Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents preexisting immunity to adenovirus in mice.
Although adenovirus (Ad) has been regarded as an excellent vaccine vector, there are 2 major drawbacks to using this platform: (a) Ad-based vaccines induce a relatively weak humoral response against encoded transgenes, and (b) preexisting immunity to Ad is highly prevalent among the general population. To overcome these obstacles, we constructed an Ad-based malaria vaccine by inserting a B cell epitope derived from a Plasmodium yoelii circumsporozoite (CS) protein (referred to as the PyCS-B epitope) into the capsid proteins of WT/CS-GFP, a recombinant Ad expressing P. yoelii CS protein and GFP as its transgene. Multiple vaccinations with the capsid-modified Ad induced a substantially increased level of protection against subsequent malaria challenge in mice when compared with that of unmodified WT/CS-GFP. Increased protection correlated with augmented antibody responses against the PyCS-B epitope expressed in the capsid. Furthermore, replacement of hypervariable region 1 (HVR1) of the Ad capsid proteins with the PyCS-B epitope circumvented neutralization of the modified Ad by preexisting Ad-specific antibody, both in vivo and in vitro. Importantly, the immunogenicity of the Ad-containing PyCS-B epitope in the HVR1 and a P. yoelii CS transgene was maintained. Overall, this study demonstrates that the HVR1-modifed Ad vastly improves upon Ad as a promising malaria vaccine platform candidate.
Shiratsuchi
Takayuki
T
HIV and Malaria Vaccine Program, Aaron Diamond AIDS Research Center, New York, New York 10016, USA.
Rai
Urvashi
U
Krause
Anja
A
Worgall
Stefan
S
Tsuji
Moriya
M
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D001483:Base Sequence; D036022:Capsid Proteins / Q000276:immunology*; D045744:Cell Line, Tumor; D018985:Epitopes, B-Lymphocyte / Q000276:immunology*; D005260:Female; D005822:Genetic Vectors / Q000276:immunology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010967:Plasmodium yoelii / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology*
D000913:Antibodies, Protozoan; D036022:Capsid Proteins; D018985:Epitopes, B-Lymphocyte; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan
J Virol. 2007 May;81(9):4654-63
17329340
Virology. 2005 Feb 5;332(1):1-7
15661134
Cell Microbiol. 2006 Jul;8(7):1134-46
16819966
Infect Immun. 2006 Dec;74(12):6929-39
17030584
J Gene Med. 2009 Jul;11(7):570-9
19391169
Cell. 1985 Sep;42(2):401-3
2411417
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W526-31
15980527
Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11491-6
11553779
Trends Parasitol. 2003 Feb;19(2):88-93
12586477
J Immunol. 1991 Feb 1;146(3):1020-5
1988490
Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5483-8
18391209
Nature. 1967 Oct 14;216(5111):160-2
6057225
J Parasitol. 1978 Feb;64(1):166-8
342682
Bull World Health Organ. 1979;57 Suppl 1:165-73
120766
J Exp Med. 2005 Jan 17;201(2):201-9
15657290
J Immunol. 1997 Feb 1;158(3):1268-74
9013969
J Clin Invest. 2005 May;115(5):1281-9
15841217
J Exp Med. 1982 Jul 1;156(1):20-30
7045272
Am J Med Sci. 1973 Sep;266(3):169-77
4583408
Science. 1997 Feb 28;275(5304):1320-3
9036860
J Immunol. 2004 Mar 1;172(5):3094-100
14978115
J Virol. 2002 Dec;76(24):12775-82
12438602
Infect Immun. 2006 Jan;74(1):313-20
16368986
J Infect Dis. 1993 Oct;168(4):1066-70
8376823
J Immunol. 1995 Mar 15;154(6):2784-93
7876549
Nature. 2006 May 11;441(7090):239-43
16625206
J Virol. 2006 Jun;80(11):5361-70
16699016
Mol Ther. 2004 Oct;10(4):616-29
15451446
J Virol. 2007 Dec;81(24):13801-8
17942539
J Virol. 2007 Feb;81(4):1680-9
17108028
J Virol. 2006 Jun;80(11):5523-30
16699033