Aggiornamento
Il vaccino contro il papillomavirus umano: efficacia dichiarata ed efficacia dimostrata
VACCINE AGAINST HUMAN PAPILLOMAVIRUSES: CLAIMED EFFICACY VERSUS ACTUAL EFFICACY
SIMONA DI MARIO1, MARCELLO BERGAMINI2, DANIELA SPETTOLI1, VITTORIO BASEVI1, NICOLA MAGRINI1
1Centro di Documentazione sulla Salute Perinatale e Riproduttiva - SaPeRiDoc - Centro per la valutazione dell’efficacia dell’assistenza sanitaria, CeVEAS, Azienda USL di Modena
2Pediatra di famiglia, Azienda USL di Ferrara
Novembre 2007 - pagg. 562 -571
Abstract
The recent introduction in the European market of the tetravalent vaccine against Human Papillomavirus raises some concerns on the opportunity to start a national vaccination campaign. In this article an analysis of the currently available evidence, a reflection on what the experts in the field add to the international debate and a comparison between the decision taken in other countries on this issue are presented to guide an informed decision making process on this topic. We searched Pubmed-Medline for RCT on vaccine efficacy. Eight RCT were identified: three studies were related to the bivalent vaccine, and five to the tetravalent vaccine (one describing the Finnish experience of field testing of the tetravalent vaccine efficacy). Flaws related to the presentation of trial results were identified and discussed. The critical analysis of the trials shows that at the moment there is no evidence that implementing a mass vaccination campaign can effectively reduce cervical cancer incidence. Researchers and experts in the field, mirroring the lack of evidence, assume various positions: some of them highlight the theoretical advantage of the vaccine, some of them discuss the limits and information gap still existing and call for more prudence. Moreover, in October 2007, eight out of 27 countries within the European Union took the decision to include the vaccine against Human Papillomavirus in their national immunization campaign. Italian policy makers could consider funding field researches on vaccine efficacy in the Italian context instead of proposing a premature implementation of a mass vaccination campaign.
Parole chiave
Suggerite dall'AI
Classificazione MeSH
Bibliografia
1. Bender ME, Ostrow RS, Watts S, et al. Immunology
of human papillomavirus: warts.
Pediatr Dermatol 1983;1:121-6.
2. Schreier AA, Allen WP, Laughlin C, et al. Prospects for human papillomavirus vaccines and immunotherapies. J Natl Cancer Inst 1988;80:896-9.
3. Kirnbauer R, Booy F, Cheng N, et al. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc Natl Acad Sci USA 1992;89: 12180-4.
4. Evans TG, Bonnez W, Rose RC, et al. A phase 1 study of a recombinant viruslike particle vaccine against human papillomavirus type 11 in healthy adult volunteers. J Infect Dis 2001; 183:1485-93.
5. Brown DR, Fife KH, Wheeler CM, et al. Early assessment of the efficacy of a human papillomavirus type 16 L1 virus-like particle vaccine. Vaccine 2004;22: 2936-42.
6. Brown DR, Bryan JT, Schroeder JM, et al. Neutralization of human papillomavirus type 11 (HPV-11) by serum from women vaccinated with yeast-derived HPV-11 L1 virus-like particles: correlation with competitive radioimmunoassay titer. J Infect Dis 2001;184: 1183-6.
7. Koutsky LA, Ault KA, Wheeler CM, Proof of Principle Study Investigators. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002;347:1645-51.
8. Ault KA, Giuliano AR, Edwards RP, et al. A phase I study to evaluate a human papillomavirus (HPV) type 18 L1 VLP vaccine. Vaccine 2004;22:3004-7.
9. Vandepapeliere P, Barrasso R, Meijer CJ, et al. Randomized controlled trial of an adjuvanted human papillomavirus (HPV) type 6 L2E7 vaccine: infection of external anogenital warts with multiple HPV types and failure of therapeutic vaccination. J Infect Dis 2005;192:2099-107.
