Scolaris Content Display Scolaris Content Display

Vacunación profiláctica contra el virus del papiloma humano para prevenir el cáncer de cuello uterino y sus precursores

Contraer todo Desplegar todo

Referencias

Referencias de los estudios incluidos en esta revisión

African_2 country trial (ph3,2v) {published data only}

Sow PS, Watson‐Jones D, Kiviat N, Changalucha J, Mbaye KD, Brown J. Safety and immunogenicity of human papillomavirus‐16/18 AS04‐adjuvanted vaccine: a randomized trial in 10‐25‐year‐old HIV‐Seronegative African girls and young women. Journal of Infectious Diseases 2013;207(11):1753‐63. CENTRAL

African_3 country trial (ph3,4v) {published data only}

Mugo N, Ansah NA, Marino D, Saah A, Garner E I. Evaluation of safety and immunogenicity of a quadrivalent human papillomavirus vaccine in healthy females between 9 and 26 years of age in Sub‐Saharan Africa. Human Vaccines & Immunotherapeutics 2015;11(6):1323‐30. CENTRAL

Chinese trial (ph3,2v)_ adolescent {published data only}

Zhu F, Li J, Hu Y, Zhang X, Yang X, Zhao H, et al. Immunogenicity and safety of the HPV‐16/18 AS04‐adjuvanted vaccine in healthy Chinese girls and women aged 9 to 45 years. Human Vaccines & Immunotherapeutics 2014;10(7):1795‐806. CENTRAL

Chinese trial (ph3,2v)_mid‐adult {published data only}

Zhu F, Li J, Hu Y, Zhang X, Yang X, Zhao H, et al. Immunogenicity and safety of the HPV‐16/18 AS04‐adjuvanted vaccine in healthy Chinese girls and women aged 9 to 45 years. Human Vaccines & Immunotherapeutics 2014;10(7):1795‐806. CENTRAL

Chinese trial (ph3,2v)_young {published data only}

Zhu FC, Chen W, Hu YM, Hong Y, Li J, Zhang X, et al. Efficacy, immunogenicity and safety of the HPV‐16/18 AS04‐adjuvanted vaccine in healthy Chinese women aged 18‐25 years: results from a randomized controlled trial. International Journal of Cancer 2014;135(11):2612‐22. CENTRAL
Zhu FC, Hu SY, Hong Y, Hu YM, Zhang X, Zhang YJ, et al. Efficacy, immunogenicity, and safety of the HPV‐16/18 AS04‐adjuvanted vaccine in Chinese women aged 18‐25 years: event‐triggered analysis of a randomized controlled trial. Cancer Medicine 2017;6(2045‐7634 (Electronic), 2045‐7634 (Linking), 1):12‐25. CENTRAL

Co‐vaccination_dTpa_IPV trial (ph3,2v) {published data only}

Garcia‐Sicilia J, Schwarz TF, Carmona A, Peters K, Malkin JE, Tran PM. Immunogenicity and safety of human papillomavirus‐16/18 AS04‐adjuvanted cervical cancer vaccine coadministered with combined diphtheria‐tetanus‐acellular pertussis‐inactivated poliovirus vaccine to girls and young women. Journal of Adolescent Health 2010;46(2):142‐51. CENTRAL

Co‐vaccination_HAB trial (Ph3, 2v) {published data only}

Pedersen C, Breindahl M, Aggarwal N, Berglund J, Oroszlan G, Silfverdal SA. Randomized trial: immunogenicity and safety of coadministered human papillomavirus‐16/18AS04‐adjuvanted vaccine and combined hepatitis A and B vaccine in girls. Journal of Adolescent Health 2012;50(1):38‐46. CENTRAL

Co‐vaccination_HepB trial (ph3, 2v) {published data only}

Schmeink CE, Bekkers RL, Josefsson A, Richardus JH, Berndtsson Blom K, et al. Co‐administration of human papillomavirus‐16/18 AS04‐adjuvanted vaccine with hepatitis B vaccine: randomized study in healthy girls. Vaccine 2011;29(49):9276‐83. CENTRAL

CVT (ph3,2v) {published data only}

Herrero R, Wacholder S, Rodriguez AC, Solomon D, Gonzalez P, Kreimer AR, et al. Prevention of persistent human papillomavirus infection by an HPV16/18 vaccine: A community‐based randomized clinical trial in Guanacaste, Costa Rica. Cancer Discovery 2011;1(5):408‐19. CENTRAL
Hildesheim A, Wacholder S, Catteau G, Struyf F, Dubin G, Herrero R. Efficacy of the HPV‐16/18 vaccine: Final according to protocol results from the blinded phase of the randomized Costa Rica HPV‐16/18 vaccine trial. Vaccine 2014;32(39):5087‐97. CENTRAL
Kreimer AR, Gonzalez P, Katki HA, Porras C, Schiffman M, Rodriguez AC. Efficacy of a bivalent HPV 16/18 vaccine against anal HPV 16/18 infection among young women: a nested analysis within the Costa Rica Vaccine Trial. Lancet Oncology 2011;12(9):862‐70. CENTRAL
Kreimer AR, Rodriguez AC, Hildesheim A, Herrero R, Porras C, Schiffman M, et al. Proof‐of‐principle evaluation of the efficacy of fewer than three doses of a bivalent HPV16/18 vaccine. Journal of the National Cancer Institute 2011;103(19):1444‐51. CENTRAL
Lang Kuhs KA, Porras C, Schiller JT, Rodriguez AC, Schiffman M, Gonzalez P. Effect of different human papillomavirus serological and DNA criteria on vaccine efficacy estimates. American Journal of Epidemiology 2014;180(6):599‐607. CENTRAL

FUT I/II trials (ph3,4v) {published data only}

Brown DR, Kjaer SK, Sigurdsson K, Iversen OE, Hernandez‐Avila M, Wheeler CM. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus‐like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in generally HPV‐naive women aged 16 to 26 years. Journal of Infectious Diseases 2009;199(7):926‐35. CENTRAL
Dillner J, Kjaer SK, Wheeler CM, Sigurdsson K, Iversen OE, Hernandez‐Avila M. Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial. BMJ 2010;341:c3493. CENTRAL
Kjaer SK, Sigurdsson K, Iversen OE, Hernandez‐Avila M, Wheeler CM, Perez G. A pooled analysis of continued prophylactic efficacy of quadrivalent human papillomavirus (Types 6/11/16/18) vaccine against high‐grade cervical and external genital lesions. Cancer Prevention Research 2009;2(10):868‐78. CENTRAL
Munoz N, Kjaer SK, Sigurdsson K, Iversen OE, Hernandez‐Avila M, Wheeler CM. Impact of human papillomavirus (HPV)‐6/11/16/18 vaccine on all HPV‐associated genital diseases in young women. Journal of the National Cancer Institute 2010;102(5):325‐39. CENTRAL
Olsson SE, Kjaer SK, Sigurdsson K, Iversen OE, Hernandez‐Avila M, Wheeler CM. Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection. Human Vaccines 2009;5(10):696‐704. CENTRAL
The FUTURE II study group. Prophylactic efficacy of a quadrivalent human papillomavirus (HPV) vaccine in women with virological evidence of HPV infection. Journal of Infectious Diseases 2007;196(10):1438‐46. CENTRAL
Wheeler CM, Kjaer SK, Sigurdsson K, Iversen OE, Hernandez‐Avila M, Perez G. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus‐like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in sexually active women aged 16 to 26 years. Journal of Infectious Diseases 2009;199(7):936‐44. CENTRAL

FUTURE III trial (ph3,4v) {published data only}

Castellsagué X, Munoz N, Pitisuttithum P, Ferris D, Monsonego J, Ault K. End‐of‐study safety, immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine in adult women 24 to 45 years of age. British Journal of Cancer 2011;105(1):28‐37. CENTRAL
Garland SM, Ault KA, Gall SA, Paavonen J, Sings HL, Ciprero KL, et al. Pregnancy and infant outcomes in the clinical trials of a human papillomavirus type 6/11/16/18vaccine: a combined analysis of five randomized controlled trials. Obstetrics and Gynecology 2009;114(6):1179‐88. CENTRAL
Munoz N, Manalastas R, Pitisuttithum P, Tresukosol D, Monsonego J, Ault K. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24‐45 years: a randomised, double‐blind trial. Lancet 2009;373(9679):1949‐57. CENTRAL

FUTURE II trial (ph3,4v) {published data only}

Garland SM, Ault KA, Gall SA, Paavonen J, Sings HL, Ciprero KL, et al. Pregnancy and infant outcomes in the clinical trials of a human papillomavirus type 6/11/16/18vaccine: a combined analysis of five randomized controlled trials. Obstetrics and Gynecology 2009;114(6):1179‐88. CENTRAL
The FUTURE II study group. Quadrivalent vaccine against human papillomavirus to prevent high‐grade cervical lesions. New England Journal of Medicine 2007;356(19):1915‐27. CENTRAL

FUTURE I trial (ph3,4v) {published data only}

Garland SM, Ault KA, Gall SA, Paavonen J, Sings HL, Ciprero KL, et al. Pregnancy and infant outcomes in the clinical trials of a human papillomavirus type 6/11/16/18vaccine: a combined analysis of five randomized controlled trials. Obstetrics and Gynecology 2009;114(6):1179‐88. CENTRAL
Garland SM, Hernandez‐Avila M, Wheeler CM, Perez G, Harper DM, Leodolter S. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. New England Journal of Medicine 2007;356(19):1928‐43. CENTRAL

Hong Kong trial (ph3,2v) {published data only}

Ngan HY, Cheung AN, Tam KF, Chan KK, Tang HW, Bi D, et al. Human papillomavirus‐16/18 AS04‐adjuvanted cervical cancer vaccine: immunogenicity and safety in healthy Chinese women from Hong Kong. Hong Kong Medical Journal 2010;16(1024‐2708 (Print), 1024‐2708 (Linking), 3):171‐9. CENTRAL

Immunobridging(ph3,2v) {published data only}

Medina DM, Valencia A, de Velasquez A, Huang LM, Prymula R, Garcia‐Sicilia J. Safety and immunogenicity of the HPV‐16/18 AS04‐adjuvanted vaccine: a randomized, controlled trial in adolescent girls. Journal of Adolescent Health 2010;46(5):414‐21. CENTRAL

Indian trial (ph3,2v) {published data only}

Bhatla N, Suri V, Basu P, Shastri S, Datta SK, Bi D, et al. Immunogenicity and safety of human papillomavirus‐16/18 AS04‐adjuvanted cervical cancer vaccine in healthy Indian women. Journal of Obstetrics and Gynaecology Research 2010;36(1):123‐32. CENTRAL

Japanese trial (ph2,2v) {published data only}

Konno R, Tamura S, Dobbelaere K, Yoshikawa H. Efficacy of human papillomavirus 16/18 AS04‐adjuvanted vaccine in Japanese women aged 20 to 25 years: interim analysis of a phase 2 double‐blind, randomized, controlled trial. International Journal of Gynecological Cancer 2010;20(3):404‐10. CENTRAL
Konno R, Tamura S, Dobbelaere K, Yoshikawa H. Efficacy of human papillomavirus type 16/18 AS04‐adjuvanted vaccine in Japanese women aged 20 to 25 years: final analysis of a phase 2 double‐blind, randomized controlled trial. International Journal of Gynecological Cancer 2010;20(5):847‐55. CENTRAL
Konno R, Yoshikawa H, Okutani M, Quint W, Suryakiran V, Lin L, et al. Efficacy of the human papillomavirus (HPV)‐16/18 AS04‐adjuvanted vaccine against cervical intraepithelial neoplasia and cervical infection in young Japanese women. Human Vaccines & Immunotherapeutics 2014;10(7):1781‐94. CENTRAL

Japanese trial (ph2,4v) {published data only}

Yoshikawa H, Ebihara K, Tanaka Y, Noda K. Efficacy of quadrivalent human papillomavirus (types 6, 11, 16 and 18) vaccine (GARDASIL) in Japanese women aged 18 to 26 years. Cancer Science 2013;104(4):465‐72. CENTRAL

Korean trial (ph2,4v) {published data only}

Kang S, Kim KH, Kim YT, Kim YT, Kim JH, Song YS. Safety and immunogenicity of a vaccine targeting human papillomavirus types 6, 11, 16 and 18: a randomized, placebo‐controlled trial in 176 Korean subjects. International Journal of Gynecological Cancer 2008;18(5):1013‐9. CENTRAL

