title: Heterologous Prime-Boost HIV-1 Vaccination Regimens in Pre-Clinical and Clinical Trials.
abstract: Currently, there are more than 30 million people infected with HIV-1 and thousands more are infected each day. Vaccination is the single most effective mechanism for prevention of viral disease, and after more than 25 years of research, one vaccine has shown somewhat encouraging results in an advanced clinical efficacy trial. A modified intent-to-treat analysis of trial results showed that infection was approximately 30% lower in the vaccine group compared to the placebo group. The vaccine was administered using a heterologous prime-boost regimen in which both target antigens and delivery vehicles were changed during the course of inoculations. Here we examine the complexity of heterologous prime-boost immunizations. We show that the use of different delivery vehicles in prime and boost inoculations can help to avert the inhibitory effects caused by vector-specific immune responses. We also show that the introduction of new antigens into boost inoculations can be advantageous, demonstrating that the effect of `original antigenic sin' is not absolute. Pre-clinical and clinical studies are reviewed, including our own work with a three-vector vaccination regimen using recombinant DNA, virus (Sendai virus or vaccinia virus) and protein. Promising preliminary results suggest that the heterologous prime-boost strategy may possibly provide a foundation for the future prevention of HIV-1 infections in humans.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, USA; scott.brown@stjude.org.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Brown
authors.forename: Sherri L
authors.initials: SL
authors.lastname: Surman
authors.forename: Robert
authors.initials: R
authors.lastname: Sealy
authors.forename: Bart G
authors.initials: BG
authors.lastname: Jones
authors.forename: Karen S
authors.initials: KS
authors.lastname: Slobod
authors.forename: Kristen
authors.initials: K
authors.lastname: Branum
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Lockey
authors.forename: Nanna
authors.initials: N
authors.lastname: Howlett
authors.forename: Pamela
authors.initials: P
authors.lastname: Freiden
authors.forename: Patricia
authors.initials: P
authors.lastname: Flynn
authors.forename: Julia L
authors.initials: JL
authors.lastname: Hurwitz
references.citation: AIDS Res Hum Retroviruses. 2001 Aug 10;17(12):1205-9
references.pmid: 11522189
references.citation: J Biol Chem. 1999 Jan 22;274(4):1905-13
references.pmid: 9890944
references.citation: J Infect Dis. 1998 May;177(5):1230-46
references.pmid: 9593008
references.citation: J Gen Virol. 2003 Feb;84(Pt 2):361-368
references.pmid: 12560568
references.citation: J Infect Dis. 1998 May;177(5):1247-59
references.pmid: 9593009
references.citation: Nat Med. 2003 Sep;9(9):1131-7
references.pmid: 12925846
references.citation: J Virol. 2003 Dec;77(23):12764-72
references.pmid: 14610198
references.citation: Nature. 2003 Mar 27;422(6930):428-33
references.pmid: 12660783
references.citation: J Virol. 1991 Jan;65(1):31-41
references.pmid: 1985202
references.citation: J Immunol. 2003 Nov 15;171(10):4969-73
references.pmid: 14607890
references.citation: Front Biosci. 2008 Jan 01;13:2696-704
references.pmid: 17981744
references.citation: Vaccine. 2009 Jun 19;27(30):3992-4000
references.pmid: 19389440
references.citation: J Virol. 1994 Sep;68(9):6083-6
references.pmid: 8057487
references.citation: Science. 2002 Jun 28;296(5577):2354-60
references.pmid: 12089434
references.citation: Cell. 1978 Oct;15(2):687-701
references.pmid: 719759
references.citation: Immunol Lett. 1996 Jun;51(1-2):129-35
