title: Protein carriers of conjugate vaccines: characteristics, development, and clinical trials.
abstract: The immunogenicity of polysaccharides as human vaccines was enhanced by coupling to protein carriers. Conjugation transformed the T cell-independent polysaccharide vaccines of the past to T cell-dependent antigenic vaccines that were much more immunogenic and launched a renaissance in vaccinology. This review discusses the conjugate vaccines for prevention of infections caused by Hemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis. Specifically, the characteristics of the proteins used in the construction of the vaccines including CRM, tetanus toxoid, diphtheria toxoid, Neisseria meningitidis outer membrane complex, and Hemophilus influenzae protein D are discussed. The studies that established differences among and key features of conjugate vaccines including immunologic memory induction, reduction of nasopharyngeal colonization and herd immunity, and antibody avidity and avidity maturation are presented. Studies of dose, schedule, response to boosters, of single protein carriers with single and multiple polysaccharides, of multiple protein carriers with multiple polysaccharides and conjugate vaccines administered concurrently with other vaccines are discussed along with undesirable consequences of conjugate vaccines. The clear benefits of conjugate vaccines in improving the protective responses of the immature immune systems of young infants and the senescent immune systems of the elderly have been made clear and opened the way to development of additional vaccines using this technology for future vaccine products.
authors: Rochester General Hospital Research Institute; Rochester, NY USA.
authors: Michael E
authors: ME
authors: Pichichero
mesh_terms: D000907:Antibodies, Bacterial / Q000097:blood; D000915:Antibody Affinity; D001426:Bacterial Proteins / Q000008:administration & dosage*; D004337:Drug Carriers / Q000008:administration & dosage*; D018073:Haemophilus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D032521:Immunity, Herd; D007156:Immunologic Memory; D022401:Meningococcal Vaccines / Q000008:administration & dosage / Q000276:immunology*; D022242:Pneumococcal Vaccines / Q000008:administration & dosage / Q000276:immunology*; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage / Q000276:immunology*; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D004337:Drug Carriers; D018073:Haemophilus Vaccines; D022401:Meningococcal Vaccines; D022242:Pneumococcal Vaccines; D011135:Polysaccharides, Bacterial; D018074:Vaccines, Conjugate
keywords: CRM197; Haemophilus influenzaeprotein D; Streptococcus pneumoniae; carrier proteins; conjugate vaccines; diphtheria toxoid; meningococcal outer membrane protein complex; tetanus toxoid
references: Pediatr Infect Dis J. 2008 Nov;27(11):1033-5
references: 18955896
references: Infect Immun. 1991 Mar;59(3):1057-64
references: 1997409
references: J Pediatr. 1984 Jul;105(1):22-7
references: 6610736
references: Pediatr Infect Dis J. 2013 Feb;32(2):169-74
references: 23080288
references: Pediatr Infect Dis J. 1991 Aug;10(8):560-4
references: 1891286
references: Pediatr Infect Dis J. 2011 Apr;30(4):e56-62
references: 21278617
references: Arch Pediatr Adolesc Med. 2005 Oct;159(10):907-13
references: 16203934
references: Emerg Infect Dis. 2011 Apr;17(4):584-91
references: 21470445
references: J Infect Dis. 1991 Nov;164(5):982-6
references: 1940479
references: J Infect Dis. 2002 Dec 15;186(12):1848-51
references: 12447774
references: Infect Immun. 2001 Jul;69(7):4337-41
references: 11401971
references: Vaccine. 2010 Jun 7;28(25):4192-203
references: 20417262
references: Pediatr Infect Dis J. 2009 Oct;28(10):e276-82