Korean trial (ph3,2v) {published data only}

Kim YJ, Kim KT, Kim JH, Cha SD, Kim JW, Bae DS, et al. Vaccination with a human papillomavirus (HPV)‐16/18 AS04‐adjuvanted cervical cancer vaccine in Korean girls aged 10‐14 years. Journal of Korean Medical Science 2010;25(8):1197‐204. CENTRAL

Korean trial (ph3b,2v) {published data only}

Kim SC, Song YS, Kim YT, Kim YT, Ryu KS, Gunapalaiah B. Human papillomavirus 16/18 AS04‐adjuvanted cervical cancer vaccine: immunogenicity and safety in 15 to 25 years old healthy Korean women. Journal of Gynecologic Oncology 2011;22(2):67‐75. CENTRAL

Malaysian trial (ph3,2v) {published data only}

Lim BK, Ng KY, Omar J, Omar SZ, Gunapalaiah B, Teoh YL, et al. Immunogenicity and safety of the AS04‐adjuvanted human papillomavirus‐16/18 cervical cancer vaccine in Malaysian women aged 18 to 35 years: a randomized controlled trial. Medical Journal of Malaysia 2014;69(0300‐5283 (Print), 0300‐5283 (Linking), 1):2‐8. CENTRAL

PATRICIA & CVT (ph3,2v) {published data only}

Wacholder S, Chen BE, Wilcox A, Macones G, Gonzalez P, Befano B. Risk of miscarriage with bivalent vaccine against human papillomavirus (HPV) types 16 and 18: pooled analysis of two randomised controlled trials. BMJ 2010;340:c712. CENTRAL

PATRICIA trial (ph3,2v) {published data only}

Lehtinen M, Paavonen J, Wheeler CM, Jaisamrarn U, Garland S, Castellsagué X. Overall efficacy of HPV‐16/18 ASO4‐adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4‐year end‐of‐study analysis of the randomised, double‐blind PATRICIA trial. Lancet Oncology 2012;13(1):89‐99. CENTRAL
Paavonen J, Jenkins D, Bosch FX, Naud P, Salmeron J, Wheeler CM. Efficacy of a prophylactic adjuvanted bivalent L1 virus‐like‐particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double‐blind, randomised controlled trial. Lancet 2007;369(9580):2161‐70. CENTRAL
Paavonen J, Naud P, Salmeron J, Wheeler CM, Chow S‐N, Apter D. Efficacy of human papillomavirus (HPV)‐16/18 ASO4‐adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double‐blind, randomised study in young women. Lancet 2009;374:301‐14. CENTRAL
Szarewski A, Poppe WA, Skinner SR, Wheeler CM, Paavonen J, Naud P. Efficacy of the human papillomavirus (HPV)‐16/18 AS04‐adjuvanted vaccine in women aged 15 to 25 years with and without serological evidence of previous exposure to HPV‐16/18. International Journal of Cancer 2011;131(1):106‐16. CENTRAL
Wheeler CM, Castellsagué X, Garland SM, Szarewski A, Paavonen J, Naud P. Cross‐protective efficacy of HPV‐16/18 ASO4‐adjuvanted vaccine against cervical infection and precancer caused by non‐vaccine oncogenic HPV‐types: 4‐year end‐of‐study analysis of the randomised, double‐blind PATRICIA trial. Lancet Oncology 2011;13(1):100‐10. CENTRAL

Phase2 trial (ph2,1v) {published data only}

Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB. A controlled trial of a human papillomavirus type 16 vaccine. New England Journal of Medicine 2002;347(21):1645‐51. CENTRAL
Mao C, Koutsky LA, Ault KA, Wheeler CM, Brown DR, Wiley DJ. Efficacy of human papillomavirus‐16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstetrics and Gynecology 2006;107(1):18‐27. CENTRAL
Rowhani‐Rahbar A, Mao C, Hughes JP, Alvarez FB, Bryan JT, Hawes SE. Longer term efficacy of a prophylactic monovalent human papillomavirus type 16 vaccine. Vaccine 2009;27(41):5612‐9. CENTRAL

Phase2 trial (ph2,2v) {published data only}

De Carvalho N, Teixeira J, Roteli‐Martins CM, Naud P, De Borba P, Zahaf T. Sustained efficacy and immunogenicity of the HPV‐16/18 AS04‐adjuvanted vaccine up to 7.3 years in young adult women. Vaccine 2010;28(38):6247‐55. CENTRAL
Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A. 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(9447):1757‐65. CENTRAL
Harper DM, Franco EL, Wheeler CM, Moscicki AB, Romanowski B, Roteli‐Martins CM. 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(9518):1247‐55. CENTRAL
Naud PS, Roteli‐Martins CM, De Carvalho NS, Teixeira JC, de Borba PC, Sanchez N, et al. Sustained efficacy, immunogenicity, and safety of the HPV‐16/18 AS04‐adjuvanted vaccine: Final analysis of a long‐term follow‐up study up to 9.4 years post‐vaccination. Human Vaccines & Immunotherapeutics 2014;10(8):2147‐62. CENTRAL
The GlaxoSmithKline Vaccine HPV‐007 Study Group. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)‐16/18 ASO4‐adjuvanted vaccine: analysis of a randomised placebo‐controlled trial up to 6.4 years. Lancet 2009;374:1975‐85. CENTRAL

Phase2 trial (ph2,4v) {published data only}

Olsson SE, Kjaer SK, Sigurdsson K, Iversen OE. Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection. Human Vaccines 2009;5(10):696‐704. CENTRAL
Villa LL, Ault KA, Giuliano AR, Costa RL, Petta CA, Andrade RP. Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. Vaccine 2006;24(27):5571‐83. CENTRAL
Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano AR. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus‐like particle vaccine in young women: a randomised double‐blind placebo‐controlled multicentre phase II efficacy trial. Lancet Oncology 2005;6(5):271‐8. CENTRAL
Villa LL, Costa RL, Petta CA, Andrade RP, Paavonen J, Iversen OE. 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. British Journal of Cancer 2006;95(11):1459‐66. CENTRAL

VIVIANE trial (ph3,2v) {published data only}

Skinner SR, Szarewski A, Romanowski B, Garland SM, Lazcano‐Ponce E, Salmeron J. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04‐adjuvanted vaccine in women older than 25 years: 4‐year interim follow‐up of the phase 3, double‐blind, randomised controlled VIVIANE study. Lancet 2014;384(9961):2213‐27. CENTRAL
Wheeler CM, Skinner SR, Del Rosario‐Raymundo MR, Garland SM, Chatterjee A, Lazcano‐Ponce E, et al. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04‐adjuvanted vaccine in women older than 25 years: 7‐year interim follow‐up of the phase 3, double‐blind, randomised controlled VIVIANE study. Lancet Infectious Diseases 2016;16(10):1154–68. CENTRAL

Referencias de los estudios excluidos de esta revisión

Angelo 2014 {published data only}

Angelo MG, David MP, Zima J, Baril L, Dubin G, Arellano F, et al. Pooled analysis of large and long‐term safety data from the human papillomavirus‐16/18‐AS04‐adjuvanted vaccine clinical trial programme. Pharmacoepidemiology and Drug Safety 2014;23(1099‐557 (Electronic), 1053‐8569 (Linking), 5):466‐79. CENTRAL

Arguedas 2010 {published data only}

Arguedas A, Soley C, Loaiza C, Rincon G, Guevara S, Perez A, et al. Safety and immunogenicity of one dose of MenACWY‐CRM, an investigational quadrivalent meningococcal glycoconjugate vaccine, when administered to adolescents concomitantly or sequentially with Tdap and HPV vaccines. Vaccine 2010;28(1873‐2518 (Electronic), 0264‐410X (Linking), 18):3171‐9. CENTRAL

Ault 2004 {published data only}

Ault KA, Giuliano AR, Edwards RP, Tamms G, Kim LL, Smith JF. A phase I study to evaluate a human papillomavirus (HPV) type 18 L1 VLP vaccine. Vaccine 2004;22(23‐24):3004‐7. CENTRAL

Ault 2007 {published data only}

Ault KA, Future II Study Group. Effect of prophylactic human papillomavirus L1 virus‐like‐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(9576):1861‐8. CENTRAL

Basu 2013 {published data only}

Basu P, Banerjee D, Singh P, Bhattacharya C, Biswas J. Efficacy and safety of human papillomavirus vaccine for primary prevention of cervical cancer: A review of evidence from phase III trials and national programs. South Asian Journal of Cancer 2013;2(4):187‐92. CENTRAL

Beachler 2016 {published data only}

Beachler DC, Kreimer AR, Schiffman M, Herrero R, Wacholder S, Rodriguez AC, et al. Multisite HPV16/18 vaccine efficacy against cervical, anal, and oral HPV infection. Journal of the National Cancer Institute 2016;108(1):djv302. CENTRAL

Brown 2004 {published data only}

Brown DR, Fife KH, Wheeler CM, Koutsky LA, Lupinacci LM, Railkar R. Early assessment of the efficacy of a human papillomavirus type 16 L1 virus‐like particle vaccine. Vaccine 2004;22(21‐22):2936‐42. CENTRAL

Couto 2014 {published data only}

Couto E, Saeterdal I, Juvet LK, Klemp M. HPV catch‐up vaccination of young women: a systematic review and meta‐analysis. BMC Public Health 2014;14(1471‐2458 (Electronic), 1471‐2458 (Linking)):867. CENTRAL

D'Addario 2017 {published data only}

D'Addario M, Redmond S, Scott P, Egli‐Gany D, Riveros‐Balta AX, Henao Restrepo AM, et al. Two‐dose schedules for human papillomavirus vaccine: Systematic review and meta‐analysis. Vaccine 2017;35(1873‐2518 (Electronic), 0264‐410X (Linking), 22):2892‐901. CENTRAL

D'Souza 2013 {published data only}

D'Souza C, Mort GS, Zyngier S, Robinson P, Schlotterlein M. Preventive innovation: an Australian case study on HPV vaccination. Health Marketing Quartely 2013;30(3):206‐20. CENTRAL

Delere 2013 {published data only}

Delere Y, Bohmer MM, Walter D, Wichmann O. HPV vaccination coverage among women aged 18‐20 years in Germany three years after recommendation of HPV vaccination for adolescent girls: results from a cross‐sectional survey. Human Vaccines & Immunotherapeutics 2013;9(8):1706‐11. CENTRAL

Denny 2013 {published data only}

Denny L, Hendricks B, Gordon C, Thomas F, Hezareh M, Dobbelaere K. Safety and immunogenicity of the HPV‐16/18 AS04‐adjuvanted vaccine in HIV‐positive women in South Africa: A partially‐blind randomised placebo‐controlled study. Vaccine 2013;31(48):5745‐53. CENTRAL

Descamps 2009 {published data only}

Descamps D, Hardt K, Spiessens B, Izurieta P, Verstraeten T, Breuer T. Safety of human papillomavirus (HPV)‐16/18 AS04‐adjuvanted vaccine for cervical cancer prevention: a pooled analysis of 11 clinical trials. Human Vaccines & Immunotherapeutics 2009;5(5):332‐40. CENTRAL

De Vincenzo 2014 {published data only}

De Vincenzo R, Conte C, Ricci C, Scambia G, Capelli G. Long‐term efficacy and safety of human papillomavirus vaccination. International Journal of Womens Health 2014;6(1179‐411 (Electronic), 1179‐411 (Linking)):999‐1010. CENTRAL

Dobson 2013 {published data only}

Dobson SR, McNeil S, Dionne M, Dawar M, Ogilvie G, Krajden M. Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial. JAMA 2013;309(17):1793‐802. CENTRAL

Draper 2011 {published data only}

Draper E, Bissett SL, Howell‐Jones R, Edwards D, Munslow G, Soldan K. Neutralization of non‐vaccine human papillomavirus pseudoviruses from the A7 and A9 species groups by bivalent HPV vaccine sera. Vaccine 2011;29(47):8585‐90. CENTRAL