10. Mao C, Koutsky LA, Ault KA, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol 2006;107:18-27.
11. Dempsey AF, Zimet GD, Davis RL, et al. Factors that are associated with parental acceptance of human papillomavirus vaccines: a randomized intervention study of written information about HPV. Pediatrics 2006;117: 1486-93.
12. Harro CD, Pang YY, Roden RB, et al. Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst 2001;93:284-92.
13. de Jong A, O’Neill T, Khan AY, et al. Enhancement of human papillomavirus (HPV) type 16 E6 and E7-specific T-cell immunity in healthy volunteers through vaccination with TA-CIN, an HPV16 L2E7E6 fusion protein vaccine. Vaccine 2002;20:3456-64.
14. Pinto LA, Edwards J, Castle PE, et al. Cellular immune responses to human papillomavirus (HPV)-16 L1 in healthy volunteers immunized with recombinant HPV-16 L1 viruslike particles. J Infect Dis 2003;188:327-38.
15. Pinto LA, Castle PE, Roden RB, et al. HPV- 16 L1 VLP vaccine elicits a broad-spectrum of cytokine responses in whole blood. Vaccine 2005;23:3555-64.
16. Pinto LA, Viscidi R, Harro CD, et al. Cellular immune responses to HPV-18, -31, and -53 in healthy volunteers immunized with recombinant HPV-16 L1 virus-like particles. Virology 2006;353:451-62.
17. Fife KH, Wheeler CM, Koutsky LA, et al. Dose-ranging studies of the safety and immunogenicity of human papillomavirus Type 11 and Type 16 virus-like particle candidate vaccines in young healthy women. Vaccine 2004; 22:2943-52.
18. Frazer IH, Quinn M, Nicklin JL, et al. Phase 1 study of HPV16-specific immunotherapy with E6E7 fusion protein and ISCOMATRIX adjuvant in women with cervical intraepithelial neoplasia. Vaccine 2004;23:172-81.
19. Poland GA, Jacobson RM, Koutsky LA, et al. Immunogenicity and reactogenicity of a novel vaccine for human papillomavirus 16: a 2- year randomized controlled clinical trial. Mayo Clin Proc 2005;80:601-10.
20. Nardelli-Haefliger D, Lurati F, Wirthner D, et al. Immune responses induced by lower airway mucosal immunisation with a human papillomavirus type 16 virus-like particle vaccine. Vaccine 2005;23:3634-41.
21. Insinga RP, Dasbach EJ, Elbasha EH, et al. Incidence and duration of cervical human papillomavirus 6, 11, 16, and 18 infections in young women: an evaluation from multiple analytic perspectives. Cancer Epidemiol Biomarkers Prev 2007;16:709-15.
22. Villa LL, Ault KA, Giuliano AR, et al. Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. Vaccine 2006;24:5571- 83.
23. Olsson SE, Villa LL, Costa RL, et al. Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus- like particle VLP) vaccine. Vaccine 2007; 25:4931-9.
24. Reisinger KS, Block SL, Lazcano-Ponce E, et al. Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial. Pediatr Infect Dis J 2007;26: 201-9.
25. Garland SM, Steben M, Hernandez-Avila M, et al. for the 012 Study Investigators. Noninferiority of antibody response to human papillomavirus type 16 in subjects vaccinated with monovalent and quadrivalent L1 viruslike particle vaccines. Clin Vaccine Immunol 2007;14:792-5
26. Pedersen C, Petaja T, Strauss G, et al. for the HPV Vaccine Adolescent Study Investigators Network. Immunization of early adolescent females with human papillomavirus type 16 and 18 L1 virus-like particle vaccine containing AS04 adjuvant. J Adolesc Health 2007; 40:564-71.
27. Harper DM, Franco EL, Wheeler C, et al. GlaxoSmithKline HPV Vaccine Study Group. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 2004; 364:1757-65.
28. Harper DM, Franco EL, Wheeler CM, et al. HPV Vaccine Study group. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 2006;367:1247-55.
29. Paavonen J, Jenkins D, Bosch FX, et al. HPV PATRICIA study group. Efficacy of a prophylactic adjuvanted bivalent L1 virus-likeparticle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III doubleblind, randomised controlled trial. Lancet 2007;369:2161-70
30. Villa LL, Costa RL, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised doubleblind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 2005;6:271-8.