references: 20118683
references: Pediatr Infect Dis J. 2013 May;32(5):509-16
references: 23190777
references: Pediatr Infect Dis J. 2000 May;19(5):463-9
references: 10819345
references: Pediatr Infect Dis J. 2002 Oct;21(10):978-9
references: 12400528
references: Pediatr Infect Dis J. 1998 Mar;17(3):211-6
references: 9535248
references: Lancet. 1992 Oct 3;340(8823):847
references: 1357260
references: Vaccine. 1999 Apr 9;17(15-16):1970-7
references: 10217596
references: Infect Immun. 1993 Feb;61(2):432-8
references: 7678586
references: Pediatr Infect Dis J. 2003 Feb;22(2):141-9
references: 12586978
references: Infect Immun. 2003 Oct;71(10):5549-55
references: 14500473
references: Clin Vaccine Immunol. 2010 Apr;17(4):537-44
references: 20164251
references: J Infect Dis. 2003 Apr 1;187(7):1142-6
references: 12660929
references: J Allergy Clin Immunol. 1983 Nov;72(5 Pt 1):481-6
references: 6605372
references: Lancet. 2006 Oct 28;368(9546):1495-502
references: 17071283
references: J Infect Dis. 1998 Apr;177(4):1112-5
references: 9534995
references: J Infect Dis. 2001 Jan 1;183(1):160-3
references: 11078484
references: Pediatr Infect Dis J. 2009 Apr;28(4 Suppl):S66-76
references: 19325449
references: Hum Vaccin. 2010 Nov;6(11):881-7
references: 21339701
references: Pediatr Infect Dis J. 2006 Nov;25(11):1001-7
references: 17072121
references: Clin Infect Dis. 2008 Oct 15;47(8):989-96
references: 18781875
references: Pediatr Infect Dis J. 2012 Jan;31(1):64-71
references: 22094635
references: Arch Dis Child. 2002 Jun;86(6):396-9
references: 12023165
references: Vaccine. 2008 Aug 18;26(35):4563-70
references: 18602724
references: Clin Vaccine Immunol. 2007 Oct;14(10):1362-9
references: 17699836
references: J Pediatr. 1987 Jul;111(1):22-7
references: 3110388
references: Vaccine. 1998 Jan;16(1):109-13
references: 9607017
references: Pediatr Infect Dis J. 1998 Aug;17(8):685-91
references: 9726341
references: Adv Immunol. 1969;10:1-50
references: 4900673
references: Pediatrics. 2010 Sep;126(3):e493-505
references: 20732948
references: Pediatr Infect Dis J. 2010 Dec;29(12):e80-90
references: 21155091
references: J Infect Dis. 1995 Nov;172(5):1273-8
references: 7594664
references: J Infect Dis. 1999 Aug;180(2):538-41
references: 10395878
references: J Pediatr. 1992 Aug;121(2):187-94
references: 1640282
references: Immunology. 2004 Oct;113(2):163-74
references: 15379976
references: Pediatr Infect Dis J. 2009 Nov;28(11):990-5
references: 19536041
references: Pediatr Infect Dis J. 2011 Mar;30(3):e41-8
references: 21200360
references: Pediatr Infect Dis J. 2004 Feb;23(2):91-8
references: 14872172
references: J Immunol. 1995 Apr 15;154(8):4195-202
references: 7706754
references: Pediatr Infect Dis J. 2003 Jun;22(6):524-32
references: 12799509
references: Pediatr Infect Dis J. 2000 May;19(5):417-23
references: 10819337
references: Vaccine. 2011 Jun 6;29(25):4274-84
references: 21443965
references: J Immunol. 1998 Jul 15;161(2):702-6
references: 9670945
references: Pediatr Infect Dis J. 2006 Jan;25(1):79-80
references: 16395110
references: Infect Immun. 1994 Aug;62(8):3391-5
references: 8039909
references: Pediatr Infect Dis J. 2006 Apr;25(4):312-9
references: 16567982
references: Clin Vaccine Immunol. 2010 Jun;17(6):1017-26
references: 20427630
references: J Infect Dis. 1999 Jun;179(6):1569-72
references: 10228085
references: JAMA. 2004 Nov 24;292(20):2491-4
references: 15562128
references: Pediatr Infect Dis J. 2012 Jan;31(1):e31-6
references: 21909049
references: Pediatr Infect Dis J. 2009 Feb;28(2):86-91
references: 19116603
references: Pediatr Infect Dis J. 2009 Apr;28(4 Suppl):S97-S108
references: 19325452
references: J Infect Dis. 2006 Dec 15;194(12):1745-52
