title: Human adenovirus 5-vectored Plasmodium falciparum NMRC-M3V-Ad-PfCA vaccine encoding CSP and AMA1 is safe, well-tolerated and immunogenic but does not protect against controlled human malaria infection.
abstract: BACKGROUND
  In a prior study, a DNA prime / adenovirus boost vaccine (DNA/Ad) expressing P. falciparum circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1) (NMRC-M3V-D/Ad-PfCA Vaccine) induced 27% protection against controlled human malaria infection (CHMI). To investigate the contribution of DNA priming, we tested the efficacy of adenovirus vaccine alone (NMRC-M3V-Ad-PfCA ) in a Phase 1 clinical trial.
  
  
  RESULTS
  The regimen was a single intramuscular injection with two non-replicating human serotype 5 adenovectors encoding CSP and AMA1, respectively. One x 10 (10) particle units of each construct were combined prior to administration. The regimen was safe and well-tolerated. Four weeks later, 18 study subjects received P. falciparum CHMI administered by mosquito bite. None were fully protected although one showed delayed onset of parasitemia. Antibody responses were low, with geometric mean CSP ELISA titer of 381 (range<50-1626) and AMA1 ELISA of 4.95 µg/mL (range 0.2-38). Summed ex vivo IFN-γ ELISpot responses to overlapping peptides were robust, with geometric mean spot forming cells/million peripheral blood mononuclear cells [sfc/m] for CSP of 273 (range 38-2550) and for AMA1 of 1303 (range 435-4594). CD4+ and CD8+ T cell IFN-γ responses to CSP were positive by flow cytometry in 25% and 56% of the research subjects, respectively, and to AMA1 in 94% and 100%, respectively.
  
  
  CONCLUSIONS
  In contrast to DNA/Ad, Ad alone did not protect against CHMI despite inducing broad, cell-mediated immunity, indicating that DNA priming is required for protection by the adenovirus-vectored vaccine. ClinicalTrials.gov Identifier: NCT00392015.
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Tamminga
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Sedegah
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Santina
authors.initials: S
authors.lastname: Maiolatesi
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Fedders
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Sharina
authors.initials: S
authors.lastname: Reyes
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Anatalio
authors.initials: A
authors.lastname: Reyes
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Vasquez
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Alcorta
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Ilin
authors.initials: I
authors.lastname: Chuang
authors.affiliation: Armed Forces Research Institute of Medical Sciences; Bangkok, Thailand.
authors.forename: Michele
authors.initials: M
authors.lastname: Spring
authors.affiliation: National Naval Medical Center; Bethesda, MD USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kavanaugh
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Harini
authors.initials: H
authors.lastname: Ganeshan
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Belmonte
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Esteban
authors.initials: E
authors.lastname: Abot
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Arnel
authors.initials: A
authors.lastname: Belmonte
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Joglenna
authors.initials: J
authors.lastname: Banania
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Fouzia
authors.initials: F
authors.lastname: Farooq
authors.affiliation: Walter Reed Army Institute of Research; Silver Spring, MD USA.
authors.forename: Jittawadee
authors.initials: J
authors.lastname: Murphy
authors.affiliation: Walter Reed Army Institute of Research; Silver Spring, MD USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Komisar
authors.affiliation: Walter Reed Army Institute of Research; Silver Spring, MD USA.
authors.forename: Nancy O
authors.initials: NO
authors.lastname: Richie
authors.affiliation: Walter Reed Army Institute of Research; Silver Spring, MD USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Bennett
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Limbach
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Noelle B
authors.initials: NB
authors.lastname: Patterson
authors.affiliation: GenVec Inc.; Gaithersburg, MD USA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Bruder
authors.affiliation: Walter Reed Army Institute of Research; Silver Spring, MD USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Shi
authors.affiliation: National Naval Medical Center; Bethesda, MD USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Miller
authors.affiliation: Walter Reed Army Institute of Research; Silver Spring, MD USA.
authors.forename: Sheetij
authors.initials: S
authors.lastname: Dutta
authors.affiliation: USAID; Washington, DC USA.
authors.forename: Carter
authors.initials: C
authors.lastname: Diggs
authors.affiliation: USAID; Washington, DC USA.