31. Villa LL, Costa RL, Petta CA, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer 2006;95:1459-66.
32. Garland SM, Hernandez-Avila M, Wheeler CM, et al. Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007;356:1928-43.
33. FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915-27.
34. Lehtinen M, Apter D, Dubin G, et al. Enrolment of 22,000 adolescent women to cancer registry follow-up for long-term human papillomavirus vaccine efficacy: guarding against guessing. Int J STD AIDS 2006;17:517-21
35. Joura EA, Leodolter S, Hernandez-Avila M, et al. Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials. Lancet 2007;369:1693-702.
36. Ault KA, Future II Study Group. Effect of prophylactic human papillomavirus L1 viruslike- particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet 2007; 369:1861-8.
37. Rambout L, Hopkins L, Hutton B, et al. Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized controlled trials. CMAJ 2007;177:469-79.
38. Temte JL. HPV vaccine: a cornerstone of female health. Am Fam Physician 2007;75:28-30.
39. CDC HPV vaccine questions and answers. CDC August 2006. Disponibile all’URL: http://www.cdc.gov/std/HPV/hpv-vaccine. pdf.
40. Newall AT, Beutels P, Wood JG, Edmunds WJ, MacIntyre CR. Cost-effectiveness analyses of human papillomavirus vaccination. Lancet Infect Dis 2007;7:289-96.
41. Lippman A, Melnychuk R, Shimmin C, et al. Human papillomavirus, vaccines and women's health: questions and cautions. CMAJ 2007;177:484-7.
42. Sheldon T. Drug company campaign adds to pressure on Dutch doctors to vaccinate against HPV. BMJ. 2007 Apr 21;334:819.
43. Tanne JH. Texas governor is criticised for decision to vaccinate all girls against HPV. BMJ 2007;334:332-3
44. Coombes R. Life saving treatment or giant experiment? BMJ 2007;334:721-3
45. Charo RA. Politics, parents, and prophylaxis-- mandating HPV vaccination in the United States. N Engl J Med 2007;356:1905-8.
46. Pecorelli S. Presentazione dei dati sperimentali sull’uso dei vaccini per HPV. Comunicazione orale al convegno: HPV e tumori dell’apparato genitale femminile: l’era dei vaccini. Bologna 8 Giugno 2007. Assessorato politiche per la salute, Regione Emilia-Romagna e Alma Mater Studiorum Università di Bologna, Istituto di Clinica Ginecologica Ostetrica, scuola di specializzazione in Ginecologia e Ostetricia.
47. Agenzia Italiana del Farmaco. Il vaccino per il cancro della cervice. Medico e Bambino pagine elettroniche 2007; 10. Disponibile all’URL: http://www.medicoebambino.com/index. php?id=IPS0704_10.html.
48. Di Mario S, Basevi V, Magrini N. Vaccinazione anti-HPV: alcuni interrogativi per il pediatra. Medico e Bambino 2007;5:279-80. Disponibile all’URL: http://www.medicoebambino. com/?id=ri_0705.
49. Sawaya GF, Smith-McCune K. HPV vaccination- more answers, more questions. N Engl J Med 2007;356:1991-3.
50. Lehtinen M, French K. Integration of the vaccine against human papillomaviruses into national vaccination programmes. Entre Nous 2007;64:12-3.
51. Centro per la Documentazione sulla Salute Perinatale, SaPeRiDoc. La prevenzione della neoplasia cervicale. Disponibile all’URL: http://www.saperidoc.it/doc_116.html.
52. Kudjawu Y, Lévy-Bruhl D, Pastore Celentano L, et al. on behalf of the VENICE working group. The current status of HPV and rotavirus vaccines in national immunisation schedules in the EU – preliminary results of a VENICE survey. Eurosurveillance Weekly Release. 26 Aprile 2007. Disponibile all’URL: http://www.eurosurveillance.org/ew/2007/0 70426.asp#1.