references: 17109348
references: Cell Immunol. 1987 Jan;104(1):79-90
references: 2433056
references: J Infect Dis. 1999 Oct;180(4):1171-6
references: 10479145
references: Pediatr Infect Dis J. 2002 Nov;21(11):1004-7
references: 12442020
references: Lancet. 2003 Aug 2;362(9381):355-61
references: 12907008
references: Pediatr Infect Dis J. 2012 Mar;31(3):297-301
references: 22330166
references: Pediatr Infect Dis J. 1996 Feb;15(2):134-9
references: 8822286
references: Pediatrics. 1997 Apr;99(4):575-80
references: 9093301
references: Pediatr Infect Dis J. 2005 Feb;24(2):132-6
references: 15702041
references: Vaccine. 2003 Sep 8;21(25-26):3653-62
references: 12922095
references: Vaccine. 1998 Apr;16(6):630-6
references: 9569475
references: Pediatr Infect Dis J. 2001 Mar;20(3):272-7
references: 11303829
references: J Pediatr. 1985 Sep;107(3):346-51
references: 3875705
references: Pediatr Infect Dis J. 2001 Feb;20(2):153-9
references: 11224833
references: Clin Infect Dis. 2009 May 15;48(10):1392-401
references: 19368505
references: Pediatr Infect Dis J. 2013 Feb;32(2):e45-53
references: 23080290
references: Emerg Infect Dis. 2013 Jul;19(7):1074-83
references: 23763847
references: Pediatr Infect Dis J. 2011 Mar;30(3):190-6
references: 20948453
references: J Pediatr. 1987 Apr;110(4):509-14
references: 3550021
references: Clin Infect Dis. 2000 Jul;31(1):34-41
references: 10913393
references: Pediatr Infect Dis J. 2002 Oct;21(10):940-7
references: 12394817
references: Pediatr Infect Dis J. 1994 May;13(5):348-55
references: 8072815
references: J Infect Dis. 1985 Sep;152(3):634-6
references: 3875668
references: Infect Immun. 2002 Sep;70(9):4946-54
references: 12183540
references: Infect Immun. 1998 May;66(5):2093-8
references: 9573094
references: JAMA. 2000 Nov 8;284(18):2334-40
references: 11066183
references: Pediatr Infect Dis J. 2000 Feb;19(2):144-50
references: 10694002
references: Am J Dis Child. 1991 Feb;145(2):223-7
references: 1994693
references: Curr Opin Immunol. 2011 Jun;23(3):407-13
references: 21514128
references: Pediatr Infect Dis J. 2000 Sep;19(9):854-62
references: 11001109
references: J Infect Dis. 1978 Oct;138(4):427-36
references: 309494
references: J Immunol. 2008 Feb 15;180(4):2165-73
references: 18250423
references: Lancet. 2001 Jan 20;357(9251):195-6
references: 11213098
references: Clin Infect Dis. 2011 Jun;52(11):1317-23
references: 21596673
references: N Engl J Med. 1991 Jun 20;324(25):1767-72
references: 1903846
references: Pediatr Infect Dis J. 2002 Apr;21(4):350-2
references: 12075771
references: J Pediatr. 1996 Apr;128(4):524-30
references: 8618187
references: JAMA. 2000 Jun 7;283(21):2795-801
references: 10838647
references: Pediatr Infect Dis J. 1996 May;15(5):425-30
references: 8724065
references: Pediatr Infect Dis J. 2000 Mar;19(3):187-95
references: 10749457
references: J Infect Dis. 2001 Jan 1;183(1):97-104
references: 11087205
references: Vaccine. 2011 Feb 24;29(10):1959-67
references: 21215830
references: J Infect Dis. 2004 Jun 1;189(11):2077-84
references: 15143476
references: J Infect Dis. 2003 Aug 15;188(4):481-5
references: 12898433
references: Arch Pediatr Adolesc Med. 1994 Jun;148(6):620-5
references: 8193690
references: J Infect Dis. 2006 Jun 1;193(11):1487-94
references: 16652275
references: N Engl J Med. 1987 Sep 17;317(12):717-22
references: 3306379
references: J Infect Dis. 1980 Nov;142(5):694-8
references: 6970233
references: Vaccine. 2001 Oct 15;20 Suppl 1:S58-67
references: 11587814
references: Pediatrics. 1998 Apr;101(4 Pt 1):604-11
references: 9521941
references: J Infect Dis. 2003 May 15;187(10):1639-45
references: 12721944
references: Clin Infect Dis. 2008 Jan 15;46(2):186-92
references: 18171249