Draper 2013 {published data only}

Draper E, Bissett SL, Howell‐Jones R, Waight P, Soldan K, Jit M. A randomized, observer‐blinded immunogenicity trial of cervarix((R)) and gardasil((R)) human papillomavirus vaccines in 12‐15 year old girls. PLOS One 2013;8(5):e61825. CENTRAL

Einstein 2009 {published data only}

Einstein MH, Baron M, Levin MJ, Chatterjee A, Edwards RP, Zepp F. Comparison of the immunogenicity and safety of Cervarix and Gardasil human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18 to 45 years. Human Vaccines & Immunotherapeutics 2009;5(10):705‐19. CENTRAL

Einstein 2011 {published data only}

Einstein MH, Baron M, Levin MJ, Chatterjee A, Fox B, Scholar S. Comparative immunogenicity and safety of human papillomavirus (HPV) 16/18 vaccine and HPV‐6/11/16/18 vaccine: Follow‐up from months 12 to 24 in a Phase III randomized study of healthy women aged 18 to 45 years. Human Vaccines & Immunotherapeutics 2011;7(12):1343‐58. CENTRAL

Evans 2001 {published data only}

Evans TG, Bonnez W, Rose RC, Koenig S, Demeter L, Suzich JA. A Phase 1 study of a recombinant viruslike particle vaccine against human papillomavirus type 11 in healthy adult volunteers. Journal of Infectious Diseases 2001;183(0022‐1899, 10):1485‐93. CENTRAL

Forinash 2011 {published data only}

Forinash AB, Yancey AM, Pitlick JM, Myles TD. Safety of the HPV bivalent and quadrivalent vaccines during pregnancy. Annals of Pharmacotherapy 2011;45(3):1‐5. CENTRAL

Garland 2016 {published data only}

Garland SM, Paavonen J, Jaisamrarn U, Naud P, Salmeron J, Chow SN, et al. Prior human papillomavirus‐16/18 AS04‐adjuvanted vaccination prevents recurrent high grade cervical intraepithelial neoplasia after definitive surgical therapy: Post‐hoc analysis from a randomized controlled trial. International Journal of Cancer 2016;139(1097‐0215 (Electronic), 0020‐7136 (Linking), 12):2812‐26. CENTRAL

Giuliano 2007 {published data only}

Giuliano AR, Lazcano‐Ponce E, Villa L, Nolan T, Marchant C, Radley D. Impact of baseline covariates on the immunogenicity of a quadrivalent (types 6, 11, 16, and 18) human papillomavirus virus‐like‐particle vaccine. Journal of Infectious Diseases 2007;196(8):1153‐62. CENTRAL

Giuliano 2011 {published data only}

Giuliano AR, Palefsky JM, Goldstone S, Moreira ED, Penny ME, Aranda C. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. New England Journal of Medcine 2011;364(5):401‐11. CENTRAL

Giuliano 2015 {published data only}

Giuliano AR, Isaacs‐Soriano K, Torres BN, Abrahamsen M, Ingles DJ, Sirak BA, et al. Immunogenicity and safety of Gardasil among mid‐adult aged men (27 to 45 years) The MAM Study. Vaccine 2015;33(1873‐2518 (Electronic), 0264‐410X (Linking), 42):5640‐6. CENTRAL

Goldstone 2013 {published data only}

Goldstone SE, Jessen H, Palefsky JM, Giuliano AR, Moreira ED, Vardas E, et al. Quadrivalent HPV vaccine efficacy against disease related to vaccine and non‐vaccine HPV types in males. Vaccine 2013;31(37):3849‐55. CENTRAL

Harro 2001 {published data only}

Harro CD, Pang YY, Roden RB, Hildesheim A, Wang Z, Reynolds MJ. Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus‐like particle vaccine. Journal of the National Cancer Institute 2001;93(4):284‐92. CENTRAL

Haupt 2011 {published data only}

Haupt RM, Wheeler CM, Brown DR, Garland SM, Ferris DG, Paavonen JA. Impact of an HPV6/11/16/18 L1 virus‐like particle vaccine on progression to cervical intraepithelial neoplasia in seropositive women with HPV16/18 infection. International Journal of Cancer 2011;129(11):2632‐42. CENTRAL

Heijstek 2014 {published data only}

Heijstek MW, Scherpenisse M, Groot N, Tacke C, Schepp RM, Buisman AM, et al. Immunogenicity and safety of the bivalent HPV vaccine in female patients with juvenile idiopathic arthritis: a prospective controlled observational cohort study. Annals of the RheumaticDiseases 2014;73(1468‐2060 (Electronic), 0003‐4967 (Linking), 8):1500‐7. CENTRAL

Hernandez‐Avila 2016 {published data only}

Hernandez‐Avila M, Torres‐Ibarra L, Stanley M, Salmeron J, Cruz‐Valdez A, Munoz N, et al. Evaluation of the immunogenicity of the quadrivalent HPV vaccine using 2 versus 3 doses at month 21: An epidemiological surveillance mechanism for alternate vaccination schemes. Human Vaccines & Immunotherapeutics 2016;12(2164‐554X (Electronic), 2164‐5515 (Linking), 1):30‐8. CENTRAL

Herrero 2013 {published data only}

Herrero R, Quint W, Hildesheim A, Gonzalez P, Struijk L, Katki HA. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLOS One 2013;8(7):e68329. CENTRAL

Hildesheim 2007 {published data only}

Hildesheim A, Herrero R, Wacholder S, Rodriguez AC, Solomon D, Bratti MC. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA 2007;298(7):743‐53. CENTRAL

Hillman 2011 {published data only}

Hillman RJ, Giuliano AR, Palefsky JM, Goldstone S, Moreira ED, Vardas E. The immunogenicity of quadrivalent HPV (type 6/11/16/18) vaccine in males aged 16 to 26. Clinical and Vaccine Immunology 2011;19:261‐7. CENTRAL

Joura 2007 {published data only}

Joura EA, Leodolter S, Hernandez‐Avila M, Wheeler CM, Perez G, Koutsky LA. 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(9574):1693‐702. CENTRAL

Kahn 2013 {published data only}

Kahn JA, Xu J, Kapogiannis BG, Rudy B, Gonin R, Liu N, et al. Immunogenicity and safety of the human papillomavirus 6, 11, 16, 18 vaccine in HIV‐infected young women. Clinical Infectious Diseases 2013;57(5):735‐44. CENTRAL

Kang 2013 {published data only}

Kang WD, Choi HS, Kim SM. Is vaccination with quadrivalent HPV vaccine after loop electrosurgical excision procedure effective in preventing recurrence in patients with high‐grade cervical intraepithelial neoplasia (CIN2‐3)?. Gynecologic Oncology 2013;130(2):264‐8. CENTRAL

Khatun 2012 {published data only}

Khatun S, Akram Hussain SM, Chowdhury S, Ferdous J, Hossain F, Begum SR. Safety and immunogenicity profile of human papillomavirus‐16/18 AS04 adjuvant cervical cancer vaccine: a randomized controlled trial in healthy adolescent girls of Bangladesh. Japanese Journal of Clinical Oncology 2012;42(1):36‐41. CENTRAL

Kjaer 2009 {published data only}

Kjaer SK, Sigurdsson K, Iversen OE, Hernandez‐Avila M, Wheeler CM, Perez G, et al. A pooled analysis of continued prophylactic efficacy of quadrivalent human papillomavirus (Types 6/11/16/18) vaccine against high‐grade cervical and external genital lesions. Cancer Prevention Research (Philadelphia, Pa.) 2009;2(1940‐6215 (Electronic), 10):868‐78. CENTRAL

Kreimer 2015 {published data only}

Kreimer AR, Sherman ME, Sahasrabuddhe VV, Safaeian M. The case for conducting a randomized clinical trial to assess the efficacy of a single dose of prophylactic HPV vaccines among adolescents. Journal of the National Cancer Institute 2015;107(3 1460‐2105 (Electronic)):1‐4 0027‐8874 (Linking). CENTRAL

Lamontagne 2013 {published data only}

Lamontagne DS, Thiem VD, Huong VM, Tang Y, Neuzil KM. Immunogenicity of quadrivalent HPV vaccine among girls 11 to 13 Years of age vaccinated using alternative dosing schedules: results 29 to 32 months after third dose. Journal of Infectious Diseases 2013;208(8):1325‐34. CENTRAL

Lang 2014 {published data only}

Lang Kuhs KA, Gonzalez P, Rodriguez AC, van Doorn LJ, Schiffman M, Struijk L, et al. Reduced prevalence of vulvar HPV16/18 infection among women who received the HPV16/18 bivalent vaccine: a nested analysis within the Costa Rica Vaccine Trial. Journal of Infectious Diseases 2014;210(12):1890‐9. CENTRAL

Lazcano‐Ponce 2014 {published data only}

Lazcano‐Ponce E, Stanley M, Munoz N, Torres L, Cruz‐Valdez A, Salmeron J, et al. Overcoming barriers to HPV vaccination: non‐inferiority of antibody response to human papillomavirus 16/18 vaccine in adolescents vaccinated with a two‐dose vs. a three‐dose schedule at 21 months. Vaccine 2014;32(6):725‐32. CENTRAL

Lehtinen 2016 {published data only}

Lehtinen M, Eriksson T, Apter D, Hokkanen M, Natunen K, Paavonen J, et al. Safety of the human papillomavirus (HPV)‐16/18 AS04‐adjuvanted vaccine in adolescents aged 12‐15 years: Interim analysis of a large community‐randomized controlled trial. Human Vaccines & Immunotherapeutics 2016;12(2164‐554X (Electronic), 2164‐5515 (Linking), 12):3177‐85. CENTRAL

Leroux‐Roels 2011 {published data only}

Leroux‐Roels G, Haelterman E, Maes C, Levy J, De Boever F, Licini L. Randomized trial of the immunogenicity and safety of the Hepatitis B vaccine given in an accelerated schedule coadministered with the human papillomavirus type 16/18 AS04‐adjuvanted cervical cancer vaccine. Clinical Vaccine Immunology 2011;18(9):1510‐8. CENTRAL

Leung 2015 {published data only}

Leung TF, Liu AP, Lim FS, Thollot F, Oh HM, Lee BW, et al. Comparative immunogenicity and safety of human papillomavirus (HPV)‐16/18 AS04‐adjuvanted vaccine and HPV‐6/11/16/18 vaccine administered according to 2‐ and 3‐dose schedules in girls aged 9‐14 years: Results to month 12 from a randomized trial. Human Vaccines & Immunotherapeutics 2015;11(2164‐554X (Electronic), 2164‐5515 (Linking), 7):1689‐702. CENTRAL

Li 2012 {published data only}

Li R, Li Y, Radley D, Liu Y, Huang T, Sings HL. Safety and immunogenicity of a vaccine targeting human papillomavirus types 6, 11, 16 and 18: a randomized, double‐blind, placebo‐controlled trial in Chinese males and females. Vaccine 2012;30(28):4284‐91. CENTRAL

Lin 2014 {published data only}

Lin CJ, Zimmerman RK, Nowalk MP, Huang HH, Raviotta JM. Randomized controlled trial of two dosing schedules for human papillomavirus vaccination among college age males. Vaccine 2014;32(6):693‐9. CENTRAL

Lu 2011 {published data only}

Lu B, Kumar A, Castellsague X, Giuliano AR. Efficacy and safety of prophylactic vaccines against cervical HPV infection and diseases among women: a systematic review & meta‐analysis. BMC Infectious Disease 2011;11(1):13. CENTRAL

Luna 2013 {published data only}

Luna J, Plata M, Gonzalez M, Correa A, Maldonado I, Nossa C. Long‐term follow‐up observation of the safety, immunogenicity, and effectiveness of Gardasil in adult women. PLOS One 2013;8(12):e83431. CENTRAL

Malagon 2012 {published data only}

Malagon T, Drolet M, Boily MC, Franco EL, Jit M, Brisson J. Cross‐protective efficacy of two human papillomavirus vaccines: a systematic review and meta‐analysis. Lancet Infectious Diseases 2012;12(10):781‐9. CENTRAL

McCormack 2011 {published data only}

McCormack PL, Joura EA. Spotlight on quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine(Gardasil®) in the prevention of premalignant genital lesions, genital cancer, and genital warts in women. BioDrugs 2011;25(5):339‐43. CENTRAL

