title: The Th1 immune response to Plasmodium falciparum circumsporozoite protein is boosted by adenovirus vectors 35 and 26 with a homologous insert.
abstract: The most advanced malaria vaccine, RTS,S, is comprised of a portion of the Plasmodium falciparum circumsporozoite (CS) protein, fused to and admixed with the hepatitis B virus surface antigen, and an adjuvant [corrected].This vaccine confers short-term protection against malaria infection, with an efficacy of about 50%, and induces particularly B-cell and CD4(+) T-cell responses.In the present study, we tested the hypothesis that the Th1 immune response to CS protein,in particular the CD8(+) T-cell response, which is needed for strong and lasting malaria immunity, is boosted to sustainable levels by adenovirus vectors 35 and 26 with a homologous insert (Ad35.CS/Ad26.CS) [corrected]. In this study, we evaluated immune responses induced with vaccination regimens based on an adjuvant-containing, yeast-produced complete CS protein followed by two recombinant low-seroprevalence adenoviruses expressing P. falciparum CS antigen, Ad35.CS (subgroup B) and Ad26.CS (subgroup D). Our results show that (i) the yeast (Hansenula polymorpha)produced, adjuvanted full-length CS protein is highly potent in inducing high CS-specific humoral responses in mice but produces poor T-cell responses, (ii) the Ad35.CS vector boosts the gamma interferon-positive (IFN-γ(+)) CD8(+) T-cell response induced by the CS protein immunization and shifts the immune response toward the Th1 type, and (iii) a three-component heterologous vaccination comprised of a CS protein prime followed by boosts with Ad35.CS and Ad26.CS elicits an even more robust and sustainable IFN-γ(+) CD8(+) T-cell response than one- or two-component regimens. The Ad35.CS/Ad26.CS combination boosted particularly the IFN-γ(+) and tumor necrosis factor alpha-positive (TNF-α(+)) T cells, confirming the shift of the immune response from the Th2 type to the Th1 type. These results support the notion of first immunizations of infants with an adjuvanted CS protein vaccine, followed by a booster Ad35.CS/Ad26.CS vaccine at a later age, to induce lasting protection against malaria for which the Th1 response and immune memory is required.
authors.affiliation: Crucell Holland B.V., Archimedesweg 4-6, 2333 CN Leiden, Netherlands. katarina.radosevic@crucell.com
authors.forename: Katarina
authors.initials: K
authors.lastname: Radosevic
authors.forename: Ariane
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Angelique A C
authors.initials: AA
authors.lastname: Lemckert
authors.forename: Marjolein
authors.initials: M
authors.lastname: van der Meer
authors.forename: Gert
authors.initials: G
authors.lastname: Gillissen
authors.forename: Carolien
authors.initials: C
authors.lastname: Warnar
authors.forename: Rie
authors.initials: R
authors.lastname: von Eyben
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Pau
authors.forename: Jaap
authors.initials: J
authors.lastname: Goudsmit
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D007117:Immunization, Secondary / Q000379:methods; D007371:Interferon-gamma / Q000378:metabolism; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010843:Pichia / Q000235:genetics; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D014611:Vaccination / Q000379:methods; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D000913:Antibodies, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; C041595:circumsporozoite protein, Protozoan; D007371:Interferon-gamma
references.citation: J Immunol. 2009 Mar 15;182(6):3469-81
references.pmid: 19265125
references.citation: J Infect Dis. 2006 Dec 15;194(12):1638-49
references.pmid: 17109335
references.citation: J Clin Invest. 2009 Aug;119(8):2379-87
references.pmid: 19620772
references.citation: J Gen Virol. 2006 Oct;87(Pt 10):2891-2899
references.pmid: 16963747
references.citation: N Engl J Med. 2008 Dec 11;359(24):2521-32
references.pmid: 19064627
references.citation: PLoS Pathog. 2008 Sep 19;4(9):e1000159
references.pmid: 18802458
references.citation: PLoS Pathog. 2008 Feb 29;4(2):e1000004
references.pmid: 18401464