references.pmid: 8811357
references.citation: Bone Marrow Transplant. 2007 Dec;40(11):1055-62
references.pmid: 17891187
references.citation: Pediatr Infect Dis J. 2009 Apr;28(4 Suppl):S66-76
references.pmid: 19325449
references.citation: J Med Virol. 1990 Mar;30(3):216-8
references.pmid: 2140407
references.citation: J Virol. 2007 Aug;81(16):8563-70
references.pmid: 17553898
references.citation: Pediatr Infect Dis J. 2006 Jul;25(7):577-83
references.pmid: 16804425
references.citation: AIDS. 2003 Jan 24;17(2):157-66
references.pmid: 12545074
references.citation: Vaccine. 2009 Dec 10;28(1):152-61
references.pmid: 19808028
references.citation: J Immunol Methods. 2006 Jan 20;308(1-2):53-67
references.pmid: 16343526
references.citation: Science. 1989 Dec 8;246(4935):1293-7
references.pmid: 2555923
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4587-92
references.pmid: 11287644
references.citation: AIDS Rev. 2003 Jan-Mar;5(1):52-61
references.pmid: 12875108
references.citation: Bioinformatics. 2008 Jul 15;24(14):1639-40
references.pmid: 18515277
references.citation: Science. 2005 Jun 24;308(5730):1906-8
references.pmid: 15860590
references.citation: J Virol. 2003 Aug;77(15):8354-65
references.pmid: 12857905
references.citation: Nature. 2008 May 29;453(7195):667-71
references.pmid: 18449194
references.citation: Virology. 1993 Jan;192(1):197-206
references.pmid: 7685962
references.citation: J Virol. 2009 Sep;83(17):9008-12
references.pmid: 19535449
references.citation: Int Immunol. 2002 Jan;14(1):31-7
references.pmid: 11751749
references.citation: Vaccine. 2009 Sep 25;27(42):5837-45
references.pmid: 19660588
references.citation: J Virol. 2002 Jun;76(11):5435-51
references.pmid: 11991972
references.citation: Curr Drug Targets Infect Disord. 2005 Jun;5(2):131-41
references.pmid: 15975019
references.citation: AIDS Res Hum Retroviruses. 1995 Sep;11(9):1131-3
references.pmid: 8554911
references.citation: AIDS. 2008 Jan 2;22(1):149-51
references.pmid: 18090404
references.citation: J Virol. 1996 Jun;70(6):3724-33
references.pmid: 8648707
references.citation: Eur J Clin Microbiol Infect Dis. 2004 Feb;23(2):106-10
references.pmid: 14735404
references.citation: Vaccine. 1995 Jan;13(1):129
references.pmid: 7539198
references.citation: J Virol. 2009 Dec;83(24):12738-50
references.pmid: 19812149
references.citation: Nature. 2009 Apr 2;458(7238):636-40
references.pmid: 19287373
references.citation: Vaccine. 2005 Sep 7;23(38):4647-57
references.pmid: 15964105
references.citation: Vaccine. 2004 Mar 12;22(9-10):1206-13
references.pmid: 15003649
references.citation: Vaccine. 1999 Mar 17;17(11-12):1567-72
references.pmid: 10195794
references.citation: MMWR Morb Mortal Wkly Rep. 2005 Mar 25;54(11):272-4
references.pmid: 15788992
references.citation: Science. 1992 Jan 24;255(5043):456-9
references.pmid: 1531159
references.citation: AIDS Res Hum Retroviruses. 1994 Nov;10(11):1443-9
references.pmid: 7888199
references.citation: AIDS Res Hum Retroviruses. 2000 Sep 20;16(14):1433-43
references.pmid: 11018863
references.citation: J Virol. 1995 Aug;69(8):5117-23
references.pmid: 7609080
references.citation: J Immunol. 2008 Feb 15;180(4):2504-13
references.pmid: 18250460
references.citation: Vaccine. 2008 Feb 20;26(8):1098-110
references.pmid: 18243434
references.citation: Pediatr Res. 2007 Nov;62(5):527
references.pmid: 18049369
references.citation: Nature. 2000 Oct 5;407(6804):636-42
references.pmid: 11034213
references.citation: Immunol Cell Biol. 1997 Aug;75(4):382-8
references.pmid: 9315482
references.citation: Biochemistry. 2002 Jun 4;41(22):7176-82
references.pmid: 12033952