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: Soisson
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hollingdale
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Epstein
authors.affiliation: Naval Medical Research Center; Silver Spring, MD USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Richie
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000913:Antibodies, Protozoan / Q000097:blood; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D007273:Injections, Intramuscular; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D016778:Malaria, Falciparum / Q000517:prevention & control*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology*; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D008565:Membrane Proteins; D015800:Protozoan Proteins; D014614:Vaccines, Synthetic; C090077:apical membrane antigen I, Plasmodium; C041595:circumsporozoite protein, Protozoan; D007371:Interferon-gamma
keywords: T cells; adenovirus; antibody; efficacy; malaria; vaccine
references.citation: PLoS One. 2009 Aug 10;4(8):e6559
references.pmid: 19668343
references.citation: PLoS One. 2013;8(2):e55571
references.pmid: 23457473
references.citation: J Clin Microbiol. 2003 Nov;41(11):5046-52
references.pmid: 14605137
references.citation: J Immunol. 2010 Apr 15;184(8):4431-9
references.pmid: 20212099
references.citation: Mol Ther. 2012 Dec;20(12):2355-68
references.pmid: 23089736
references.citation: Nat Rev Immunol. 2008 Apr;8(4):247-58
references.pmid: 18323851
references.citation: Immunol Rev. 2008 Oct;225:272-83
references.pmid: 18837788
references.citation: Lancet. 2008 Mar 15;371(9616):923-31
references.pmid: 18342687
references.citation: PLoS One. 2009;4(4):e5075
references.pmid: 19347042
references.citation: Expert Rev Vaccines. 2011 Mar;10(3):355-64
references.pmid: 21434803
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4836-41
references.pmid: 15781866
references.citation: Cell Host Microbe. 2011 Jun 16;9(6):451-62
references.pmid: 21669394
references.citation: J Immunol. 2011 Sep 15;187(6):3391-401
references.pmid: 21844392
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10817-22
references.pmid: 11526203
references.citation: Hum Gene Ther. 2002 Sep 1;13(13):1551-60
references.pmid: 12228010
references.citation: Infect Immun. 1998 Sep;66(9):4193-202
references.pmid: 9712767
references.citation: Infect Immun. 2010 Jan;78(1):145-53
references.pmid: 19858306
references.citation: PLoS One. 2012;7(2):e31208
references.pmid: 22363582
references.citation: Int Immunol. 1996 Dec;8(12):1877-87
references.pmid: 8982772
references.citation: PLoS One. 2011;6(10):e25868
references.pmid: 22003411
references.citation: Hum Vaccin Immunother. 2012 Nov 1;8(11):1564-84
references.pmid: 23151451
references.citation: Am J Trop Med Hyg. 1986 Jan;35(1):66-8
references.pmid: 3511753
references.citation: N Engl J Med. 1997 Jan 9;336(2):86-91
references.pmid: 8988885
references.citation: PLoS One. 2011;6(10):e24586
references.pmid: 22003383
references.citation: J Immunol. 2011 Aug 1;187(3):1347-57
references.pmid: 21715686
references.citation: Vaccine. 2000 Mar 17;18(18):1893-901
references.pmid: 10699338
references.citation: AIDS Res Hum Retroviruses. 2009 Jan;25(1):103-14
references.pmid: 19108693
references.citation: J Immunother. 2010 Jun;33(5):510-22
references.pmid: 20463596
references.citation: Malar J. 2009 Dec 30;8:312
references.pmid: 20042088
references.citation: J Immunol. 1987 Jan 1;138(1):306-11
references.pmid: 2431058
references.citation: Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9866-70
references.pmid: 7937907