McKeage 2011 {published data only}

McKeage K, Romanowski B. Spotlight on AS04‐adjuvanted human papillomavirus (HPV) types 16 and 18 vaccine (Cervarix®). BioDrugs 2011;25(4):265‐9. CENTRAL

Money 2016 {published data only}

Money DM, Moses E, Blitz S, Vandriel SM, Lipsky N, Walmsley SL, et al. HIV viral suppression results in higher antibody responses in HIV‐positive women vaccinated with the quadrivalent human papillomavirus vaccine. Vaccine 2016;34(40):4799‐806. CENTRAL

Moreira 2011 {published data only}

Moreira ED, Palefsky JM, Giuliano AR, Goldstone S, Aranda C, Jessen H. Safety and reactogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 viral‐like‐particle vaccine in older adolescents and young adults. Human Vaccines & Immunotherapeutics 2011;7(7):768‐75. CENTRAL

Nakalembe 2015 {published data only}

Nakalembe M, Mirembe FM, Banura C. Vaccines against human papillomavirus in low and middle income countries: a review of safety, immunogenicity and efficacy. Infectious Agents and Cancer 2015;10(1750‐9378 (Electronic), 1750‐9378 (Linking)):17. CENTRAL

Nelson 2013 {published data only}

Nelson EA, Lam HS, Choi KC, Ho WCS, Fung LWE, Cheng FWT. A pilot randomized study to assess immunogenicity, reactogenicity, safety and tolerability of two human papillomavirus vaccines administered intramuscularly and intradermally to females aged 18‐26 years. Vaccine 2013;31(34):3452‐60. CENTRAL

Neuzil 2011 {published data only}

Neuzil KM, Canh DG, Thiem VD, Janmohamed A, Huong VM, Tang Y. Immunogenicity and reactogenicity of alternative schedules of HPV vaccine in Vietnam: a cluster randomized noninferiority trial. JAMA 2011;305(14):1424‐31. CENTRAL

Olsson 2009 {published data only}

Olsson SE, Kjaer SK, Sigurdsson K, Iversen OE, Hernandez‐Avila M, Wheeler CM, et al. Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection. Human Vaccines 2009;5(1554‐8619 (Electronic), 10):696‐704. CENTRAL

Palefsky 2011 {published data only}

Palefsky JM, Giuliano AR, Goldstone SE, Moreira ED, Aranda C, Jessen H. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. New England Journal of Medicine 2011;365(17):1576‐85. CENTRAL

Pedersen 2007 {published data only}

Pedersen C, Petaja T, Strauss G, Rumke HC, Poder A, Richardus JH, et al. Immunization of early adolescent females with human papillomavirus type 16 and 18 L1 virus‐like particle vaccine containing AS04 adjuvant. Journal of Adolescent Health 2007;40(6):564‐71. CENTRAL

Perez 2008 {published data only}

Perez G, Lazcano‐Ponce E, Hernandez‐Avila M, Garcia PJ, Munoz N, Villa LL. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus‐like‐particle vaccine in Latin American women. International Journal of Cancer 2008;122(6):1311‐8. CENTRAL

Petaja 2009 {published data only}

Petaja T, Keranen H, Karppa T, Kawa A, Lantela S, Siitari‐Mattila M. Immunogenicity and safety of human papillomavirus (HPV)‐16/18 AS04‐adjuvanted vaccine in healthy boys aged 10‐18 years. Journal of Adolescent Health 2009;44(1):33‐40. CENTRAL

Petaja 2011 {published data only}

Petaja T, Pedersen C, Poder A, Strauss G, Catteau G, Thomas F, et al. Long‐term persistence of systemic and mucosal immune response to HPV‐16/18 AS04‐adjuvanted vaccine in preteen/adolescent girls and young women. International Journal of Cancer 2011;129(9):2147‐57. CENTRAL

Poland 2005 {published data only}

Poland GA, Jacobson RM, Koutsky LA, Tamms GM, Railkar R, Smith JF. Immunogenicity and reactogenicity of a novel vaccine for human papillomavirus 16: a 2‐year randomized controlled clinical trial. Mayo Clinic Proceedings 2005;80(5):601‐10. CENTRAL

Puthanakit 2016 {published data only}

Puthanakit T, Huang LM, Chiu CH, Tang RB, Schwarz TF, Esposito S, et al. Randomized open trial comparing 2‐dose regimens of the human papillomavirus 16/18 AS04‐adjuvanted vaccine in girls aged 9‐14 years versus a 3‐dose regimen in women aged 15‐25 years. Journal of Infectious Diseases 2016;214(4):525‐36. CENTRAL

Ramanakumar 2016 {published data only}

Ramanakumar AV, Naud P, Roteli‐Martins CM, de Carvalho NS, de Borba PC, Teixeira JC, et al. Incidence and duration of type‐specific human papillomavirus infection in high‐risk HPV‐naive women: results from the control arm of a phase II HPV‐16/18 vaccine trial. BMJ Open. 2016;6(2044‐6055 (Electronic), 2044‐6055 (Linking), 8):e011371. CENTRAL

Read 2011 {published data only}

Read TR, Hocking JS, Chen MY, Donovan B, Bradshaw CS, Fairley CK. The near disappearance of genital warts in young women 4 years after commencing a national human papillomavirus (HPV) vaccination programme. Sexually Transmitted Infections 2011;87(7):544‐7. CENTRAL

Reisinger 2007 {published data only}

Reisinger KS, Block SL, Lazcano‐Ponce E, Samakoses R, Esser MT, Erick J, 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. Pediatric Infectious Disease Journal 2007;26(3):201‐9. CENTRAL

Reisinger 2010 {published data only}

Reisinger KS, Block SL, Collins‐Ogle M, Marchant C, Catlett M, Radley D, et al. Safety, tolerability, and immunogenicity of gardasil given concomitantly with Menactra and Adacel. Pediatrics 2010;125(6):1142‐51. CENTRAL

Romanowski 2016 {published data only}

Romanowski B, Schwarz TF, Ferguson L, Peters K, Dionne M, Behre U, et al. Sustained immunogenicity of the HPV‐16/18 AS04‐adjuvanted vaccine administered as a two‐dose schedule in adolescent girls: Five‐year clinical data and modeling predictions from a randomized study. Human Vaccines & Immunotherapeutics 2016;12(2164‐554X (Electronic), 2164‐5515 (Linking), 1):20‐9. CENTRAL

Rowhani‐Rahbar 2012 {published data only}

Rowhani‐Rahbar A, Alvarez FB, Bryan JT, Hughes JP, Hawes SE, Weiss NS. Evidence of immune memory 8.5 years following administration of a prophylactic human papillomavirus type 16 vaccine. Journal of Clinical Virology 2012;53(3):239‐43. CENTRAL

Safaeian 2013 {published data only}

Safaeian M, Kemp TJ, Pan DY, Porras C, Rodriguez AC, Schiffman M, et al. Cross‐protective vaccine efficacy of the bivalent HPV vaccine against HPV31 is associated with humoral immune responses: results from the Costa Rica Vaccine Trial. Human Vaccines & Immunotherapeutics 2013;9(7):1399‐406. CENTRAL

Schwarz 2008 {published data only}

Schwarz TF, Leo O. Immune response to human papillomavirus after prophylactic vaccination with AS04‐adjuvanted HPV‐16/18 vaccine: improving upon nature. Gynecologic Oncology 2008;110(3 Suppl 1):S1‐10. CENTRAL

Schwarz 2009 {published data only}

Schwarz TF, Spaczynski M, Schneider A, Wysocki J, Galaj A, Perona P. Immunogenicity and tolerability of an HPV‐16/18 AS04‐adjuvanted prophylactic cervical cancer vaccine in women aged 15‐55 years. Vaccine 2009;27(4):581‐7. CENTRAL

Schwarz 2010 {published data only}

Schwarz TF, Kocken M, Petaja T, Einstein MH, Spaczynski M, Louwers JA. Correlation between levels of human papillomavirus (HPV) 16 and 18 antibodies in serum and cervicovaginal secretions in girls and women vaccinated with the HPV‐16/18 AS04‐adjuvanted vaccine. Human Vaccine & Immunotherapeutics 2010;6(12):1054‐61. CENTRAL

Schwarz 2011 {published data only}

Schwarz TF, Spaczynski M, Schneider A, Wysocki J, Galaj A, Schulze K. Persistence of immune response to HPV‐16/18 AS04‐adjuvanted cervical cancer vaccine in women aged 15‐55 years. Human Vaccines & Immunotherapeutics 2011;7(9):958‐65. CENTRAL

Schwarz 2014 {published data only}

Schwarz TF, Huang LM, Lin TY, Wittermann C, Panzer F, Valencia A, et al. Long‐term immunogenicity and safety of the HPV‐16/18 AS04‐adjuvanted vaccine in 10‐ to 14‐year‐old girls: open 6‐year follow‐up of an initial observer‐blinded, randomized trial. Pediatric Infectious Disease Journal 2014;33(1532‐0987 (Electronic), 0891‐3668 (Linking), 12):1255‐61. CENTRAL

Sengupta 2011 {published data only}

Sengupta A, Shenoi A, Sarojini NB, Madhavi Y. Human papillomavirus vaccine trials in India. Lancet 2011;377(9767):719. CENTRAL

Singhal 2011 {published data only}

Singhal SC. Human papilloma virus vaccines and current controversy. Indian Pediatrics 2011;48(3):248‐9. CENTRAL

Skinner 2016 {published data only}

Skinner SR, Apter D, De Carvalho N, Harper DM, Konno R, Paavonen J, et al. Human papillomavirus (HPV)‐16/18 AS04‐adjuvanted vaccine for the prevention of cervical cancer and HPV‐related diseases. Expert Review of Vaccines 2016;15(1744‐8395 (Electronic), 1476‐0584 (Linking), 3):367‐87. CENTRAL

Smith‐McCune 2010 {published data only}

Smith‐McCune K. Quadrivalent HPV vaccine administered to women who became pregnant during trials did not appear to adversely affect pregnancy outcome; however, use during pregnancy is not recommended. Evidence Based Medicine 2010;15(3):80‐1. CENTRAL

Srinivasan 2011 {published data only}

Srinivasan S. HPV vaccine trials and sleeping watchdogs. Indian Journal of Medical Ethics 2011;8(2):73‐4. CENTRAL

Toft 2014 {published data only}

Toft L, Storgaard M, Muller M, Sehr P, Bonde J, Tolstrup M, et al. Comparison of the immunogenicity and reactogenicity of Cervarix and Gardasil human papillomavirus vaccines in HIV‐infected adults: a randomized, double‐blind clinical trial. Journal of Infectious Diseases 2014;209(8):1165‐73. CENTRAL

Van Klooster 2011 {published data only}

Klooster TM, Kemmeren JM, van der Maas NA, de Melker HE. Reported adverse events in girls aged 13‐16 years after vaccination with the human papillomavirus (HPV)‐16/18 vaccine in the Netherlands. Vaccine 2011;29(28):4601‐7. CENTRAL

Vesikari 2010 {published data only}

Vesikari T, Van Damme P, Lindblad N, Pfletschinger U, Radley D, Ryan D, et al. An open‐label, randomized, multicenter study of the safety, tolerability, and immunogenicity of quadrivalent human papillomavirus (types 6/11/16/18) vaccine given concomitantly with diphtheria, tetanus, pertussis, and poliomyelitis vaccine in healthy adolescents 11 to 17 years of age. Pediatric Infectious Disease Journal 2010;29(4):314‐8. CENTRAL

Wheeler 2008 {published data only}

Wheeler CM, Bautista OM, Tomassini JE, Nelson M, Sattler CA, Barr E. Safety and immunogenicity of co‐administered quadrivalent human papillomavirus (HPV)‐6/11/16/18 L1 virus‐like particle (VLP) and hepatitis B (HBV) vaccines. Vaccine 2008;26(0264‐410X (Print), 5):686‐96. CENTRAL

Wheeler 2011 {published data only}

Wheeler CM, Harvey BM, Pichichero ME, Simon MW, Combs SP, Blatter MM. Immunogenicity and safety of human papillomavirus‐16/18 AS04‐adjuvanted vaccine coadministered with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine and/or meningococcal conjugate vaccine to healthy girls 11 to 18 years of age: results from a randomized open trial. Pediatric Infectious Disease Journal 2011;30(12):e225‐34. CENTRAL

Yancey 2010 {published data only}

Yancey AM, Pitlick JM, Forinash AB. The prophylactic role for the human papillomavirus quadrivalent vaccine in males. Annals of Pharmacotherapy 2010;44(7‐8):1314‐8. CENTRAL

Zhu 2011 {published data only}

Zhu FC, Li CG, Pan HX, Zhang YJ, Bi D, Tang HW. Safety and immunogenicity of human papillomavirus‐16/18 AS04‐adjuvanted vaccine in healthy Chinese females aged 15 to 45 years: a phase I trial. Chinese Journal of Cancer 2011;30(8):559‐64. CENTRAL

Zimmerman 2010 {published data only}

Zimmerman RK, Nowalk MP, Lin CJ, Fox DE, Ko FS, Wettick E. Randomized trial of an alternate human papillomavirus vaccine administration schedule in college‐aged women. Journal of Women's Health 2010;19(8):1441‐7. CENTRAL

Andrews 2017

Andrews N, Stowe J, Miller E. No increased risk of Guillain‐Barré syndrome after human papilloma virus vaccine: A self‐controlled case‐series study in England. Vaccine 2017;35(1):1729‐32.