references.citation: J Immunol. 2003 Oct 15;171(8):4140-8
references.pmid: 14530336
references.citation: Am J Respir Crit Care Med. 2004 Apr 1;169(7):801-5
references.pmid: 14742302
references.citation: J Virol. 2003 Jul;77(13):7367-75
references.pmid: 12805435
references.citation: Science. 2001 Nov 9;294(5545):1361-5
references.pmid: 11701933
references.citation: J Virol. 2001 Dec;75(23):11891-6
references.pmid: 11689672
references.citation: Curr Opin Immunol. 2009 Jun;21(3):346-51
references.pmid: 19500964
references.citation: J Immunol. 2009 May 15;182(10):6587-99
references.pmid: 19414814
references.citation: J Infect Dis. 2003 Aug 1;188(3):397-405
references.pmid: 12870121
references.citation: Mol Ther. 2005 Dec;12(6):1197-205
references.pmid: 16112909
references.citation: J Virol. 2005 Nov;79(21):13338-49
references.pmid: 16227256
references.citation: Vaccine. 2005 May 16;23(26):3434-45
references.pmid: 15837367
references.citation: Virology. 1997 Aug 4;234(2):328-39
references.pmid: 9268165
references.citation: Mol Ther. 2007 Sep;15(9):1724-33
references.pmid: 17579577
references.citation: J Acquir Immune Defic Syndr (1988). 1994 Mar;7(3):211-9
references.pmid: 8106963
references.citation: J Virol. 2006 Jul;80(14):6745-56
references.pmid: 16809280
references.citation: Plant Biotechnol J. 2008 Dec;6(9):914-29
references.pmid: 19548345
references.citation: J Infect Dis. 2004 Aug 15;190(4):702-6
references.pmid: 15272397
references.citation: Proc Natl Acad Sci U S A. 1987 Aug;84(16):5645-9
references.pmid: 3039499
references.citation: J Immunol. 2004 Nov 15;173(10):6274-83
references.pmid: 15528366
references.citation: Microbes Infect. 2005 Nov;7(14):1386-91
references.pmid: 16275150
references.citation: Science. 2009 Oct 9;326(5950):285-9
references.pmid: 19729618
references.citation: Science. 2009 Sep 18;325(5947):1482-3
references.pmid: 19762610
references.citation: Vaccine. 2007 Apr 12;25(15):2951-8
references.pmid: 17360078
references.citation: Vaccine. 2009 Dec 11;28(2):474-83
references.pmid: 19853074
references.citation: Hum Gene Ther. 2001 Jun 10;12(9):1047-61
references.pmid: 11399227
references.citation: J Virol. 2002 Aug;76(15):7506-17
references.pmid: 12097563
references.citation: Vaccine. 2009 Sep 25;27(42):5735-9
references.pmid: 19647812
references.citation: J Gen Virol. 1996 Dec;77 ( Pt 12):2969-81
references.pmid: 9000087
references.citation: MMWR Morb Mortal Wkly Rep. 2008 Oct 3;57(39):1073-6
references.pmid: 18830210
references.citation: Vaccine. 2008 Nov 11;26(48):6124-31
references.pmid: 18812199
references.citation: J Exp Med. 1991 Apr 1;173(4):881-7
references.pmid: 2007856
references.citation: Vaccine. 2007 May 16;25(20):4085-92
references.pmid: 17391815
references.citation: Immunity. 2003 Apr;18(4):549-59
references.pmid: 12705857
references.citation: J Immunol. 2009 Sep 1;183(5):3294-301
references.pmid: 19648276
references.citation: Nat Med. 1997 Jun;3(6):651-8
references.pmid: 9176492
references.citation: Vaccine. 1994 Dec;12(16):1495-8
references.pmid: 7879412
references.citation: Virology. 1996 Jan 15;215(2):124-33
references.pmid: 8560759
references.citation: Vaccine. 2009 Jul 30;27(35):4857-66
references.pmid: 19520196
references.citation: Science. 2004 Jan 16;303(5656):316
references.pmid: 14726576
references.citation: Science. 1999 Jan 15;283(5400):357-62
references.pmid: 9888845
references.citation: Vaccine. 2005 Nov 16;23(46-47):5306-20
references.pmid: 16095768
references.citation: Immunity. 1998 Mar;8(3):363-72
references.pmid: 9529153
references.citation: J Virol. 2004 Jan;78(1):94-103
references.pmid: 14671091
references.citation: Nature. 1981 Apr 23;290(5808):713-7