references.citation: Vaccine. 2009 Oct 19;27(44):6226-33
references.pmid: 19686691
references.citation: Vaccine. 2008 Feb 20;26(8):1072-82
references.pmid: 18258343
references.citation: Am J Trop Med Hyg. 2005 Jul;73(1):222-8
references.pmid: 16014863
references.citation: J Clin Invest. 2009 Jul;119(7):1899-909
references.pmid: 19509469
references.citation: J Virol. 2007 May;81(9):4654-63
references.pmid: 17329340
references.citation: Vaccine. 2006 May 22;24(21):4471-4
references.pmid: 16140432
references.citation: Nature. 2002 Jan 17;415(6869):331-5
references.pmid: 11797011
references.citation: J Immunol. 2004 May 15;172(10):6290-7
references.pmid: 15128818
references.citation: Infect Immun. 2006 Apr;74(4):2187-95
references.pmid: 16552049
references.citation: J Virol. 2008 May;82(10):4844-52
references.pmid: 18337575
references.citation: Nature. 2009 Jan 1;457(7225):87-91
references.pmid: 18997770
references.citation: Gastroenterology. 2009 Jan;136(1):247-56
references.pmid: 18948106
references.citation: Vaccine. 2002 Jan 15;20(7-8):1039-45
references.pmid: 11803063
references.citation: Clin Infect Dis. 2008 Jun 1;46(11):1769-81
references.pmid: 18433307
references.citation: Vaccine. 2008 Apr 24;26(18):2191-202
references.pmid: 18387719
references.citation: J Virol. 2003 Aug;77(15):8263-71
references.pmid: 12857895
references.citation: J Immunol. 1997 Feb 1;158(3):1268-74
references.pmid: 9013969
references.citation: Nat Rev Microbiol. 2006 Jun;4(6):469-76
references.pmid: 16710326
references.citation: Nat Med. 2008 Mar;14(3):275-81
references.pmid: 18264110
references.citation: Annu Rev Med. 2004;55:355-72
references.pmid: 14746526
references.citation: J Exp Med. 1994 Jul 1;180(1):353-8
references.pmid: 7516412
references.citation: J Gen Virol. 2006 Aug;87(Pt 8):2135-2143
references.pmid: 16847108
references.citation: Am J Med Sci. 1973 Sep;266(3):169-77
references.pmid: 4583408
references.citation: Expert Rev Vaccines. 2009 May;8(5):577-92
references.pmid: 19397415
references.citation: J Immunol. 2003 Feb 1;170(3):1416-22
references.pmid: 12538702
references.citation: Infect Immun. 2007 May;75(5):2283-90
references.pmid: 17307942
references.citation: Infect Immun. 2006 Jan;74(1):313-20
references.pmid: 16368986
references.citation: Infect Immun. 2007 Aug;75(8):4105-15
references.pmid: 17526747
references.citation: Vet Immunol Immunopathol. 2006 Dec 15;114(3-4):259-72
references.pmid: 17045659
references.citation: J Infect Dis. 2009 Aug 1;200(3):337-46
references.pmid: 19569965
references.citation: Infect Immun. 2008 Apr;76(4):1709-18
references.pmid: 18212075
references.citation: J Immunol. 2003 Dec 15;171(12):6774-9
references.pmid: 14662882
references.citation: Gastroenterology. 2009 Jun;136(7):2237-2246.e1
references.pmid: 19272385
references.citation: Curr Mol Med. 2006 Mar;6(2):169-85
references.pmid: 16515509
references.citation: J Virol. 2004 Dec;78(23):13207-15
references.pmid: 15542673
references.citation: Scand J Immunol. 2002 Oct;56(4):327-43
references.pmid: 12234254
references.citation: Immunol Rev. 2008 Oct;225:272-83
references.pmid: 18837788
references.citation: Nature. 2006 May 11;441(7090):239-43
references.pmid: 16625206
references.citation: Vaccine. 2008 Jul 4;26(29-30):3640-6
references.pmid: 18514980
references.citation: Proc Natl Acad Sci U S A. 1988 Jan;85(2):573-6
references.pmid: 2963334
references.citation: Int Immunol. 1991 Jun;3(6):579-85
references.pmid: 1716146
references.citation: Vaccine. 2007 Feb 9;25(8):1426-36
references.pmid: 17161889
references.citation: J Infect Dis. 2008 Feb 15;197(4):519-26
references.pmid: 18275273
references.citation: Nature. 1987 Dec 17-23;330(6149):664-6
references.pmid: 3120015
references.citation: Vaccine. 2009 Dec 30;27 Suppl 6:G67-71
references.pmid: 20006143
references.citation: Mol Ther. 2004 Oct;10(4):616-29
references.pmid: 15451446
references.citation: Nat Immunol. 2007 Apr;8(4):369-77
references.pmid: 17351619
references.citation: J Virol. 2004 Jul;78(14):7490-7
references.pmid: 15220422
references.citation: J Immunol. 2005 Jul 15;175(2):788-95
references.pmid: 16002675
references.citation: J Virol. 2004 Oct;78(20):11434-8
references.pmid: 15452269