ANSM/SANTE 2015

ANSM/SANTE. Risk of auto‐immune diseases after vaccination against HPV: a pharmacoepidemiological study [Vaccins anti‐HPV et risque de maladies auto‐immunes : étude pharmacoépidémiologique]. http://ansm.sante.fr/S‐informer/Points‐d‐information‐Points‐d‐information/Vaccination‐contre‐les‐infections‐a‐HPV‐et‐risque‐de‐maladies‐auto‐immunes‐une‐etude‐Cnamts‐ANSM‐rassurante‐Point‐d‐information September 2015;Website accessed 10‐12‐15:1‐91.

Arbyn 2007

Arbyn M, Dillner J. Review of current knowledge on HPV vaccination: an appendix to the European Guidelines for Quality Assurance in Cervical Cancer Screening. Journal of Clinical Virology 2007;38(3):189‐97.

Arbyn 2009

Arbyn M, Rebolj M, de Kok IM, Becker N, O'Reilly M, Andrae B. The challenges for organising cervical screening programmes in the 15 old member states of the European Union. European Journal of Cancer 2009;45(15):2671‐8.

Arbyn 2010

Arbyn M, Van Veen EB, Andersson K, Bogers J, Boulet G, Bergeron C, et al. Cervical cytology biobanking in Europe. Internatonal Journal of Biological Markers 2010;25(3):117‐25.

Arbyn 2011

Arbyn M, Castellsagué X, de Sanjosé S, Bruni L, Saraiya M, Bray F, et al. Worldwide burden of cervical cancer in 2008. Annals of Oncology 2011;22:2675‐86.

Arbyn 2012

Arbyn M, Ronco G, Anttila A, Meijer CJ, Poljak M, Ogilvie G, et al. Evidence regarding HPV testing in secondary prevention of cervical cancer. Vaccine 2012;30(Suppl 5):F88‐F99.

Arbyn 2014

Arbyn M, Tommasino M, Depuydt C, Dillner J. Are 20 human papillomavirus types causing cervical cancer?. Journal of Pathology 2014;234(4):431‐5.

Arbyn 2016

Arbyn M, Vanden Broeck D, Benoy I, Bogers J, Depuydt C, Praet M, et al. Surveillance of effects of HPV vaccination in Belgium. Cancer Epidemiology 2016;41:152‐8.

Arbyn 2017

Arbyn M, Redman CW, Verdoodt F, Kyrgiou M, Tzafetas M, Ghaem‐Maghami S, et al. Incomplete excision of cervical pre‐cancer as predictor of treatment failure: a systematic review and meta‐analysis. Lancet Oncology 2017;18(12):1665‐79.

Arnheim‐Dahlstrom 2013

Arnheim‐Dahlstrom L, Pasternak B, Svanstrom H, Sparen P, Hviid A. Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study. BMJ 2013;347:f5906.

Baldur‐Felskov 2014

Baldur‐Felskov B, Dehlendorff C, Munk C, Kjaer SK. Early impact of human papillomavirus vaccination on cervical neoplasia‐nationwide follow‐up of young Danish women. Journal of the National Cancer Institute 2014;106(3):dtj460.

Baril 2015

Baril L, Rosillon D, Willame C, Angelo MG, Zima J, van den Bosch JH, et al. Risk of spontaneous abortion and other pregnancy outcomes in 15‐25 year old women exposed to human papillomavirus‐16/18 AS04‐adjuvanted vaccine in the United Kingdom. Vaccine 2015;33:6884‐91.

Bhatla 2010

Bhatla N, Suri V, Basu P, Shastri S, Datta SK, Bi D, et al. Immunogenicity and safety of human papillomavirus‐16/18 AS04‐adjuvanted cervical cancer vaccine in healthy Indian women. Journal of Obstetrics and Gynaecology Research 2010;36(1):123‐32.

Bosch 2002

Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV. The causal relation between human papillomavirus and cervical cancer. Journal of Clinical Pathology 2002;55:244‐65.

Bosch 2008

Bosch FX, Burchell AN, Schiffman M, Giuliano AR, de Sanjose S, Bruni L, et al. Epidemiology and natural history of human papillomavirus infections and type‐specific implications in cervical neoplasia. Vaccine 2008;26(Suppl 10):K1‐K16.

Bosch 2016

Bosch FX, Robles C, Diaz M, Arbyn M, Baussano I, Clavel C, et al. HPV‐FASTER: broadening the scope for prevention of HPV‐related cancer. Nature Reviews, Clinical Oncology 2016;13:119‐32.

Bouvard 2009

Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F. A review of human carcinogens ‐ Part B: biological agents. Lancet Oncology 2009;10(4):321‐2.

Bray 2005

Bray F, Carstensen B, Moller H, Zappa M, Zakelj MP, Lawrence G. Incidence trends of adenocarcinoma of the cervix in 13 European countries. Cancer Epidemiology, Biomarkers and Prevention 2005;14(9):2191‐9.

Bray 2005a

Bray F, Loos AH, McCarron P, Weiderpass E, Arbyn M, Moller H. Trends in cervical squamous cell carcinoma incidence in 13 European countries: changing risk and the effects of screening. Cancer Epidemiology, Biomarkers and Prevention 2005;14(3):677‐86.

Breitburd 1995

Breitburd F, Kirnbauer R, Hubbert NL, Nonnenmacher B, Trin‐Dinh‐Desmarquet C, Orth G. Immunization with virus like particles from cottontail rabbit papillomavirus (CRPV) can protect against experimental CRPV infection. Journal of Virology 1995;69(6):3959‐63.

Brotherton 2011

Brotherton JM, Fridman M, May CL, Chappell G, Saville AM, Gertig DM. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study. Lancet 2011;377(1474‐547X (Electronic), 0140‐6736 (Linking), 9783):2085‐92.

Brotherton 2015

Brotherton JML, Malloy M, Budd AC, Saville M, Drennan KT, Gertig DM. Effectiveness of less than three doses of quadrivalent human papillomavirus vaccine against cervical intraepithelial neoplasia when administered using a standard dose spacing schedule: Observational cohort of young women in Australia. Papillomavirus Research 2015;1(1):59‐73.

Brown 2001

Brown DR, Bryan JT, Schroeder JM, Robinson TS, Fife KH, Wheeler CM. 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. Journal of Infectious Diseases 2001;184(9):1183‐6.

Bzhalava 2013

Bzhalava D, Guan P, Franceschi S, Dillner J, Clifford G. A systematic review of the prevalence of mucosal and cutaneous human papillomavirus types. Virology 2013;445(1‐2):224‐31.

Cancer Research UK 2018

Cancer Researck UK. Cervical cancer incidence statistics. http://www.cancerresearchuk.org/health‐professional/cancer‐statistics/statistics‐by‐cancer‐type/cervical‐cancer/incidenceAccessed Jan 2018.

Castellsagué 2006

Castellsagué X, Diaz M, De Sanjose S, Munoz N, Herrero R, Franceschi S. Worldwide human papillomavirus etiology of cervical adenocarcinoma and its cofactors: implications for screening and prevention. Journal of the National Cancer Institute 2006;98(1460‐2105 (Electronic), 5):303‐15.

Castellsagué 2011

Castellsagué X, Munoz N, Pitisuttithum P, Ferris D, Monsonego J, Ault K. End‐of‐study safety, immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine in adult women 24‐45 years of age. British Journal of Cancer 2011;105(1):28‐37.

Cates 2015

Cates M, Karner C. Clinical importance cannot be ruled out using mean difference alone. BMJ 2015;351:h5496.

CDC 2015

Sukumaran L, Advisory Committee on Immunization Practices ‐ Immunization Safety Office ‐ Centers for Disease Control and Prevention (CDC, Atlanta). Human Papillomavirus Vaccine Safety Update. http://www.cdc.gov/vaccines/acip/meetings/downloads/slides‐2015‐10/hpv‐04‐sukumaran.pdf 21/10/2015.

Chao 2012

Chao C, Klein NP, Velicer CM, Sy LS, Slezak JM, Takhar H, et al. Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine. Journal of Internal Medicine 2012;271(2):193‐203.

Cogliano 2005

Cogliano V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F. Carcinogenicity of human papillomaviruses. Lancet Oncology 2005;6(1470‐2045, 4):204.

Crowe 2014

Crowe E, Pandeya N, Brotherton JM, Dobson AJ, Kisely S, Lambert SB, et al. Effectiveness of quadrivalent human papillomavirus vaccine for the prevention of cervical abnormalities: case‐control study nested within a population based screening programme in Australia. BMJ 2014;348(g1458):1‐10.

Cuschieri 2016

Cuschieri K, Kavanagh K, Moore C, Bhatia R, Love J, Pollock KG. mpact of partial bivalent HPV vaccination on vaccine‐type infection: a population‐based analysis. British Journal of Cancer 2016;114(11):1261‐4.

Dana 2009

Dana A, Buchanan KM, Goss MA, Seminack MM, Shields KE, Korn S. Pregnancy outcomes from the pregnancy registry of a human papillomavirus type 6/11/16/18 vaccine. Obstetrics and Gynaecology 2009;114(1873‐233X (Electronic), 6):1170‐8.

De Carvalho 2010

De Carvalho N, Teixeira J, Roteli‐Martins CM, Naud P, De Borba P, Zahaf T. Sustained efficacy and immunogenicity of the HPV‐16/18 AS04‐adjuvanted vaccine up to 7.3 years in young adult women. Vaccine 2010;28(38):6247‐55.

de Sanjose 2007

de Sanjose S, Diaz M, Castellsagué X, Clifford G, Bruni L, Munoz N. Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta‐analysis. Lancet Infectious Diseases 2007;7(7):453‐9.

de Sanjose 2010

de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross‐sectional worldwide study. Lancet Oncology 2010;11(11):1048‐56.

Deeks 2001

Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity and combining results from several studies in meta‐analysis. In: Egger M, Davey Smith G, Altman DG (eds).  Systematic Reviews in Health Care: Meta‐Analysis in Context (2nd edition). London: BMJ Publication Group, 2001.

Delere 2014

Delere Y, Wichmann O, Klug SJ, van der Sande M, Terhardt M, Zepp F. The efficacy and duration of vaccine protection against human papillomavirus: a systematic review and meta‐analysis. Deutsches Arzteblatt International 2014;111(35‐36):584‐91.

DerSimonian 1986

DerSimonian R, Laird N. Meta‐analysis in clinical trials. Controlled Clinical Trials 1986;7:177‐88.

Dillner 2011

Dillner J, Arbyn M, Unger E, Dillner L. Monitoring of human papillomavirus vaccination. Clinical & Experimental Immunology 2011;163(1):17‐25.

Donegan 2013

Donegan K, Beau‐Lejdstrom R, King B, Seabroke S, Thomson A, Bryan P. Bivalent human papillomavirus vaccine and the risk of fatigue syndromes in girls in the UK. Vaccine 2013;31(43):4961‐7.

Donovan 2011

Donovan B, Franklin N, Guy R, Grulich AE, Regan DG, Ali H, et al. Quadrivalent human papillomavirus vaccination and trends in genital warts in Australia: analysis of national sentinel surveillance data. Lancet Infectious Diseases 2011;11(1474‐4457 (Electronic), 1473‐3099 (Linking), 1):39‐44.