53. Stroffolini T, Cialdea L, Tosti ME, Grandolfo M, Mele A. Vaccination campaign against hepatitis B for 12-year-old subjects in Italy. Vaccine 1997;15:583-5.
54. World Health Organization. Preparing for the introduction of HPV vaccines. Policy and programme guidance for countries. UNFPA & World Health Organization, Geneva. 2006. Disponibile all’URL: http://www.who.int/reproductive- health/publications/hpvvaccines/ text.pdf.
55. BMJ learning. Screening for cervical cancer: in association with the NHS Cancer Screening Programmes. Disponibile all’URL: http: //learning.bmj.com/learning/search-result. html?moduleId=5004436 .
56. Franceschi S, Herrero R, Clifford GM, et al. Variations in the age-specific curves of human papillomavirus prevalence in women worldwide. Int J Cancer 2006;119:2677-84.
57. Carozzi FM. Le basi biologiche dei vaccini per il papillomavirus umano. Epid-Prev 2007; 31:92-9.
58. Lazdane G. Questions and answers. Common questions related to prevention of cervical cancer and the HPV vaccine. Entre Nous 2007;64:29.
59. AAVV. Human papillomavirus vaccine for genotypes 6, 11, 16 and 18: new drug. Cervical cancer prevention: high hopes. Prescrire Int 2007;16:91-4.
60. MacDonald N, Hebert PC. Human papillomavirus vaccine: waiting for a miracle. CMAJ 2007;177:433-5.
61. Lo B. Human papillomavirus vaccination programmes. BMJ 2007;335:357-8.
62. Baden LR, Curfman GD, Morrissey S, Drazen JM. Human papillomavirus vaccine-opportunity and challenge. N Engl J Med 2007; 356:1990-1.
63. Kahn JA, Burk RD. Papillomavirus vaccines in perspective. Lancet 2007;369:2135-7.
64. Markman M. Human papillomavirus vaccines to prevent cervical cancer. Lancet 2007; 369:1837-9.
65. Agosti JM, Goldie SJ. Introducing HPV vaccine in developing countries-key challenges and issues. N Engl J Med 2007;356:1908-10.
66. Suba EJ, Raab SS; Viet/American Cervical Cancer Prevention Project. Human papillomavirus vaccine. N Engl J Med 2007;357:1155.
67. Mauri D, Polyzos NP. Effects of quadrivalent human papillomavirus vaccination. Lancet 2007;370:1031.
68. Arbyn M. Effects of quadrivalent human papillomavirus vaccination. Lancet 2007;370: 1031-2.
69. Miller NB, Raychaudhuri G, Toerner JG. Human papillomavirus vaccine. N Engl J Med 2007;357:1154-5.
70. Raffle AE. Human papillomavirus vaccine policy. Lancet 2007;369:367-8.
71. Stewart AM. Mandating HPV vaccinationprivate rights, public good. N Engl J Med 2007;356:1998-9.
72. Segraves BT. Compulsory HPV vaccination. N Engl J Med 2007;356:1074.
73. Basu S. Compulsory HPV vaccination. N Engl J Med 2007;356:1074.
2. Schreier AA, Allen WP, Laughlin C, et al. Prospects for human papillomavirus vaccines and immunotherapies. J Natl Cancer Inst 1988;80:896-9.
3. Kirnbauer R, Booy F, Cheng N, et al. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc Natl Acad Sci USA 1992;89: 12180-4.
4. Evans TG, Bonnez W, Rose RC, et al. A phase 1 study of a recombinant viruslike particle vaccine against human papillomavirus type 11 in healthy adult volunteers. J Infect Dis 2001; 183:1485-93.
5. Brown DR, Fife KH, Wheeler CM, et al. Early assessment of the efficacy of a human papillomavirus type 16 L1 virus-like particle vaccine. Vaccine 2004;22: 2936-42.
6. Brown DR, Bryan JT, Schroeder JM, et al. Neutralization of human papillomavirus type 11 (HPV-11) by serum from women vaccinated with yeast-derived HPV-11 L1 virus-like particles: correlation with competitive radioimmunoassay titer. J Infect Dis 2001;184: 1183-6.
