title: Adenovirus 5-vectored P. falciparum vaccine expressing CSP and AMA1. Part A: safety and immunogenicity in seronegative adults.
abstract: BACKGROUND
  Models of immunity to malaria indicate the importance of CD8+ T cell responses for targeting intrahepatic stages and antibodies for targeting sporozoite and blood stages. We designed a multistage adenovirus 5 (Ad5)-vectored Plasmodium falciparum malaria vaccine, aiming to induce both types of responses in humans, that was tested for safety and immunogenicity in a Phase 1 dose escalation trial in Ad5-seronegative volunteers.
  
  
  RESULTS
  The NMRC-M3V-Ad-PfCA vaccine combines two adenovectors encoding circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). Group 1 (n = 6) healthy volunteers received one intramuscular injection of 2×10∧10 particle units (1×10∧10 each construct) and Group 2 (n = 6) a five-fold higher dose. Transient, mild to moderate adverse events were more pronounced with the higher dose. ELISpot responses to CSP and AMA1 peaked at 1 month, were higher in the low dose (geomean CSP = 422, AMA1 = 862 spot forming cells/million) than in the high dose (CSP = 154, p = 0.049, AMA1 = 423, p = 0.045) group and were still positive at 12 months in a number of volunteers. ELISpot depletion assays identified dependence on CD4+ or on both CD4+ and CD8+ T cells, with few responses dependent only on CD8+ T cells. Intracellular cytokine staining detected stronger CD8+ than CD4+ T cell IFN-γ responses (CSP p = 0.0001, AMA1 p = 0.003), but similar frequencies of multifunctional CD4+ and CD8+ T cells secreting two or more of IFN-γ, TNF-α or IL-2. Median fluorescence intensities were 7-10 fold higher in triple than single secreting cells. Antibody responses were low but trended higher in the high dose group and did not inhibit growth of cultured P. falciparum blood stage parasites.
  
  
  CONCLUSIONS
  As found in other trials, adenovectored vaccines appeared safe and well-tolerated at doses up to 1×10∧11 particle units. This is the first demonstration in humans of a malaria vaccine eliciting strong CD8+ T cell IFN-γ responses.
  
  
  BACKGROUND
  ClinicalTrials.govNCT00392015.
authors: U.S. Military Malaria Vaccine Program, Naval Medical Research Center, Silver Spring, Maryland, United States of America. Martha.Sedegah@med.navy.mil
authors: Martha
authors: M
authors: Sedegah
authors: Cindy
authors: C
authors: Tamminga
authors: Shannon
authors: S
authors: McGrath
authors: Brent
authors: B
authors: House
authors: Harini
authors: H
authors: Ganeshan
authors: Jennylynn
authors: J
authors: Lejano
authors: Esteban
authors: E
authors: Abot
authors: Glenna J
authors: GJ
authors: Banania
authors: Renato
authors: R
authors: Sayo
authors: Fouzia
authors: F
authors: Farooq
authors: Maria
authors: M
authors: Belmonte
authors: Nalini
authors: N
authors: Manohar
authors: Nancy O
authors: NO
authors: Richie
authors: Chloe
authors: C
authors: Wood
authors: Carole A
authors: CA
authors: Long
authors: David
authors: D
authors: Regis
authors: Francis T
authors: FT
authors: Williams
authors: Meng
authors: M
authors: Shi
authors: Ilin
authors: I
authors: Chuang
authors: Michele
authors: M
authors: Spring
authors: Judith E
authors: JE
authors: Epstein
authors: Jose
authors: J
authors: Mendoza-Silveiras
authors: Keith
authors: K
authors: Limbach
authors: Noelle B
authors: NB
authors: Patterson
authors: Joseph T
authors: JT
authors: Bruder
authors: Denise L
authors: DL
authors: Doolan
authors: C Richter
authors: CR
authors: King
authors: Lorraine
authors: L
authors: Soisson
authors: Carter
authors: C
authors: Diggs
authors: Daniel
authors: D
authors: Carucci
authors: Sheetij
authors: S
authors: Dutta
authors: Michael R
authors: MR
authors: Hollingdale
authors: Christian F
authors: CF
authors: Ockenhouse
authors: Thomas L
authors: TL
authors: Richie
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000953:Antigens, Protozoan / Q000009:adverse effects* / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D056724:Immunity, Humoral / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D017780:Malaria Vaccines / Q000009:adverse effects* / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000009:adverse effects / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000009:adverse effects / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D008565:Membrane Proteins; D010446:Peptide Fragments; D015800:Protozoan Proteins; C090077:apical membrane antigen I, Plasmodium; C041595:circumsporozoite protein, Protozoan; D007371:Interferon-gamma