parasitemia twelve days after high dose exposure. Together the findings indicate that Pf p52-/p36- GAP was severely but not completely attenuated. All six volunteers developed antibodies to CSP. Furthermore, IFN-γ responses to whole sporozoites and multiple antigens were elicited in 5 of 6 volunteers, with both CD4 and CD8 cell cytokine production detected. Conclusion: Severe attenuation and favorable immune responses following administration of a first generation Pf p52-/p36- GAP suggests that further development of live-attenuated strains using genetic engineering should be pursued.

Original languageEnglish
Pages (from-to)4975-4983
Number of pages9
JournalVaccine
Volume31
Issue number43
DOIs
StatePublished - 9 Oct 2013
Externally publishedYes

Keywords

  • First-in-human
  • Genetically attenuated parasite
  • Malaria
  • Plasmodium falciparum

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