title: Randomized, placebo-controlled trial to assess the safety and immunogenicity of an adenovirus type 35-based circumsporozoite malaria vaccine in healthy adults.
abstract: Malaria results in over 650,000 deaths each year; thus, there is an urgent need for an effective vaccine. Pre-clinical studies and recently reported human trials suggest that pre-erythrocytic stage vaccines can provide protection against infection. A Phase 1, randomized, placebo-controlled, dose-escalation study was conducted with a vaccine composed of a replication-deficient adenovirus-35 backbone with P. falciparum circumsporozoite (CS) surface antigen (Ad35.CS.01). Healthy adult subjects received three doses of 10 (8), 10 (9), 10 (10), or 10 (11) vp/mL Ad35.CS.01 vaccine or saline placebo intramuscularly at 0, 1, and 6-mo intervals. Adverse events were assessed and anti-CS antibody responses were determined by ELISA. Seventy-two individuals were enrolled, with age, gender, and ethnicity similar across each study arm. While the vaccine was generally well tolerated, adverse events were more frequent in the highest dose groups (10 (10) and 10 (11) vp/mL). More robust humoral responses were also noted at the highest doses, with 73% developing a positive ELISA response after the three dose series of 10 (11) vp/mL. The Ad35.CS.01 vaccine was most immunogenic at the highest dosages (10 (10) and 10 (11) vp/mL). Reactogenicity findings were more common after the 10 (11) vp/mL dose, although most were mild or moderate in nature and resolved without therapy.
authors: Vanderbilt Vaccine Research Program; Department of Pediatrics; Vanderbilt University School of Medicine; Nashville, TN USA.
authors: C Buddy
authors: CB
authors: Creech
authors: Stanford-LPCH Vaccine Program, Department of Pediatrics-Infectious Diseases; Stanford University School of Medicine; Stanford, CA USA.
authors: Cornelia L
authors: CL
authors: Dekker
authors: Stanford-LPCH Vaccine Program, Department of Pediatrics-Infectious Diseases; Stanford University School of Medicine; Stanford, CA USA.
authors: Dora
authors: D
authors: Ho
authors: Vanderbilt Vaccine Research Program; Department of Pediatrics; Vanderbilt University School of Medicine; Nashville, TN USA.
authors: Shanda
authors: S
authors: Phillips
authors: Stanford-LPCH Vaccine Program, Department of Pediatrics-Infectious Diseases; Stanford University School of Medicine; Stanford, CA USA.
authors: Sally
authors: S
authors: Mackey
authors: Division of Epidemiology, Biostatistics and Preventive Medicine; Department of Internal Medicine; University of New Mexico Health Sciences Center; Albuquerque, NM USA.
authors: Cristina
authors: C
authors: Murray-Krezan
authors: Crucell; Leiden, The Netherlands.
authors: Maria
authors: M
authors: Grazia Pau
authors: Crucell; Leiden, The Netherlands.
authors: Jenny
authors: J
authors: Hendriks
authors: EMMES Corporation; Rockville, MD USA.
authors: Valerie
authors: V
authors: Brown
authors: EMMES Corporation; Rockville, MD USA.
authors: Leonard G
authors: LG
authors: Dally
authors: Crucell; Leiden, The Netherlands.
authors: Isabella
authors: I
authors: Versteege
authors: Vanderbilt Vaccine Research Program; Department of Pediatrics; Vanderbilt University School of Medicine; Nashville, TN USA.
authors: Kathryn M
authors: KM
authors: Edwards
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000913:Antibodies, Protozoan / Q000097:blood; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology*; D004337:Drug Carriers; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D008288:Malaria / Q000276:immunology / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D016896:Treatment Outcome; D014611:Vaccination / Q000009:adverse effects* / Q000379:methods*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D004337:Drug Carriers; D017780:Malaria Vaccines; D010919:Placebos; D015800:Protozoan Proteins; D014614:Vaccines, Synthetic; C041595:circumsporozoite protein, Protozoan
keywords: adenovirus; circumsporozoite; malaria; vaccine
references: Virology. 1968 Sep;36(1):126-36
references: 5669983
references: Clin Vaccine Immunol. 2011 May;18(5):776-82
references: 21411600
references: Vaccine. 2011 Aug 11;29(35):6059-67
references: 21443960
references: PLoS One. 2010 Oct 27;5(10):e13579
references: 21048953
references: PLoS One. 2011;6(10):e24586
references: 22003383
references: Infect Immun. 2006 Jan;74(1):313-20
references: 16368986
references: N Engl J Med. 2011 Nov 17;365(20):1863-75
references: 22007715
references: Parasite Immunol. 2000 Mar;22(3):157-60
references: 10672197
references: J Immunol. 2005 Mar 15;174(6):3757-64
references: 15749916
references: Lancet. 2008 Nov 29;372(9653):1881-1893
references: 19012954
references: Infect Immun. 2003 Aug;71(8):4320-5
references: 12874308
references: Vaccine. 2010 Dec 16;29(2):304-13
references: 21034824
references: N Engl J Med. 2012 Dec 13;367(24):2284-95
references: 23136909
references: PLoS One. 2013;8(2):e55571
references: 23457473
references: Lancet. 2008 Nov 29;372(9653):1894-1905
references: 19012957
references: PLoS One. 2011;6(10):e25868
references: 22003411
references: J Virol. 2003 Aug;77(15):8263-71
references: 12857895
references: Vaccine. 1998 Nov;16(19):1812-7
references: 9795385
references: Infect Immun. 2007 May;75(5):2283-90
references: 17307942
references: Malar J. 2012 Jun 21;11:209
references: 22720732
references: Vaccine. 2012 Jul 27;30(35):5191-8
references: 22683663
references: Virology. 2005 Jul 5;337(2):335-43
references: 15916793
references: Lancet Infect Dis. 2011 Feb;11(2):102-9
references: 21237715
references: PLoS One. 2011;6(10):e25786
references: 21998698
references: N Engl J Med. 2008 Dec 11;359(24):2521-32
references: 19064627
references: Nature. 2005 Mar 10;434(7030):214-7
references: 15759000
references: J Infect Dis. 2006 Aug 15;194(4):435-43
references: 16845626
references: J Infect Dis. 2011 Jul 1;204(1):9-18
references: 21628653
references: J Infect Dis. 2008 Feb 15;197(4):519-26
references: 18275273
references: Clin Microbiol Rev. 2002 Oct;15(4):564-94
references: 12364370
references: Am J Trop Med Hyg. 2005 Jul;73(1):222-8
references: 16014863
references: Immunology. 2003 Apr;108(4):474-80
references: 12667209
references: Vaccine. 2004 Aug 13;22(23-24):3035-44
references: 15297053
references: Vaccine. 2008 Jun 2;26(23):2818-23
references: 18455276
references: Clin Vaccine Immunol. 2010 Nov;17(11):1687-94
references: 20826614
references: Lancet. 2001 Dec 8;358(9297):1927-34
references: 11747915
references: J Infect Dis. 1998 Oct;178(4):1139-44
references: 9806046