7. Koutsky LA, Ault KA, Wheeler CM, Proof of Principle Study Investigators. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002;347:1645-51.
8. Ault KA, Giuliano AR, Edwards RP, et al. A phase I study to evaluate a human papillomavirus (HPV) type 18 L1 VLP vaccine. Vaccine 2004;22:3004-7.
9. Vandepapeliere P, Barrasso R, Meijer CJ, et al. Randomized controlled trial of an adjuvanted human papillomavirus (HPV) type 6 L2E7 vaccine: infection of external anogenital warts with multiple HPV types and failure of therapeutic vaccination. J Infect Dis 2005;192:2099-107.
10. Mao C, Koutsky LA, Ault KA, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol 2006;107:18-27.
11. Dempsey AF, Zimet GD, Davis RL, et al. Factors that are associated with parental acceptance of human papillomavirus vaccines: a randomized intervention study of written information about HPV. Pediatrics 2006;117: 1486-93.
12. Harro CD, Pang YY, Roden RB, et al. Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst 2001;93:284-92.
13. de Jong A, O’Neill T, Khan AY, et al. Enhancement of human papillomavirus (HPV) type 16 E6 and E7-specific T-cell immunity in healthy volunteers through vaccination with TA-CIN, an HPV16 L2E7E6 fusion protein vaccine. Vaccine 2002;20:3456-64.
14. Pinto LA, Edwards J, Castle PE, et al. Cellular immune responses to human papillomavirus (HPV)-16 L1 in healthy volunteers immunized with recombinant HPV-16 L1 viruslike particles. J Infect Dis 2003;188:327-38.
15. Pinto LA, Castle PE, Roden RB, et al. HPV- 16 L1 VLP vaccine elicits a broad-spectrum of cytokine responses in whole blood. Vaccine 2005;23:3555-64.
16. Pinto LA, Viscidi R, Harro CD, et al. Cellular immune responses to HPV-18, -31, and -53 in healthy volunteers immunized with recombinant HPV-16 L1 virus-like particles. Virology 2006;353:451-62.
17. Fife KH, Wheeler CM, Koutsky LA, et al. Dose-ranging studies of the safety and immunogenicity of human papillomavirus Type 11 and Type 16 virus-like particle candidate vaccines in young healthy women. Vaccine 2004; 22:2943-52.
18. Frazer IH, Quinn M, Nicklin JL, et al. Phase 1 study of HPV16-specific immunotherapy with E6E7 fusion protein and ISCOMATRIX adjuvant in women with cervical intraepithelial neoplasia. Vaccine 2004;23:172-81.
19. Poland GA, Jacobson RM, Koutsky LA, et al. Immunogenicity and reactogenicity of a novel vaccine for human papillomavirus 16: a 2- year randomized controlled clinical trial. Mayo Clin Proc 2005;80:601-10.
20. Nardelli-Haefliger D, Lurati F, Wirthner D, et al. Immune responses induced by lower airway mucosal immunisation with a human papillomavirus type 16 virus-like particle vaccine. Vaccine 2005;23:3634-41.
21. Insinga RP, Dasbach EJ, Elbasha EH, et al. Incidence and duration of cervical human papillomavirus 6, 11, 16, and 18 infections in young women: an evaluation from multiple analytic perspectives. Cancer Epidemiol Biomarkers Prev 2007;16:709-15.
22. Villa LL, Ault KA, Giuliano AR, et al. Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. Vaccine 2006;24:5571- 83.
23. Olsson SE, Villa LL, Costa RL, et al. Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus- like particle VLP) vaccine. Vaccine 2007; 25:4931-9.
24. Reisinger KS, Block SL, Lazcano-Ponce E, et al. Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial. Pediatr Infect Dis J 2007;26: 201-9.