references.pmid: 6163993
references.citation: J Virol. 2005 Mar;79(5):2956-63
references.pmid: 15709015
references.citation: AIDS Res Hum Retroviruses. 2005 Jul;21(7):629-43
references.pmid: 16060834
references.citation: J Exp Med. 2008 Jan 21;205(1):63-77
references.pmid: 18195071
references.citation: J Virol. 1998 Dec;72(12):10180-8
references.pmid: 9811759
references.citation: Science. 2000 Jun 9;288(5472):1789-96
references.pmid: 10846155
references.citation: Cell Immunol. 1987 Oct 1;109(1):53-64
references.pmid: 3498544
references.citation: AIDS Res Hum Retroviruses. 2004 Jun;20(6):654-65
references.pmid: 15242543
references.citation: Science. 1990 Aug 24;249(4971):932-5
references.pmid: 2392685
references.citation: Front Biosci. 2008 Jan 01;13:609-20
references.pmid: 17981574
references.citation: Vaccine. 1997 Feb;15(3):265-72
references.pmid: 9139484
references.citation: Vaccine. 2005 Mar 31;23(19):2454-64
references.pmid: 15752831
references.citation: Lancet. 2008 Nov 29;372(9653):1857-1858
references.pmid: 19012958
references.citation: J Virol. 2002 Jun;76(11):5357-68
references.pmid: 11991964
references.citation: J Acquir Immune Defic Syndr (1988). 1990;3(4):366-71
references.pmid: 2313562
references.citation: Proc Natl Acad Sci U S A. 1980 Sep;77(9):5424-8
references.pmid: 6776537
references.citation: AIDS Res Hum Retroviruses. 1998 May 20;14(8):717-9
references.pmid: 9618085
references.citation: Vaccine. 2009 Jul 16;27(33):4468-74
references.pmid: 19450644
references.citation: Vaccine. 2007 Feb 9;25(8):1398-408
references.pmid: 17113201
references.citation: J Virol Methods. 1989 Dec;26(3):279-90
references.pmid: 2695538
references.citation: Science. 2004 Sep 10;305(5690):1545-7
references.pmid: 15361591
references.citation: J Virol. 2009 Sep;83(18):9584-90
references.pmid: 19553307
references.citation: Nature. 1991 Oct 3;353(6343):393
references.pmid: 1815549
references.citation: Vaccine. 2009 May 26;27(25-26):3443-9
references.pmid: 19201386
references.citation: Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8308-12
references.pmid: 1518862
references.citation: AIDS Res Hum Retroviruses. 1997 Nov 20;13(17):1487-95
references.pmid: 9390747
references.citation: Virology. 2008 Dec 20;382(2):226-38
references.pmid: 18945463
references.citation: Clin Vaccine Immunol. 2008 Apr;15(4):713-9
references.pmid: 18235043
references.citation: J Virol. 2009 Oct;83(19):9813-23
references.pmid: 19625392
references.citation: Proc Natl Acad Sci U S A. 1975 Oct;72(10):3961-5
references.pmid: 1105573
references.citation: Virology. 2003 Sep 1;313(2):387-400
references.pmid: 12954207
references.citation: QJM. 1995 Feb;88(2):77-9
references.pmid: 7704566
references.citation: AIDS Res Hum Retroviruses. 1991 Jul;7(7):615-20
references.pmid: 1768463
references.citation: Nat Rev Immunol. 2002 Jan;2(1):60-5
references.pmid: 11905839
references.citation: Curr Drug Targets Infect Disord. 2005 Jun;5(2):143-56
references.pmid: 15975020
references.citation: Curr HIV Res. 2005 Apr;3(2):107-12
references.pmid: 15853717
references.citation: Science. 1988 Nov 25;242(4882):1171-3
references.pmid: 2460925
references.citation: Gene Ther. 2010 Jan;17(1):37-49
references.pmid: 19741733
references.citation: J Virol. 2006 Sep;80(18):9217-25
references.pmid: 16940533
references.citation: Virology. 2006 May 10;348(2):341-53
references.pmid: 16460776
references.citation: Science. 2004 Jul 9;305(5681):177-80; author reply 177-80
references.pmid: 15247455
references.citation: PLoS One. 2008;3(12):e3937
references.pmid: 19081789
references.citation: Immunology. 2008 Mar;123(3):426-37
references.pmid: 17916164
