title: Sterile immunity to malaria after DNA prime/adenovirus boost immunization is associated with effector memory CD8+T cells targeting AMA1 class I epitopes.
abstract: BACKGROUND
  Fifteen volunteers were immunized with three doses of plasmid DNA encoding P. falciparum circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1) and boosted with human adenovirus-5 (Ad) expressing the same antigens (DNA/Ad). Four volunteers (27%) demonstrated sterile immunity to controlled human malaria infection and, overall, protection was statistically significantly associated with ELISpot and CD8+ T cell IFN-γ activities to AMA1 but not CSP. DNA priming was required for protection, as 18 additional subjects immunized with Ad alone (AdCA) did not develop sterile protection.
  
  
  RESULTS
  We sought to identify correlates of protection, recognizing that DNA-priming may induce different responses than AdCA alone. Among protected volunteers, two and three had higher ELISpot and CD8+ T cell IFN-γ responses to CSP and AMA1, respectively, than non-protected volunteers. Unexpectedly, non-protected volunteers in the AdCA trial showed ELISpot and CD8+ T cell IFN-γ responses to AMA1 equal to or higher than the protected volunteers. T cell functionality assessed by intracellular cytokine staining for IFN-γ, TNF-α and IL-2 likewise did not distinguish protected from non-protected volunteers across both trials. However, three of the four protected volunteers showed higher effector to central memory CD8+ T cell ratios to AMA1, and one of these to CSP, than non-protected volunteers for both antigens. These responses were focused on discrete regions of CSP and AMA1. Class I epitopes restricted by A*03 or B*58 supertypes within these regions of AMA1 strongly recalled responses in three of four protected volunteers. We hypothesize that vaccine-induced effector memory CD8+ T cells recognizing a single class I epitope can confer sterile immunity to P. falciparum in humans.
  
  
  CONCLUSIONS
  We suggest that better understanding of which epitopes within malaria antigens can confer sterile immunity and design of vaccine approaches that elicit responses to these epitopes will increase the potency of next generation gene-based vaccines.
authors.affiliation: US Military Malaria Vaccine Program, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
authors.forename: Martha
authors.initials: M
authors.lastname: Sedegah
authors.affiliation: US Military Malaria Vaccine Program, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hollingdale
authors.affiliation: US Military Malaria Vaccine Program, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
authors.forename: Fouzia
authors.initials: F
authors.lastname: Farooq
authors.affiliation: US Military Malaria Vaccine Program, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
authors.forename: Harini
authors.initials: H
authors.lastname: Ganeshan
authors.affiliation: US Military Malaria Vaccine Program, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Belmonte
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Kim
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.affiliation: US Military Malaria Vaccine Program, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.affiliation: US Military Malaria Vaccine Program, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
authors.forename: Shannon
authors.initials: S
authors.lastname: McGrath
authors.affiliation: US Military Malaria Vaccine Program, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
authors.forename: Esteban
authors.initials: E
authors.lastname: Abot
authors.affiliation: US Military Malaria Vaccine Program, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
authors.forename: Keith
authors.initials: K
authors.lastname: Limbach
authors.affiliation: Division of Medical, Audio, Visual, Library and Statistical Services, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Meng
authors.initials: M
authors.lastname: Shi
authors.affiliation: USAID, Washington, DC, United States of America.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Soisson
authors.affiliation: USAID, Washington, DC, United States of America.
authors.forename: Carter
authors.initials: C
authors.lastname: Diggs
authors.affiliation: US Military Malaria Vaccine Program, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
authors.forename: Ilin
authors.initials: I
authors.lastname: Chuang
authors.affiliation: US Military Malaria Vaccine Program, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
authors.forename: Cindy
authors.initials: C
authors.lastname: Tamminga
authors.affiliation: US Military Malaria Vaccine Program, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Epstein
authors.affiliation: US Military Malaria Vaccine Program, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
authors.forename: Eileen
authors.initials: E
authors.lastname: Villasante
authors.affiliation: US Military Malaria Vaccine Program, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Richie
mesh_terms: D000256:Adenoviridae / Q000276:immunology; D000328:Adult; D000953:Antigens, Protozoan / Q000008:administration & dosage / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004247:DNA / Q000008:administration & dosage / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D008565:Membrane Proteins / Q000008:administration & dosage / Q000276:immunology*; D010963:Plasmodium falciparum / Q000276:immunology* / Q000472:pathogenicity; D015800:Protozoan Proteins / Q000008:administration & dosage / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D000939:Epitopes; D007376:Interleukin-2; D017780:Malaria Vaccines; D008565:Membrane Proteins; D015800:Protozoan Proteins; D014409:Tumor Necrosis Factor-alpha; C090077:apical membrane antigen I, Plasmodium; C041595:circumsporozoite protein, Protozoan; D007371:Interferon-gamma; D004247:DNA