references: J Immunol. 1989 Apr 1;142(7):2464-8
references: 2784464
references: J Infect Dis. 2000 Oct;182(4):1260-3
references: 10979930
references: J Immunol. 1989 Apr 15;142(8):2635-40
references: 2467933
references: J Infect Dis. 2000 Nov;182(5):1553-6
references: 11023481
references: J Infect Dis. 2001 Nov 1;184(9):1211-5
references: 11598848
references: Clin Infect Dis. 2013 Feb;56(3):e30-9
references: 23118268
references: Semin Immunol. 2004 Oct;16(5):323-33
references: 15528077
references: Clin Infect Dis. 1997 Dec;25(6):1378-84
references: 9431382
references: Pediatr Infect Dis J. 2004 Jun;23(6):490-7
references: 15194828
references: Pediatr Infect Dis J. 2012 Jan;31(1):e15-23
references: 22094636
references: J Infect Dis. 1997 Jan;175(1):200-4
references: 8985221
references: Pediatr Infect Dis J. 2012 Jan;31(1):72-7
references: 21960186
references: Vaccine. 2007 Jul 20;25(29):5390-8
references: 17583392
references: Pediatr Infect Dis J. 2001 Jan;20(1):25-33
references: 11176563
references: J Infect Dis. 1997 Aug;176(2):445-55
references: 9237711
references: Clin Infect Dis. 2008 Aug 1;47(3):401-9
references: 18558875
references: N Engl J Med. 1990 Nov 15;323(20):1381-7
references: 2233904
references: Ann N Y Acad Sci. 1995 May 31;754:278-88
references: 7625664
references: Vaccine. 1998 Jan;16(1):83-91
references: 9607014
references: Vaccine. 2009 Jan 1;27(1):161-8
references: 18834910
references: Hum Vaccin. 2011 Feb;7(2):239-47
references: 21343698
references: J Infect Dis. 2002 Apr 1;185(7):927-36
references: 11920317
references: Clin Infect Dis. 2009 Jul 15;49(2):241-8
references: 19522655
references: Vaccine. 2001 Oct 12;20(1-2):194-201
references: 11567764
references: J Exp Med. 1986 Feb 1;163(2):262-9
references: 3484778
references: Lancet. 2013 Jan 19;381(9862):214-22
references: 23158882
references: Pediatr Infect Dis J. 2000 Jul;19(7):589-91
references: 10917213
references: J Infect Dis. 2004 Dec 1;190(11):2031-8
references: 15529269
references: Eur J Pediatr. 1997 Jan;156(1):18-24
references: 9007484
references: JAMA. 1992 Mar 18;267(11):1489-94
references: 1538539
references: Vaccine. 2010 Jan 8;28(3):744-53
references: 19887137
references: Pediatr Infect Dis J. 2004 May;23(5):429-35
references: 15131466
references: Lancet. 1986 Aug 9;2(8502):299-302
references: 2874327
references: Pediatr Infect Dis J. 2011 Jun;30(6):451-5
references: 21206392
references: J Exp Med. 1929 Sep 30;50(4):533-50
references: 19869645
references: Hum Vaccin Immunother. 2012 Jul;8(7):873-80
references: 22485050
references: J Clin Invest. 1981 May;67(5):1482-9
references: 6971877
references: J Pediatr. 1996 May;128(5 Pt 1):649-53
references: 8627437
references: Pediatr Infect Dis J. 2009 Mar;28(3):186-93
references: 19209097
references: N Engl J Med. 1990 Nov 15;323(20):1393-401
references: 2233906
references: Pediatr Infect Dis J. 2003 Jul;22(7):659-61
references: 12886896
references: J Infect Dis. 1993 Sep;168(3):663-71
references: 8354908
references: Lancet. 2005 Mar 26-Apr 1;365(9465):1139-46
references: 15794968
references: Vaccine. 2003 May 16;21(17-18):1894-900
references: 12706674
references: J Pediatr. 1992 Feb;120(2 Pt 1):184-9
references: 1735812
references: Nature. 1980 Jun 26;285(5767):664-7
references: 6967189
references: J Infect Dis. 2005 Aug 1;192(3):367-76
references: 15995949
references: J Pediatr. 1990 Jun;116(6):929-31
references: 2348298
references: Clin Infect Dis. 2009 Jul 1;49(1):e1-10
references: 19476428
references: Chang Gung Med J. 2003 May;26(5):315-22
references: 12934847
references: Pediatr Infect Dis J. 1996 Apr;15(4):333-9
references: 8866803
references: J Infect Dis. 2002 Nov 15;186(10):1422-9
references: 12404157