25. Garland SM, Steben M, Hernandez-Avila M, et al. for the 012 Study Investigators. Noninferiority of antibody response to human papillomavirus type 16 in subjects vaccinated with monovalent and quadrivalent L1 viruslike particle vaccines. Clin Vaccine Immunol 2007;14:792-5
26. Pedersen C, Petaja T, Strauss G, et al. for the HPV Vaccine Adolescent Study Investigators Network. Immunization of early adolescent females with human papillomavirus type 16 and 18 L1 virus-like particle vaccine containing AS04 adjuvant. J Adolesc Health 2007; 40:564-71.
27. Harper DM, Franco EL, Wheeler C, et al. GlaxoSmithKline HPV Vaccine Study Group. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 2004; 364:1757-65.
28. Harper DM, Franco EL, Wheeler CM, et al. HPV Vaccine Study group. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 2006;367:1247-55.
29. Paavonen J, Jenkins D, Bosch FX, et al. HPV PATRICIA study group. Efficacy of a prophylactic adjuvanted bivalent L1 virus-likeparticle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III doubleblind, randomised controlled trial. Lancet 2007;369:2161-70
30. Villa LL, Costa RL, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised doubleblind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 2005;6:271-8.
31. Villa LL, Costa RL, Petta CA, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer 2006;95:1459-66.
32. Garland SM, Hernandez-Avila M, Wheeler CM, et al. Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007;356:1928-43.
33. FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915-27.
34. Lehtinen M, Apter D, Dubin G, et al. Enrolment of 22,000 adolescent women to cancer registry follow-up for long-term human papillomavirus vaccine efficacy: guarding against guessing. Int J STD AIDS 2006;17:517-21
35. Joura EA, Leodolter S, Hernandez-Avila M, et al. Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials. Lancet 2007;369:1693-702.
36. Ault KA, Future II Study Group. Effect of prophylactic human papillomavirus L1 viruslike- particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet 2007; 369:1861-8.
37. Rambout L, Hopkins L, Hutton B, et al. Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized controlled trials. CMAJ 2007;177:469-79.
38. Temte JL. HPV vaccine: a cornerstone of female health. Am Fam Physician 2007;75:28-30.
39. CDC HPV vaccine questions and answers. CDC August 2006. Disponibile all’URL: http://www.cdc.gov/std/HPV/hpv-vaccine. pdf.
40. Newall AT, Beutels P, Wood JG, Edmunds WJ, MacIntyre CR. Cost-effectiveness analyses of human papillomavirus vaccination. Lancet Infect Dis 2007;7:289-96.
41. Lippman A, Melnychuk R, Shimmin C, et al. Human papillomavirus, vaccines and women's health: questions and cautions. CMAJ 2007;177:484-7.
42. Sheldon T. Drug company campaign adds to pressure on Dutch doctors to vaccinate against HPV. BMJ. 2007 Apr 21;334:819.
43. Tanne JH. Texas governor is criticised for decision to vaccinate all girls against HPV. BMJ 2007;334:332-3
44. Coombes R. Life saving treatment or giant experiment? BMJ 2007;334:721-3
45. Charo RA. Politics, parents, and prophylaxis-- mandating HPV vaccination in the United States. N Engl J Med 2007;356:1905-8.
46. Pecorelli S. Presentazione dei dati sperimentali sull’uso dei vaccini per HPV. Comunicazione orale al convegno: HPV e tumori dell’apparato genitale femminile: l’era dei vaccini. Bologna 8 Giugno 2007. Assessorato politiche per la salute, Regione Emilia-Romagna e Alma Mater Studiorum Università di Bologna, Istituto di Clinica Ginecologica Ostetrica, scuola di specializzazione in Ginecologia e Ostetricia.
47. Agenzia Italiana del Farmaco. Il vaccino per il cancro della cervice. Medico e Bambino pagine elettroniche 2007; 10. Disponibile all’URL: http://www.medicoebambino.com/index. php?id=IPS0704_10.html.
48. Di Mario S, Basevi V, Magrini N. Vaccinazione anti-HPV: alcuni interrogativi per il pediatra. Medico e Bambino 2007;5:279-80. Disponibile all’URL: http://www.medicoebambino. com/?id=ri_0705.