references.citation: Vaccine. 2003 Jan 30;21(7-8):638-43
references.pmid: 12531332
references.citation: J Virol. 2007 Nov;81(22):12535-42
references.pmid: 17652379
references.citation: Ann N Y Acad Sci. 1995 Nov 27;772:257-60
references.pmid: 8546402
references.citation: Curr Drug Targets Infect Disord. 2005 Jun;5(2):157-70
references.pmid: 15975021
references.citation: Hum Vaccin. 2009 Jul;5(7):436-8
references.pmid: 19662687
references.citation: AIDS Res Hum Retroviruses. 2007 Dec;23(12):1555-62
references.pmid: 18160013
references.citation: Vaccine. 1998 Nov;16(19):1803-11
references.pmid: 9795384
references.citation: Curr HIV Res. 2009 Sep;7(5):497-503
references.pmid: 19925400
references.citation: J Exp Med. 1966 Sep 1;124(3):331-45
references.pmid: 5922742
references.citation: Virology. 1997 Apr 14;230(2):265-74
references.pmid: 9143282
references.citation: AIDS Res Hum Retroviruses. 2000 Dec 10;16(18):2019-35
references.pmid: 11153085
references.citation: AIDS Res Hum Retroviruses. 1995 Mar;11(3):373-81
references.pmid: 7598771
references.citation: Int Rev Immunol. 2009;28(1):49-68
references.pmid: 19241253
references.citation: Gene Ther. 2004 Jul;11(14):1146-54
references.pmid: 15103320
references.citation: J Infect Dis. 1997 Aug;176(2):384-97
references.pmid: 9237703
references.citation: Virology. 2008 May 10;374(2):528-34
references.pmid: 18272194
references.citation: J Exp Med. 1966 Sep 1;124(3):347-61
references.pmid: 5926092
references.citation: J Immunol. 2002 May 1;168(9):4455-61
references.pmid: 11970989
references.citation: Immunol Rev. 2006 Jun;211:320-37
references.pmid: 16824139
references.citation: J Virol. 2008 Jul;82(13):6458-69
references.pmid: 18448544
references.citation: J Gen Virol. 1994 Aug;75 ( Pt 8):2089-95
references.pmid: 7519249
references.citation: Clin Diagn Lab Immunol. 2003 Sep;10(5):744-50
references.pmid: 12965898
references.citation: JAMA. 2008 Aug 6;300(5):520-9
references.pmid: 18677024
references.citation: Vaccine. 2009 May 26;27(25-26):3299-305
references.pmid: 19200842
references.citation: J Virol. 2002 Jun;76(12):6138-46
references.pmid: 12021347
references.citation: Microbes Infect. 2005 Nov;7(14):1414-23
references.pmid: 16257558
references.citation: Nat Med. 2003 Jun;9(6):729-35
references.pmid: 12766765
references.citation: Vaccine. 1993;11(9):957-60
references.pmid: 8212843
references.citation: J Gen Virol. 2007 Jan;88(Pt 1):217-225
references.pmid: 17170454
references.citation: J Virol. 2003 Oct;77(20):11244-59
references.pmid: 14512572
references.citation: Expert Opin Biol Ther. 2008 Sep;8(9):1347-63
references.pmid: 18694354
references.citation: Vaccine. 2002 May 6;20(15):1949-55
references.pmid: 11983252
references.citation: Virol J. 2009 Jun 25;6:87
references.pmid: 19555490
references.citation: Virology. 2002 Oct 10;302(1):44-57
references.pmid: 12429515
references.citation: Nat Med. 2001 May;7(5):625-9
references.pmid: 11329066
references.citation: Science. 1995 Mar 24;267(5205):1820-5
references.pmid: 7892606
references.citation: Virology. 1997 Mar 3;229(1):143-54
references.pmid: 9123856
references.citation: Immunol Today. 2000 Apr;21(4):163-5
references.pmid: 10740236
references.citation: AIDS. 1996;10 Suppl A:S123-32
references.pmid: 8883619
references.citation: J Exp Med. 1975 Jan 1;141(1):56-71
references.pmid: 46913
references.citation: IUBMB Life. 2002 Apr-May;53(4-5):209-11
references.pmid: 12120997
references.citation: Science. 1992 Dec 18;258(5090):1938-41
references.pmid: 1470917
references.citation: J Virol. 2005 Aug;79(16):10200-9
references.pmid: 16051813
references.citation: Virology. 2007 Jan 20;357(2):199-214
references.pmid: 16962628