references: J Infect Dis. 1996 Jan;173(1):256-8
references: 8537671
references: Clin Infect Dis. 2010 Jun 15;50(12):1601-10
references: 20459323
references: Vaccine. 2000 Jan 18;18(13):1218-26
references: 10649623
references: Eur J Clin Microbiol Infect Dis. 2010 Mar;29(3):259-67
references: 20033465
references: J Infect Dis. 2003 Jun 1;187(11):1704-8
references: 12751027
references: Vaccine. 1999 Jan;17(2):126-33
references: 9987146
references: Clin Infect Dis. 2011 Nov;53(9):885-92
references: 21946190
references: Vaccine. 2007 Sep 3;25 Suppl 1:A101-7
references: 17532101
references: J Infect Dis. 1984 Sep;150(3):402-6
references: 6332863
references: Pediatr Infect Dis J. 2009 Mar;28(3):220-4
references: 19209096
references: Clin Infect Dis. 2011 Mar 15;52(6):736-42
references: 21367726
references: Pediatr Infect Dis J. 2001 Dec;20(12):1105-7
references: 11740313
references: Nucleic Acids Res. 1984 May 25;12(10):4063-9
references: 6427753
references: Pediatr Infect Dis J. 2011 Jul;30(7):566-9
references: 21326136
references: Pediatr Infect Dis J. 2005 Jan;24(1):57-62
references: 15665711
references: Pediatr Infect Dis J. 2005 Nov;24(11):969-73
references: 16282931
references: N Engl J Med. 2003 Oct 2;349(14):1341-8
references: 14523142
references: J Infect Dis. 1996 Dec;174(6):1271-8
references: 8940218
references: Pediatrics. 2006 Aug;118(2):e421-9
references: 16882783
references: Clin Infect Dis. 2005 Apr 15;40(8):1116-22
references: 15791510
references: J Infect Dis. 2009 Apr 15;199(8):1168-76
references: 19265481
references: Pediatr Infect Dis J. 2003 Jun;22(6):532-40
references: 12799510
references: J Infect Dis. 1996 Dec;174(6):1337-40
references: 8940229
references: Proc Natl Acad Sci U S A. 1997 Jan 7;94(1):271-6
references: 8990198
references: JAMA. 2007 Oct 17;298(15):1772-8
references: 17940232
references: Commun Dis Public Health. 2003 Apr;6(1):55-8
references: 12736974
references: Pediatr Infect Dis J. 2006 Nov;25(11):995-1000
references: 17072120
references: N Engl J Med. 2003 May 1;348(18):1737-46
references: 12724479
references: Vaccine. 2010 Jan 8;28(3):657-63
references: 19895922
references: Clin Vaccine Immunol. 2009 Dec;16(12):1810-5
references: 19812260
references: Pediatr Infect Dis J. 1998 Nov;17(11):1026-33
references: 9849987
references: Pediatr Infect Dis J. 1999 Sep;18(9):764-72
references: 10493335
references: J Clin Invest. 1985 Jul;76(1):52-9
references: 3874882
references: Pediatrics. 1987 Aug;80(2):283-7
references: 3112729
references: Infect Immun. 1997 Jan;65(1):242-7
references: 8975918
references: Pediatrics. 2009 Dec;124(6):1633-41
references: 19933727
references: J Infect Dis. 1996 Dec;174(6):1360-3
references: 8940235
references: Clin Vaccine Immunol. 2010 Jan;17(1):154-9
references: 19906895
references: Pediatrics. 2009 Jul;124(1):e1-11
references: 19564254
references: BMJ. 2003 Feb 15;326(7385):365-6
references: 12586669
references: J Microbiol Methods. 2001 Nov;47(2):135-49
references: 11576678
references: Pediatr Infect Dis J. 2005 Feb;24(2):108-14
references: 15702037
references: Infect Immun. 2007 Apr;75(4):1794-800
references: 17261612
references: Pediatr Infect Dis J. 1993 Jul;12(7):593-9
references: 8346004
references: Lancet. 2006 Mar 4;367(9512):740-8
references: 16517274
references: Clin Infect Dis. 2007 May 1;44(9):1173-9
references: 17407035
references: Hum Vaccin. 2011 Feb;7(2):258-64
references: 21307655
references: Pediatrics. 2003 Jul;112(1 Pt 1):66-73
references: 12837869
references: Pediatr Infect Dis J. 1997 Jan;16(1):72-4
references: 9002106
references: J Infect Dis. 2008 Oct 1;198(7):1019-27
references: 18710324
references: Pediatr Infect Dis J. 2012 Jan;31(1):e24-30
references: 22157567