49. Sawaya GF, Smith-McCune K. HPV vaccination- more answers, more questions. N Engl J Med 2007;356:1991-3.
50. Lehtinen M, French K. Integration of the vaccine against human papillomaviruses into national vaccination programmes. Entre Nous 2007;64:12-3.
51. Centro per la Documentazione sulla Salute Perinatale, SaPeRiDoc. La prevenzione della neoplasia cervicale. Disponibile all’URL: http://www.saperidoc.it/doc_116.html.
52. Kudjawu Y, Lévy-Bruhl D, Pastore Celentano L, et al. on behalf of the VENICE working group. The current status of HPV and rotavirus vaccines in national immunisation schedules in the EU – preliminary results of a VENICE survey. Eurosurveillance Weekly Release. 26 Aprile 2007. Disponibile all’URL: http://www.eurosurveillance.org/ew/2007/0 70426.asp#1.
53. Stroffolini T, Cialdea L, Tosti ME, Grandolfo M, Mele A. Vaccination campaign against hepatitis B for 12-year-old subjects in Italy. Vaccine 1997;15:583-5.
54. World Health Organization. Preparing for the introduction of HPV vaccines. Policy and programme guidance for countries. UNFPA & World Health Organization, Geneva. 2006. Disponibile all’URL: http://www.who.int/reproductive- health/publications/hpvvaccines/ text.pdf.
55. BMJ learning. Screening for cervical cancer: in association with the NHS Cancer Screening Programmes. Disponibile all’URL: http: //learning.bmj.com/learning/search-result. html?moduleId=5004436 .
56. Franceschi S, Herrero R, Clifford GM, et al. Variations in the age-specific curves of human papillomavirus prevalence in women worldwide. Int J Cancer 2006;119:2677-84.
57. Carozzi FM. Le basi biologiche dei vaccini per il papillomavirus umano. Epid-Prev 2007; 31:92-9.
58. Lazdane G. Questions and answers. Common questions related to prevention of cervical cancer and the HPV vaccine. Entre Nous 2007;64:29.
59. AAVV. Human papillomavirus vaccine for genotypes 6, 11, 16 and 18: new drug. Cervical cancer prevention: high hopes. Prescrire Int 2007;16:91-4.
60. MacDonald N, Hebert PC. Human papillomavirus vaccine: waiting for a miracle. CMAJ 2007;177:433-5.
61. Lo B. Human papillomavirus vaccination programmes. BMJ 2007;335:357-8.
62. Baden LR, Curfman GD, Morrissey S, Drazen JM. Human papillomavirus vaccine-opportunity and challenge. N Engl J Med 2007; 356:1990-1.
63. Kahn JA, Burk RD. Papillomavirus vaccines in perspective. Lancet 2007;369:2135-7.
64. Markman M. Human papillomavirus vaccines to prevent cervical cancer. Lancet 2007; 369:1837-9.
65. Agosti JM, Goldie SJ. Introducing HPV vaccine in developing countries-key challenges and issues. N Engl J Med 2007;356:1908-10.
66. Suba EJ, Raab SS; Viet/American Cervical Cancer Prevention Project. Human papillomavirus vaccine. N Engl J Med 2007;357:1155.
67. Mauri D, Polyzos NP. Effects of quadrivalent human papillomavirus vaccination. Lancet 2007;370:1031.
68. Arbyn M. Effects of quadrivalent human papillomavirus vaccination. Lancet 2007;370: 1031-2.
69. Miller NB, Raychaudhuri G, Toerner JG. Human papillomavirus vaccine. N Engl J Med 2007;357:1154-5.
70. Raffle AE. Human papillomavirus vaccine policy. Lancet 2007;369:367-8.
71. Stewart AM. Mandating HPV vaccinationprivate rights, public good. N Engl J Med 2007;356:1998-9.
72. Segraves BT. Compulsory HPV vaccination. N Engl J Med 2007;356:1074.
73. Basu S. Compulsory HPV vaccination. N Engl J Med 2007;356:1074.
Corrispondenza: s.dimario@ausl.mo.it