title: First-in-human evaluation of genetically attenuated Plasmodium falciparum sporozoites administered by bite of Anopheles mosquitoes to adult volunteers.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Walter Reed Army Institute for Research, Silver Spring, MD 20910, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Spring
authors.forename: Jittawadee
authors.initials: J
authors.lastname: Murphy
authors.forename: Robin
authors.initials: R
authors.lastname: Nielsen
authors.forename: Megan
authors.initials: M
authors.lastname: Dowler
authors.forename: Jason W
authors.initials: JW
authors.lastname: Bennett
authors.forename: Stasya
authors.initials: S
authors.lastname: Zarling
authors.forename: Jack
authors.initials: J
authors.lastname: Williams
authors.forename: Patricia
authors.initials: P
authors.lastname: de la Vega
authors.forename: Lisa
authors.initials: L
authors.lastname: Ware
authors.forename: Jack
authors.initials: J
authors.lastname: Komisar
authors.forename: Mark
authors.initials: M
authors.lastname: Polhemus
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Richie
authors.forename: Judy
authors.initials: J
authors.lastname: Epstein
authors.forename: Cindy
authors.initials: C
authors.lastname: Tamminga
authors.forename: Ilin
authors.initials: I
authors.lastname: Chuang
authors.forename: Nancy
authors.initials: N
authors.lastname: Richie
authors.forename: Michael
authors.initials: M
authors.lastname: O'Neil
authors.forename: D Gray
authors.initials: DG
authors.lastname: Heppner
authors.forename: Julie
authors.initials: J
authors.lastname: Healer
authors.forename: Matthew
authors.initials: M
authors.lastname: O'Neill
authors.forename: Hannah
authors.initials: H
authors.lastname: Smithers
authors.forename: Olivia C
authors.initials: OC
authors.lastname: Finney
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Mikolajczak
authors.forename: Ruobing
authors.initials: R
authors.lastname: Wang
authors.forename: Alan
authors.initials: A
authors.lastname: Cowman
authors.forename: Christian
authors.initials: C
authors.lastname: Ockenhouse
authors.forename: Urszula
authors.initials: U
authors.lastname: Krzych
authors.forename: Stefan H I
authors.initials: SH
authors.lastname: Kappe
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000852:Anopheles / Q000469:parasitology*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D017125:Genes, Protozoan; D064368:Healthy Volunteers; D006801:Humans; D007114:Immunization / Q000009:adverse effects / Q000379:methods*; D008288:Malaria / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D008297:Male; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D034101:Sporozoites / Q000276:immunology*; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: D017780:Malaria Vaccines; D014613:Vaccines, Attenuated
keywords: First-in-human; Genetically attenuated parasite; Malaria; Plasmodium falciparum