Protection of rabbits against challenge with rabbit papillomaviruses by immunization with the N terminus of human papillomavirus type 16 minor capsid antigen L2.
Current L1 virus-like particle (VLP) vaccines provide type-restricted protection against a small subset of the human papillomavirus (HPV) genotypes associated with cervical cancer, necessitating continued cytologic screening of vaccinees. Cervical cancer is most problematic in countries that lack the resources for screening or highly multivalent HPV VLP vaccines, suggesting the need for a low-cost, broadly protective vaccinogen. Here, N-terminal L2 polypeptides comprising residues 1 to 88 or 11 to 200 derived from HPV16, bovine papillomavirus type 1 (BPV1), or cottontail rabbit papillomavirus (CRPV) were produced in bacteria. Rabbits were immunized with these N-terminal L2 polypeptides and concurrently challenged with CRPV and rabbit oral papillomavirus (ROPV). Vaccination with either N-terminal L2 polypeptides of CRPV effectively protected rabbits from CRPV challenge but not from papillomas induced by cutaneous challenge with CRPV genomic DNA. Furthermore, papillomas induced by CRPV genomic DNA deficient for L2 expression grew at the same rate as those induced by wild-type CRPV genomic DNA, further suggesting that the L2 polypeptide vaccines lack therapeutic activity. Neutralizing serum antibody titers of >15 correlated with protection (P < 0.001), a finding consistent with neutralizing antibody-mediated protection. Surprisingly, a remarkable degree of protection against heterologous papillomavirus types was observed after vaccination with N-terminal L2 polypeptides. Notably, vaccination with HPV16 L2 11-200 protected against cutaneous and mucosal challenge with CRPV and ROPV, respectively, papillomaviruses that are evolutionarily divergent from HPV16. Further, vaccination with HPV16 L2 11-200 generates broadly cross-neutralizing serum antibody, suggesting the potential of L2 as a second-generation preventive HPV vaccine antigen.
Gambhira
Ratish
R
Department of Pathology, Johns Hopkins School of Medicine, 1550 Orleans Street, Baltimore, MD 21231, USA.
Jagu
Subhashini
S
Karanam
Balasubramanyam
B
Gravitt
Patti E
PE
Culp
Timothy D
TD
Christensen
Neil D
ND
Roden
Richard B S
RB
D000818:Animals; D036022:Capsid Proteins / Q000737:chemistry* / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D009500:Neutralization Tests; D009856:Oncogene Proteins, Viral / Q000737:chemistry* / Q000378:metabolism; D010212:Papilloma / Q000517:prevention & control / Q000821:virology; D027383:Papillomaviridae / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011817:Rabbits; D012867:Skin / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control / Q000821:virology; D014765:Viral Vaccines / Q000737:chemistry*
D036022:Capsid Proteins; D004279:DNA, Viral; C063316:L2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D010455:Peptides; D014765:Viral Vaccines
J Virol. 2001 Mar;75(5):2331-6
11160736
Virology. 2005 Jul 5;337(2):365-72
15885736
J Virol. 2002 Oct;76(19):9798-805
12208958
N Engl J Med. 2002 Nov 21;347(21):1645-51
12444178
J Virol. 2003 Mar;77(6):3531-41
12610128
J Biol Chem. 2003 Apr 4;278(14):12546-53
12560332
Virology. 2004 Apr 10;321(2):205-16
15051381
Obstet Gynecol. 2006 Jan;107(1):18-27
16394035
Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1522-7
16432208
Lancet. 2006 Apr 15;367(9518):1247-55
16631880
Vaccine. 2006 Jun 29;24(26):5516-25
16725236
Nat Rev Cancer. 2006 Oct;6(10):753-63
16990853
Cancer Res. 2006 Dec 1;66(23):11120-4
17145854
Lancet. 2007 Jun 30;369(9580):2161-70
17602732
Viral Immunol. 2006 Summer;19(3):492-507
16987067
Virology. 2000 May 10;270(2):254-7
10792983
Virology. 2004 Jun 20;324(1):17-27
15183049
Int J Cancer. 2004 Aug 20;111(2):278-85
15197783
J Virol. 1990 Jul;64(7):3151-6
1693698
Virology. 1991 Apr;181(2):572-9
1707567
Virology. 1992 Apr;187(2):612-9
1312271
Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12180-4
1334560
J Virol. 1993 Apr;67(4):1936-44
8383219
J Gen Virol. 1994 Sep;75 ( Pt 9):2445-9
8077946
J Virol. 1995 Jun;69(6):3959-63
7745754
Virology. 1995 Aug 1;211(1):204-8
7544045
Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11553-7
8524802
J Virol. 1996 May;70(5):3298-301
8627814
J Virol. 1996 Sep;70(9):5875-83
8709207
J Gen Virol. 1996 Aug;77 ( Pt 8):1793-8
8760428
J Gen Virol. 1996 Jul;77 ( Pt 7):1577-83
8758002
Virology. 1996 Oct 15;224(2):477-86
8874508
Clin Dermatol. 1997 Mar-Apr;15(2):275-83
9167911
Virology. 1997 Aug 4;234(2):261-6
9268157
Res Vet Sci. 1997 May-Jun;62(3):289-91
9300551
J Virol. 1998 Jul;72(7):6151-4
9621080
J Virol. 1999 Jul;73(7):6188-90
10364381
J Pathol. 1999 Sep;189(1):12-9
10451482
J Virol. 1999 Nov;73(11):9609-13
10516071
Lancet. 2004 Nov 13-19;364(9447):1757-65
15541448
Cancer Epidemiol Biomarkers Prev. 2005 Jan;14(1):283-8
15668510
Lancet Oncol. 2005 May;6(5):271-8
15863374
Vaccine. 2001 Jan 8;19(11-12):1496-502
11163673