references: J Infect Dis. 1983 Jun;147(6):1100
references: 6602191
references: Clin Infect Dis. 2006 Dec 1;43(11):1387-94
references: 17083009
references: Infect Immun. 1999 May;67(5):2366-70
references: 10225896
references: Pediatr Infect Dis J. 1997 Nov;16(11):1060-4
references: 9384340
references: Lancet. 1997 Apr 26;349(9060):1191-7
references: 9130939
references: Vaccine. 2004 Dec 21;23(6):802-6
references: 15542205
references: Pediatr Infect Dis J. 2004 Jun;23(6):485-9
references: 15194827
references: J Infect Dis. 1991 Dec;164(6):1154-9
references: 1955715
references: Pediatr Infect Dis J. 1993 Jun;12(6):484-92
references: 8345981
references: Int J Infect Dis. 2010 Oct;14(10):e868-75
references: 20655261
references: J Infect Dis. 2002 Nov 1;186(9):1353-7
references: 12402208
references: Pediatr Infect Dis J. 2002 Sep;21(9):810-5
references: 12352800
references: Pediatr Infect Dis J. 1999 Sep;18(9):757-63
references: 10493334
references: Int J Epidemiol. 2000 Aug;29(4):753-6
references: 10922355
references: Lancet. 2011 Dec 3;378(9807):1962-73
references: 21492929
references: Infect Immun. 2003 Jun;71(6):3402-8
references: 12761124
references: Vaccine. 1998 Jan-Feb;16(2-3):313-9
references: 9607048
references: FEMS Microbiol Rev. 2007 Jan;31(1):27-36
references: 17168995
references: J Immunol. 1990 Nov 15;145(10):3379-84
references: 2230124
references: Vaccine. 2005 Feb 25;23(14):1715-9
references: 15705477
references: Vaccine. 2012 Mar 9;30(12):2054-9
references: 22198517
references: J Infect Dis. 2008 Mar 1;197(5):737-43
references: 18271745
references: JAMA. 2008 Jan 9;299(2):173-84
references: 18182599
references: JAMA. 1998 Nov 18;280(19):1685-9
references: 9832000
references: J Pediatr. 1985 Feb;106(2):185-9
references: 3871477
references: Hum Vaccin Immunother. 2012 Dec 1;8(12):1882-91
references: 23032168
references: Pediatrics. 2005 Sep;116(3):e408-13
references: 16140686
references: Pediatr Infect Dis J. 2002 Aug;21(8):747-53
references: 12192163
references: Clin Infect Dis. 2004 Oct 1;39(7):930-8
references: 15472842
references: Vaccine. 2010 Apr 19;28(18):3171-9
references: 20189491
references: Pediatr Infect Dis J. 2011 Nov;30(11):e203-8
references: 21673612
references: J Infect Dis. 1982 Aug;146(2):243-8
references: 6980956
references: Vaccine. 2000 May 8;18(22):2359-67
references: 10738092
references: Lancet. 2004 Jul 24-30;364(9431):365-7
references: 15276396
references: Infect Immun. 1986 May;52(2):519-28
references: 3516876
references: Infect Immun. 2004 Sep;72(9):5383-91
references: 15322036
references: Pediatr Infect Dis J. 2012 Nov;31(11):1173-83
references: 22814965
references: Pediatr Infect Dis J. 2004 Nov;23(11):1015-22
references: 15545856
references: N Engl J Med. 2001 Feb 8;344(6):403-9
references: 11172176
references: Clin Infect Dis. 2003 Nov 1;37(9):1155-64
references: 14557958
references: J Med Microbiol. 2006 Jul;55(Pt 7):887-896
references: 16772416
references: Pediatr Infect Dis J. 1997 Nov;16(11):1053-9
references: 9384339
references: J Infect Dis. 1992 Jun;165 Suppl 1:S160-1
references: 1588154
references: Lancet. 2003 May 3;361(9368):1521-3
references: 12737866
references: J Immunol. 1986 Aug 15;137(4):1181-6
references: 3016088
references: J Clin Microbiol. 2013 Oct;51(10):3395-9
references: 23824778
references: Pediatrics. 2010 May;125(5):866-75
references: 20435707
references: Pediatr Infect Dis J. 2002 Apr;21(4):309-14
references: 12075762
references: Lancet. 2002 May 25;359(9320):1829-31
references: 12044380
references: J Infect Dis. 2011 May 15;203(10):1360-8
references: 21398395
references: Epidemiol Infect. 2012 Aug;140(8):1343-55
references: 22583474
references: J Exp Med. 1980 Aug 1;152(2):361-76
references: 6967514