Drolet 2015

Drolet M, Benard E, Boily MC, Ali H, Baandrup L, Bauer H, et al. Population‐level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta‐analysis. Lancet Infectious Diseases 2015;15(5):565‐80.

EMA 2016

European Medicines Agency. HPV vaccines: EMA confirms evidence does not support that they cause CRPS or POTS. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/HPV_vaccines_20/European_Commission_final_decision/WC500196773.pdf 16/01/2016.

EMEA 2014a

European Medicines Agency. EMEA/H/C/000721‐Cervarix‐EPAR summary for the public 2014. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_‐_Summary_for_the_public/human/000721/WC500024634.pdf. Februrary 2014;Accessed 10‐12‐15:1‐3.

EMEA 2014b

European Medicines Agency. EMEA/H/C/000703‐Gardasil‐EPAR summary for the public 2014. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_‐_Summary_for_the_public/human/000703/WC500021146.pdf August 2014;Accessed 10‐12‐15:1‐4.

EMEA 2015

EMEA. Review concludes evidence does not support that HPV vaccines cause CRPS or POTS. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2015/11/news_detail_002429.jsp&mid=WC0b01ac058004d5c1 05/11/2015.

Ferlay 2013

Ferlay J, Steliarova‐Foucher E, Lortet‐Tieulent J, Rosso S, Coebergh JW, Comber H, et al. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012. European Journal of Cancer 2013;49(6):1374‐403.

Ferlay 2015

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer 2015;136(5):E359‐96.

Forman 2012

Forman D, de Martel C, Lacey CJ, Soerjomataram I, Lortet‐Tieulent J, Bruni L, et al. Global burden of human papillomavirus and related diseases. Vaccine 2012;30 Suppl 5:F12‐23.

Frazer 2004

Frazer IH. Prevention of cervical cancer through papillomavirus vaccination. Nature Reviews Immunology 2004;4:46‐55.

FUTURE‐II 2007

The FUTURE II study group. Quadrivalent vaccine against human papillomavirus to prevent high‐grade cervical lesions. New England Journal of Medicine 2007;356(19):1915‐27.

Galloway 2003

Galloway DA. Papillomavirus vaccines in clinical trials. Lancet 2003;3:469‐75.

Garcia‐Sicilia 2010

Garcia‐Sicilia J, Schwarz TF, Carmona A, Peters K, Malkin JE, Tran PM. Immunogenicity and safety of human papillomavirus‐16/18 AS04‐adjuvanted cervical cancer vaccine coadministered with combined diphtheria‐tetanus‐acellular pertussis‐inactivated poliovirus vaccine to girls and young women. Journal of Adolescent Health 2010;46(2):142‐51.

Garland 2007

Garland SM, Hernandez‐Avila M, Wheeler CM, Perez G, Harper DM, Leodolter S. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. New England Journal of Medicine 2007;356(19):1928‐43.

Garland 2007a

Garland SM, Steben M, Hernandez‐Avila M, Koutsky LA, Wheeler CM, Perez G, et al. An evaluation of non‐inferiority in antibody response to human papillomavirus (HPV) 16 in subjects vaccinated with monovalent (HPV 16) and quadrivalent (HPV 6, 11, 16, 18) L1 virus like particle vaccines. Clinical and Vaccine Immunology 2007;10(1128):1‐17.

Garland 2009

Garland SM, Ault KA, Gall SA, Paavonen J, Sings HL, Ciprero KL, et al. Pregnancy and infant outcomes in the clinical trials of a human papillomavirus type 6/11/16/18 Vaccine: a combined analysis of five randomized controlled trials. Obstetrics and Gynecology 2009;114(6):1179‐88.

Gee 2017

Gee J, Sukumaran L, Weintraub E. Risk of Guillain‐Barré syndrome following quadrivalent human papillomavirus vaccine in the Vaccine Safety Datalink. Vaccine 2017;35(43):5756‐8.

Gertig 2013

Gertig DM, Brotherton JM, Budd AC, Drennan K, Chappell G, Saville AM. mpact of a population‐based HPV vaccination program on cervical abnormalities: a data linkage study. BMC Medicine 2013;11:227.

Ghim 2000

Ghim S, Newsome J, Bell J, Sundberg JP, Schlegel R, Jenson AB. Spontaneously regressing oral papillomas induce systemic antibodies that neutralize canine oral papillomavirus. Experimental and Molecular Pathology 2000;68(3):147‐51.

Giannini 2006

Giannini SL, Hanon E, Moris P, Van Mechelen M, Morel S, Dessy F, et al. Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only. Vaccine 2006;24:5937‐49.

Goss 2015

Goss MA, Lievano F, Buchanan KM, Seminack MM, Cunningham ML, Dana A. Final report on exposure during pregnancy from a pregnancy registry for quadrivalent human papillomavirus vaccine. Vaccine 2015;33:3422‐8.

Grimaldi‐Bensouda 2014

Grimaldi‐Bensouda L, Guillemot D, Godeau B, Benichou J, Lebrun‐Frenay C, Papeix C, et al. Autoimmune disorders and quadrivalent human papillomavirus vaccination of young female subjects. Journal of Internal Medicine 2014;275(4):398‐408.

Grimaldi‐Bensouda 2017

Grimaldi‐Bensouda L, Rossignol M, Kone‐Paut I, Krivitzky A, Lebrun‐Frenay C, Clet J, et al. Risk of autoimmune diseases and human papilloma virus (HPV) vaccines: Six years of case‐referent surveillance. Journal of Autoimmunity 2017;79:84‐90.

Guyatt 2008

Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck‐Ytter Y, Alonso‐Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650):924‐6.

Harbord 2009

Harbord RM, Harris RJ, Sterne JAC. Updated tests for small‐study effects in meta‐analyses. Stata Journal 2009;9(2):197‐210.

Harper 2004

Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A. 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(9447):1757‐65.

Harper 2006

Harper DM, Franco EL, Wheeler CM, Moscicki AB, Romanowski B, Roteli‐Martins CM. 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(9518):1247‐55.

Harper 2009

Harper DM. Currently approved prophylactic HPV vaccines. Expert Review of Vaccines 2009;8(12):1663‐79.

Herrero 2011

Herrero R, Wacholder S, Rodriguez AC, Solomon D, Gonzalez P, Kreimer AR. Prevention of persistent human papillomavirus infection by an HPV16/18 vaccine: A community‐based randomized clinical trial in guanacaste, Costa Rica. Cancer Discovery 2011;1(5):408‐19.

Higgins 2003

Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ 2003;327:557‐60.

Higgins 2011a

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.

Higgins 2011b

Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. Cochrane Bias Methods Group, Cochrane Statistical Methods Group. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928.

Hildesheim 2014

Hildesheim A, Wacholder S, Catteau G, Struyf F, Dubin G, Herrero R. Efficacy of the HPV‐16/18 vaccine: Final according to protocol results from the blinded phase of the randomized Costa Rica HPV‐16/18 vaccine trial. Vaccine 2014;32(39):5087‐97.

Ho 1998

Ho GYF, Bierman R, Beardsley I, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. New England Journal of Medicine 1998;338:423‐8.

Hofstetter 2016

Hofstetter AM, Ompad DC, Stockwell MS, Rosenthal SL, Soren K. Human papillomavirus vaccination and cervical cytology outcomes among urban low‐income minority females. JAMA Pediatrics 2016;170(5):445‐52.

Huh 2017

Huh WK, Joura EA, Giuliano AR, Iversen OE, de Andrade RP, Ault KA, et al. Final efficacy, immunogenicity, and safety analyses of a nine‐valent human papillomavirus vaccine in women aged 16‐26 years: a randomised, double‐blind trial. Lancet 2017;390(10108):2043‐59.

IARC 2005

IARC Expert team cervical cancer screening, (Day N, Hakama M, Arbyn M). Cervix Cancer Screening. IARC Handbooks of Cancer Prevention. Vol. 10, Lyon: IARC Press, 2005:1‐302.

IARC 2007

IARC Monograph Working Group on Carcinogenesis (Coglinano V, Baan R, Straif K, Secretan B, El Ghissasi F, Zur Hausen H, et al)  . In: Cogliano V, Baan R, Straif K, Grosse Y, Secretan B, Ghissassi F editor(s). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol 90: Human Papillomaviruses. Vol. 90, Lyon: IARC Press, 2007:1‐670.

IARC 2013

IARC HPV Working Group. Primary end‐points for prophylactic HPV vaccine trials. IARC Working Group Reports. Vol. 7, Lyon, France: WHO Press, 2013:1‐120.

Iftner 2003

Iftner T, Villa LL. Chapter 12: Human papillomavirus technologies. Journal of National Cancer Institute Monographs 2003;31:80‐8.

Initiative 2009

Initiative for Vaccine Research of the Department of Immunization VaB. Human Papillomavirus (HPV) Vaccine Background Paper. World Health Organization (WHO). Geneva, 2009:1‐249.

Jordan 2008

Jordan J, Arbyn M, Martin‐Hirsch P, Schenck U, Baldauf J‐J, Da Silva D, et al. European guidelines for quality assurance in cervical cancer screening: recommendations for clinical management of abnormal cervical cytology, part 1. Cytopathology 2008;19(6):342‐54.

Jordan 2009

Jordan J, Martin‐Hirsch P, Arbyn M, Schenck U, Baldauf J‐J, Da Silva D, et al. European guidelines for management of abnormal cervical cytology, Part 2. Cytopathology 2009;20(1):5‐16.

Joura 2015

Joura EA, Giuliano AR, Iversen OE, Bouchard C, Mao C, Mehlsen J, et al. A 9‐Valent HPV Vaccine against Infection and Intraepithelial Neoplasia in Women. New England Journal of Medicine 2015;372(8):711‐23.

Kahn 2009

Kahn JA. HPV vaccination for the prevention of cervical intraepithelial neoplasia. New England Journal of Medicine 2009;361(3):271‐8.

Kang 2008

Kang S, Kim KH, Kim YT, Kim YT, Kim JH, Song YS. Safety and immunogenicity of a vaccine targeting human papillomavirus types 6, 11, 16 and 18: a randomized, placebo‐controlled trial in 176 Korean subjects. International Journal of Gynecological Cancer 2008;18(5):1013‐9.

Kavanagh 2014

Kavanagh K, Pollock KG, Potts A, Love J, Cuschieri K, Cubie H, et al. Introduction and sustained high coverage of the HPV bivalent vaccine leads to a reduction in prevalence of HPV 16/18 and closely related HPV types. British Journal of Cancer 2014;110(11):2804‐11.

Kavanagh 2017

Kavanagh K, Pollock KG, Cuschieri K, Palmer T, Cameron RL, Watt C, et al. Changes in the prevalence of human papillomavirus following a national bivalent human papillomavirus vaccination programme in Scotland: a 7‐year cross‐sectional study. Lancet Infectious Diseases 2017;17(12):1293‐302.

Kim 2010

Kim YJ, Kim KT, Kim JH, Cha SD, Kim JW, Bae DS, et al. Vaccination with a human papillomavirus (HPV)‐16/18 AS04‐adjuvanted cervical cancer vaccine in Korean girls aged 10‐14 years. Journal of Korean Medical Science 2010;25(8):1197‐204.

Kim 2011

Kim SC, Song YS, Kim YT, Kim YT, Ryu KS, Gunapalaiah B. Human papillomavirus 16/18 AS04‐adjuvanted cervical cancer vaccine: immunogenicity and safety in 15‐25 years old healthy Korean women. Journal of Gynecologic Oncology 2011;22(2):67‐75.

Konno 2010

Konno R, Tamura S, Dobbelaere K, Yoshikawa H. Efficacy of human papillomavirus 16/18 AS04‐adjuvanted vaccine in Japanese women aged 20 to 25 years: interim analysis of a phase 2 double‐blind, randomized, controlled trial. International Journal of Gynecological Cancer 2010;20(3):404‐10.

Konno 2010a

Konno R, Tamura S, Dobbelaere K, Yoshikawa H. Efficacy of human papillomavirus type 16/18 AS04‐adjuvanted vaccine in Japanese women aged 20 to 25 years: final analysis of a phase 2 double‐blind, randomized controlled trial. International Journal of Gynecological Cancer 2010;20(5):847‐55.

