title: Adenovirus-5-vectored P. falciparum vaccine expressing CSP and AMA1. Part B: safety, immunogenicity and protective efficacy of the CSP component.
abstract: BACKGROUND
  A protective malaria vaccine will likely need to elicit both cell-mediated and antibody responses. As adenovirus vaccine vectors induce both these responses in humans, a Phase 1/2a clinical trial was conducted to evaluate the efficacy of an adenovirus serotype 5-vectored malaria vaccine against sporozoite challenge.
  
  
  RESULTS
  NMRC-MV-Ad-PfC is an adenovirus vector encoding the Plasmodium falciparum 3D7 circumsporozoite protein (CSP). It is one component of a two-component vaccine NMRC-M3V-Ad-PfCA consisting of one adenovector encoding CSP and one encoding apical membrane antigen-1 (AMA1) that was evaluated for safety and immunogenicity in an earlier study (see companion paper, Sedegah et al). Fourteen Ad5 seropositive or negative adults received two doses of NMRC-MV-Ad-PfC sixteen weeks apart, at 1 x 1010 particle units per dose. The vaccine was safe and well tolerated. All volunteers developed positive ELISpot responses by 28 days after the first immunization (geometric mean 272 spot forming cells/million[sfc/m]) that declined during the following 16 weeks and increased after the second dose to levels that in most cases were less than the initial peak (geometric mean 119 sfc/m). CD8+ predominated over CD4+ responses, as in the first clinical trial. Antibody responses were poor and like ELISpot responses increased after the second immunization but did not exceed the initial peak. Pre-existing neutralizing antibodies (NAb) to Ad5 did not affect the immunogenicity of the first dose, but the fold increase in NAb induced by the first dose was significantly associated with poorer antibody responses after the second dose, while ELISpot responses remained unaffected. When challenged by the bite of P. falciparum-infected mosquitoes, two of 11 volunteers showed a delay in the time to patency compared to infectivity controls, but no volunteers were sterilely protected.
  
  
  CONCLUSIONS
  The NMRC-MV-Ad-PfC vaccine expressing CSP was safe and well tolerated given as two doses, but did not provide sterile protection.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00392015.
authors: U.S. Military Malaria Vaccine Program, Naval Medical Research Center, Silver Spring, Maryland, United States of America. cindy.tamminga@med.navy.mil
authors: Cindy
authors: C
authors: Tamminga
authors: Martha
authors: M
authors: Sedegah
authors: David
authors: D
authors: Regis
authors: Ilin
authors: I
authors: Chuang
authors: Judith E
authors: JE
authors: Epstein
authors: Michele
authors: M
authors: Spring
authors: Jose
authors: J
authors: Mendoza-Silveiras
authors: Shannon
authors: S
authors: McGrath
authors: Santina
authors: S
authors: Maiolatesi
authors: Sharina
authors: S
authors: Reyes
authors: Victoria
authors: V
authors: Steinbeiss
authors: Charlotte
authors: C
authors: Fedders
authors: Kathryn
authors: K
authors: Smith
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: Jittawadee
authors: J
authors: Murphy
authors: Jack
authors: J
authors: Komisar
authors: Jackie
authors: J
authors: Williams
authors: Meng
authors: M
authors: Shi
authors: Donald
authors: D
authors: Brambilla
authors: Nalini
authors: N
authors: Manohar
authors: Nancy O
authors: NO
authors: Richie
authors: Chloe
authors: C
authors: Wood
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: Carter
authors: C
authors: Diggs
authors: Lorraine
authors: L
authors: Soisson
authors: Daniel
authors: D
authors: Carucci
authors: Gail
authors: G
authors: Levine
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 / Q000235:genetics / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D017780:Malaria Vaccines / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000166:cytology / Q000276:immunology*; D015800:Protozoan Proteins / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology*; D034101:Sporozoites / Q000276:immunology; D055815:Young Adult
chemical_list: D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D008565:Membrane Proteins; D015800:Protozoan Proteins; C090077:apical membrane antigen I, Plasmodium; C041595:circumsporozoite protein, Protozoan