Konno 2014

Konno R, Yoshikawa H, Okutani M, Quint W, Suryakiran V, Lin L, et al. Efficacy of the human papillomavirus (HPV)‐16/18 AS04‐adjuvanted vaccine against cervical intraepithelial neoplasia and cervical infection in young Japanese women. Human Vaccines & Immunotherapeutics 2014;10(7):1781‐94.

Koutsky 2002

Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB. A controlled trial of a human papillomavirus type 16 vaccine. New England Journal of Medicine 2002;347:1645‐51.

Koutsky 2006

Koutsky LA, Harper DM. Chapter 13: Current findings from prophylactic HPV vaccine trials. Vaccine 2006;24(Suppl 3):114‐21.

Kreimer 2011

Kreimer AR, Rodriguez AC, Hildesheim A, Herrero R, Porras C, Schiffman M, et al. Proof‐of‐principle evaluation of the efficacy of fewer than three doses of a bivalent HPV16/18 vaccine. Journal of the National Cancer Institute 2011;103(19):1444‐51.

Kreimer 2015b

Kreimer AR, Sherman ME, Sahasrabuddhe VV, Safaeian M. The case for conducting a randomized clinical trial to assess the efficacy of a single dose of prophylactic HPV vaccines among adolescents. Journal of the National Cancer Institute 2015;107(3):dju436.

Kuhs 2014

Kuhs KA, Porras C, Schiller JT, Rodriguez AC, Schiffman M, Gonzalez P. Effect of different human papillomavirus serological and DNA criteria on vaccine efficacy estimates. American Journal of Epidemiology 2014;180(6):599‐607.

Kyrgiou 2017

Kyrgiou M, Athanasiou A, Kalliala IEJ, Paraskevaidi M, Mitra A, Martin‐Hirsch PPL, et al. Obstetric outcomes after conservative treatment for cervical intraepithelial lesions and early invasive disease. Cochrane Database of Systematic Reviews 2017, Issue 11. [DOI: 10.1002/14651858.CD012847]

Lacey 2006

Lacey CJ, Lowndes CM, Shah KV. Chapter 4: Burden and management of non‐cancerous HPV‐related conditions: HPV‐6/11 disease. Vaccine 2006;24(0264‐410X (Print), Suppl 3):35‐41.

Larson 2011

Larson HJ, Cooper LZ, Eskola J, Katz SL, Ratzan S. Addressing the vaccine confidence gap. Lancet 2011;378(9790):526‐35.

Lehtinen 2006

Lehtinen M, Apter D, Dubin G, Kosunen E, Isaksson R, Korpivaara EL. Enrolment of 22,000 adolescent women to cancer registry follow‐up for long‐term human papillomavirus vaccine efficacy: guarding against guessing. International Journal of STD & AIDS 2006;17(0956‐4624 (Print), 8):517‐21.

Lehtinen 2012

Lehtinen M, Paavonen J, Wheeler CM, Jaisamrarn U, Garland S, Castellsagué X. Overall efficacy of HPV‐16/18 ASO4‐adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4‐year end‐of‐study analysis of the randomised, double‐blind PATRICIA trial. Lancet Oncology 2012;13(1):89‐99.

Lehtinen 2013

Lehtinen M, Dillner J. Clinical trials of human papillomavirus vaccines and beyond. Nature Reviews Clinical Oncology 2013;10(7):400‐10.

Leval 2013

Leval A, Herweijer E, Ploner A, Eloranta S, Fridman Simard J, Dillner J, et al. Quadrivalent human papillomavirus vaccine effectiveness: a Swedish national cohort study. Journal of the National Cancer Institute 2013;105(7):469‐74.

Lim 2014

Lim BK, Ng KY, Omar J, Omar SZ, Gunapalaiah B, Teoh YL, et al. Immunogenicity and safety of the AS04‐adjuvanted human papillomavirus‐16/18 cervical cancer vaccine in Malaysian women aged 18‐35 years: a randomized controlled trial. Medical Journal of Malaysia 2014;69(0300‐5283 (Print), 0300‐5283 (Linking), 1):2‐8.

Lipkind 2017

Lipkind HS, Vazquez‐Benitez G, Nordin JD, Romitti PA, Naleway AL, Klein NP, et al. Maternal and infant outcomes after human papillomavirus vaccination in the periconceptional period or during pregnancy. Obstetrics and Gynecology 2017;130(3):599‐608.

Luxembourg 2015

Luxembourg A, Brown D, Bouchard C, Giuliano AR, Iversen OE, Joura EA, et al. Phase II studies to select the formulation of a multivalent HPV L1 virus‐like particle (VLP) vaccine. Human Vaccines & Immunotherapeutics 2015;11(6):1313‐22.

Mao 2006

Mao C, Koutsky LA, Ault KA, Wheeler CM, Brown DR, Wiley DJ. Efficacy of human papillomavirus‐16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstetrics and Gynecology 2006;107(1):18‐27.

Markowitz 2013

Markowitz LE, Hariri S, Lin C, Dunne EF, Steinau M, McQuillan G, et al. Reduction in in human papillomavirus (HPV) prevalence among young women following HPVvaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003‐2010. Journal of Infectious Diseases 2013;208(3):385‐93.

Martin‐Hirsch 2013

Martin‐Hirsch PP, Paraskevaidis E, Bryant A, Dickinson HO. Surgery for cervical intraepithelial neoplasia. Cochrane Database of Systematic Reviews 2013, Issue 12. [DOI: 10.1002/14651858.CD001318.pub3]

McCredie 2008

McCredie MR, Sharples KJ, Paul C, Baranyai J, Medley G, Jones RW. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncology 2008;9(5):425‐34.

Medeiros 2009

Medeiros LR, Rosa DD, Da Rosa MI, Bozzetti MC, Zanini RR. Efficacy of human papillomavirus vaccines: a systematic quantitative review. International Journal of Gynecological Cancer 2009;19(7):1166‐76.

Medina 2010

Medina DM, Valencia A, de Velasquez A, Huang LM, Prymula R, Garcia‐Sicilia J. Safety and immunogenicity of the HPV‐16/18 AS04‐adjuvanted vaccine: a randomized, controlled trial in adolescent girls. Journal of Adolescent Health 2010;46(1879‐1972 (Electronic), 1054‐139X (Linking), 5):414‐21.

Merckx 2015

Merckx M, Vanden Broeck D, Benoy I, Depuydt C, Weyers S, Arbyn M. Early effects of human papillomavirus vaccination in Belgium. European Journal of Cancer Prevention 2015;24(4):340‐2.

Molbak 2016

Molbak K, Hansen ND, Valentiner‐Branth P. Pre‐vaccination care‐seeking in females reporting severe adverse reactions to HPV vaccine. A registry based case‐control study. PLOS One 2016;11(9):e0162520.

Mugo 2015

Mugo N, Ansah NA, Marino D, Saah A, Garner EIO. Evaluation of safety and immunogenicity of a quadrivalent human papillomavirus vaccine in healthy females between 9 and 26 years of age in Sub‐Saharan Africa. Human Vaccines & Immunotherapeutics 2015;11(6):1323‐30.

Munoz 2004

Munoz N, Bosch FX, Castellsague X, Diaz M, De Sanjose S, Hammouda D. Against which human papillomavirus types shall we vaccinate and screen? The international perspective. International Journal of Cancer 2004;111:278‐85.

Munoz 2009

Munoz N, Manalastas R, Pitisuttithum P, Tresukosol D, Monsonego J, Ault K. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24‐45 years: a randomised, double‐blind trial. Lancet 2009;373(9679):1949‐57.

Munoz 2010

Munoz N, Kjaer SK, Sigurdsson K, Iversen OE, Hernandez‐Avila M, Wheeler CM. Impact of human papillomavirus (HPV)‐6/11/16/18 vaccine on all HPV‐associated genital diseases in young women. Journal of the National Cancer Institute 2010;102(5):325‐39.

Naleway 2016

Naleway AL, Crane B, Smith N, Daley MF, Donahue J, Gee J, et al. Absence of venous thromboembolism risk following quadrivalent human papillomavirus vaccination, Vaccine Safety Datalink, 2008‐2011. Vaccine 2016;34(1):167‐71.

Naud 2014

Naud PS, Roteli‐Martins CM, De Carvalho NS, Teixeira JC, de Borba PC, Sanchez N, et al. Sustained efficacy, immunogenicity, and safety of the HPV‐16/18 AS04‐adjuvanted vaccine: Final analysis of a long‐term follow‐up study up to 9.4 years post‐vaccination. Human Vaccines & Immunotherapeutics 2014;10(8):2147‐62.

Ngan 2010

Ngan HY, Cheung AN, Tam KF, Chan KK, Tang HW, Bi D, et al. Human papillomavirus‐16/18 AS04‐adjuvanted cervical cancer vaccine: immunogenicity and safety in healthy Chinese women from Hong Kong. Hong Kong Medical Journal 2010;16(1024‐2708 (Print), 1024‐2708 (Linking), 3):171‐9.

Noronha 2014

Noronha AS, Markowitz LE, Dunne EF. Systematic review of human papillomavirus vaccine coadministration. Vaccine 2014;32(23):2670‐4.

Ojha 2014

Ojha RP, Jackson BE, Tota JE, Offutt‐Powell TN, Singh KP, Bae S. Guillain‐Barré syndrome following quadrivalent human papillomavirus vaccination among vaccine‐eligible individuals in the United States. Human Vaccines & Immunotherapeutics 2014;10(1):232‐7.

Ostor 1993

Ostor AG. Natural history of cervical intraepithelial neoplasia: a critical review. International Journal of Gynegological Pathology 1993;12(2):186‐92.

Paavonen 2007

Paavonen J, Jenkins D, Bosch FX, Naud P, Salmeron J, Wheeler CM. Efficacy of a prophylactic adjuvanted bivalent L1 virus‐like‐particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double‐blind, randomised controlled trial. Lancet 2007;369(9580):2161‐70.

Paavonen 2009

Paavonen J, Naud P, Salmeron J, Wheeler CM, Chow S‐N, Apter D. Efficacy of human papillomavirus (HPV)‐16/18 ASO4‐adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double‐blind, randomised study in young women. Lancet 2009;374:301‐14.

Pagliusi 2004

Pagliusi SR, Teresa Aguado M. Efficacy and other milestones for human papillomavirus vaccine introduction. Vaccine 2004;23(0264‐410X, 5):569‐78.

Panagiotou 2015

Panagiotou OA, Befano BL, Gonzalez P, Rodriguez AC, Herrero R, Schiller JT, et al. Effect of bivalent human papillomavirus vaccination on pregnancy outcomes: long term observational follow‐up in the Costa Rica HPV Vaccine Trial. BMJ 2015;351:h4358.

Pedersen 2012

Pedersen C, Breindahl M, Aggarwal N, Berglund J, Oroszlan G, Silfverdal SA. Randomized trial: immunogenicity and safety of coadministered human papillomavirus‐16/18AS04‐adjuvanted vaccine and combined hepatitis A and B vaccine in girls. Journal of Adolescent Health 2012;50(1):38‐46.

Pollock 2014

Pollock KG, Kavanagh K, Potts A, Love J, Cuschieri K, Cubie H, et al. Reduction of low‐ and high‐grade cervical abnormalities associated with high uptake of the HPV bivalent vaccine in Scotland. British Journal of Cancer 2014;111(9):1261‐4.

Rambout 2007

Rambout L, Hopkins L, Hutton B, Fergusson D. Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized controlled trials. Canadian Medical Association Journal 2007;177(5):469‐79.

Review Manager 2014 [Computer program]

Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager 5 (RevMan 5). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Richart 1973

Richart RM. Cervical intraepithelial neoplasia. Pathology Annual 1973;8:301‐23.

Romanowski 2009

Romanowski B, de Borba PC, Naud PS, Roteli‐Martins CM, De Carvalho NS, Teixeira JC, et al The GlaxoSmithKline Vaccine HPV‐007 Study Group. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)‐16/18 AS04‐adjuvanted vaccine: analysis of a randomised placebo‐controlled trial up to 6.4 years. Lancet 2009;374(9706):1975‐85.

Romanowski 2011

Romanowski B. Long term protection against cervical infection with the human papillomavirus: Review of currently available vaccines. Human Vaccines 2011;7(2):161‐9.

Ronco 2014

Ronco G, Dillner J, Elfstrom KM, Tunesi S, Snijders PJ, Arbyn M, et al. Efficacy of HPV‐based screening for prevention of invasive cervical cancer: follow‐up of four European randomised controlled trials. Lancet 2014;383(9916):524‐32.

Rowhani‐Rahbar 2009

Rowhani‐Rahbar A, Mao C, Hughes JP, Alvarez FB, Bryan JT, Hawes SE. Longer term efficacy of a prophylactic monovalent human papillomavirus type 16 vaccine. Vaccine 2009;27(41):5612‐9.

Safaeian 2018

Safaeian M, Sampson JN, Pan Y, Porras C, Kemp TJ, Herrero R, et al. Durability of protection afforded by fewer doses of the HPV16/18 vaccine: The CVT Trial. Journal of the National Cancer Institute 2018;110(2):djx158.

Sankaranarayanan 2016

Sankaranarayanan R, Prabhu PR, Pawlita M, Gheit T, Bhatla N, Muwonge R, et al. Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre prospective cohort study. Lancet Oncology 2016;17(1):67‐77.

Scheller 2014

Scheller NM, Pasternak B, Svanstrom H, Hviid A. Quadrivalent human papillomavirus vaccine and the risk of venous thromboembolism. JAMA 2014;312(2):187‐8.

Scheller 2015

Scheller NM, Svanstrom H, Pasternak B, Arnheim‐Dahlstrom L, Sundstrom K, Fink K, et al. Quadrivalent HPV vaccination and risk of multiple sclerosis and other demyelinating diseases of the central nervous system. JAMA 2015;313:54‐61.

Schiffman 2005

Schiffman MA, Herrero R, Desalle R, Hildesheim A, Wacholder S, Rodriguez AC, et al. The carcinogenicity of human papillomavirus types reflects viral evolution. Virology 2005;337(1):76‐84.

Schiffman 2009

Schiffman M, Clifford G, Buonaguro FM. Classification of weakly carcinogenic human papillomavirus types: addressing the limits of epidemiology at the borderline. Infectious Agents and Cancer2009; Vol. 4, issue 1:1‐8.

Schiller 2009

Schiller JT, Lowy DR. Immunogenicity testing in human papillomavirus virus‐like‐particle vaccine trials. Journal of Infectious Diseases 2009;200(2):166‐71.

Schiller 2012

Schiller JT, Castellsague X, Garland SM. A review of clinical trials of human papillomavirus prophylactic vaccines. Vaccine 2012;30 Suppl 5:F123‐38.

Schmeink 2011

Schmeink CE, Bekkers RL, Josefsson A, Richardus JH, Berndtsson Blom K, David MP, et al. Co‐administration of human papillomavirus‐16/18 AS04‐adjuvanted vaccine with hepatitis B vaccine: randomized study in healthy girls. Vaccine 2011;29(1873‐2518):9276‐83.

Schneider 2003

Schneider A, Gissmann L. Cervical cancer. The potential role of human papillomavirus (HPV)‐specific vaccines in prevention and treatment. American Journal of Cancer 2003;2:1‐253.

Schwarz 2012

Schwarz TF, Huang LM, Medina DM, Valencia A, Lin TY, Behre U, et al. Four‐year follow‐up of the immunogenicity and safety of the HPV‐16/18 AS04‐adjuvanted vaccine when administered to adolescent girls aged 10‐14 years. Journal of Adolescent Health 2012;50(2):187‐94.

Sharp 1998

Sharp S. Meta‐analysis regression. Statistics Technical Bulletin 1998;7(42):148‐55. [MEDLINE: 11989]

Skinner 2014

Skinner SR, Szarewski A, Romanowski B, Garland SM, Lazcano‐Ponce E, Salmeron J. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04‐adjuvanted vaccine in women older than 25 years: 4‐year interim follow‐up of the phase 3, double‐blind, randomised controlled VIVIANE study. Lancet 2014;384(9961):2213‐27.

Skufca 2017

Skufca J, Ollgren J, Ruokokoski E, Lyytikäinen O, Nohynek H. Incidence rates of Guillain‐Barré‚ (GBS), chronic fatigue/systemic exertion intolerance disease (CFS/SEID) and postural orthostatic tachycardia syndrome (POTS) prior to introduction of human papilloma virus (HPV) vaccination among adolescent girls in Finland, 2002‐2012. Papillomavirus Research 2017;3:91‐6.

Slade 2009

Slade BA, Leidel L, Vellozzi C, Woo EJ, Hua W, Sutherland A, et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA 2009;302(7):750‐7.

Smith 2000

Smith HO, Tiffany MF, Qualls CR, Key CR. The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in the United States‐a 24‐year population‐based study. Gynecologic Oncology2000; Vol. 78, issue 2:97‐105.

Solomon 2002

Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002;287:2114‐9.

Sow 2013

Sow PS, Watson‐Jones D, Kiviat N, Changalucha J, Mbaye KD, Brown J. Safety and immunogenicity of human papillomavirus‐16/18 AS04‐adjuvanted vaccine: a randomized trial in 10‐25‐year‐old HIV‐seronegative African girls and young women. Journal of Infectious Diseases 2013;207(11):1753‐63.

Stanley 2006

Stanley MA. Human papillomavirus vaccines. Reviews in Medical Virology 2006;16(1052‐9276 (Print), 3):139‐49.

Stanley 2012

Stanley M, Pinto LA, Trimble C. Human papillomavirus vaccines ‐ immune responses. Vaccine 2012;30 (Suppl 5):F83‐7.

Stanley 2014

Stanley MA, Sudenga SL, Giuliano AR. Alternative dosage schedules with HPV virus‐like particle vaccines. Expert Review of Vaccines 2014;13(8):1027‐38.

Starkie Camejo 2016

Starkie Camejo H, Li X, Van Kriekinge G, Ryser M. Response letter regarding the letter to the editors by Butt et al. Does it matter Discounting and its role in the cost‐effectiveness of preventative interventions. The case of HPV vaccination. Public Health 2016;132:110‐2.

Szarewski 2010

Szarewski A. HPV vaccine: Cervarix. Expert Opinion on Biological Therapy 2010;10(3):477‐87.

Szarewski 2011

Szarewski A, Poppe WA, Skinner SR, Wheeler CM, Paavonen J, Naud P. Efficacy of the human papillomavirus (HPV)‐16/18 AS04‐adjuvanted vaccine in women aged 15‐25 years with and without serological evidence of previous exposure to HPV‐16/18. Internaitonal Journal of Cancer 2011;131(1):106‐16.

Tabrizi 2012

Tabrizi SN, Brotherton JM, Kaldor JM, Skinner SR, Cummins E, Liu B, et al. Fall in human papillomavirus prevalence following a national vaccination program. Journal of Infectious Diseases 2012;206(11):1645‐51.

Tabrizi 2014

Tabrizi SN, Brotherton JM, Kaldor JM, Skinner SR, Liu B, Bateson D, et al. Assessment of herd immunity and cross‐protection after a human papillomavirus vaccination programme in Australia: a repeat cross‐sectional study. Lancet Infectious Diseases 2014;14(10):958‐66.

Taylor 2016

Taylor S, Ryser M, Mihalyi A, van Effelterre T. Response letter regarding the letter to the editors by Brown et al. Human Vaccinnes and Immunotherapeutics2016; Vol. 7:1943‐6.

The GSK Study Group 2009

The GlaxoSmithKline Vaccine HPV‐007 Study Group. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)‐16/18 ASO4‐adjuvanted vaccine: analysis of a randomised placebo‐controlled trial up to 6.4 years. Lancet 2009;374:1975‐85.

Thompson 1999

Thompson SG, Sharp SJ. Explaining heterogeneity in meta‐analysis: a comparison of methods. Statistics in Medicine 1999;18(20):2693‐708. [MEDLINE: 11967]

Unger 2010

Unger E, Dillner J. Human Papillomavirus Laboratory Manual. 1st Edition. Geneva: WHO (Quality, Safety and Standards (QSS) team of the Department of Immunization, Vaccines and Biologicals), 2010.

Van Damme 2014

van Damme P, Leroux‐Roels G, Simon P, Foidart JM, Donders G, Hoppenbrouwers K, et al. Effects of varying antigens and adjuvant systems on the immunogenicity and safety of investigational tetravalent human oncogenic papillomavirus vaccines: results from two randomized trials. Vaccine 2014;32(29):3694‐705.

Van Damme 2015

Van Damme P, Olsson SE, Block S, Castellsague X, Gray GE, Herrera T, et al. Immunogenicity and Safety of a 9‐Valent HPV Vaccine. Pediatrics 2015;136(1):e28‐e39.

Verstraeten 2008

Verstraeten T, Descamps D, David MP, Zahaf T, Hardt K, Izurieta P, et al. Analysis of adverse events of potential autoimmune aetiology in a large integrated safety database of AS04 adjuvanted vaccines. Vaccine 2008;26(0264‐410X (Print), 0264‐410X (Linking), 51):6630‐8.

Vesikari 2015

Vesikari T, Brodszki N, Van Damme P, Diez‐Domingo J, Icardi G, Kjeld PL, et al. A randomized, double‐blind, phase III study of the immunogenicity and safety of a 9‐valent human papillomavirus L1 virus‐like particle vaccine (V503) versus Gardasil(R) in 9‐15‐year‐old girls. Pediatric Infectious Disease Journal 2015;34(9):992‐8.

Vichnin 2015

Vichnin M, Bonanni P, Klein NP, Garland SM, Block SL, Kjaer SK, et al. An overview of quadrivalent human papillomavirus vaccine safety: 2006 to 2015. Pediatric Infectious Disease Journal 2015;34(9):983‐1.

Villa 2005

Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano AR. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus‐like particle vaccine in young women: a randomised double‐blind placebo‐controlled multicentre phase II efficacy trial. Lancet Oncology 2005;6(5):271‐8.

Villa 2006

Villa LL, Ault KA, Giuliano AR, Costa RL, Petta CA, Andrade RP. Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. Vaccine 2006;24(27):5571‐83.

Villa 2006a

Villa LL, Costa RL, Petta CA, Andrade RP, Paavonen J, Iversen OE. 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. British Journal of Cancer 2006;95(11):1459‐66.

Wacholder 2010

Wacholder S, Chen BE, Wilcox A, Macones G, Gonzalez P, Befano B. Risk of miscarriage with bivalent vaccine against human papillomavirus (HPV) types 16 and 18: pooled analysis of two randomised controlled trials. BMJ 2010;340:c712.

Wheeler 2016

Wheeler CM, Skinner SR, Del Rosario‐Raymundo MR, Garland SM, Chatterjee A, Lazcano‐Ponce E, et al. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04‐adjuvanted vaccine in women older than 25 years: 7‐year interim follow‐up of the phase 3, double‐blind, randomised controlled VIVIANE study. Lancet Infectious Diseases 2016;16 (10):1154‐68.

WHO 2009

Initiative for Vaccine Research of the Department of Immunization Vaccines and Biologicals (WHO). Human Papillomavirus (HPV) Vaccine Background Paper. World Health Organization (WHO)2009:1‐249.

WHO 2014

WHO. Global Advisory Committee on Vaccine Safety Statement on the continued safety of HPV vaccination. http://www.who.int/vaccine_safety/committee/topics/hpv/GACVS_Statement_HPV_12_Mar_2014.pdf2014.

WHO 2016

WHO. Safety of HPV vaccines (from meeting of 2‐3 December, 2015). Weekly Epidemiological Record 2016;91(3):26‐8.

Winer 2003

Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Journal of Epidemiology 2003;157:218‐26.

Winer 2008

Winer RL, Feng Q, Hughes JP, O'Reilly S, Kiviat NB, Koutsky LA. Risk of female human papillomavirus acquisition associated with first male sex partner. Journal of Infectious Diseases 2008;197(0022‐1899 (Print), 2):279‐82.

Yoshikawa 2013

Yoshikawa H, Ebihara K, Tanaka Y, Noda K. Efficacy of quadrivalent human papillomavirus (types 6, 11, 16 and 18) vaccine (GARDASIL) in Japanese women aged 18‐26 years. Cancer Science 2013;104(4):465‐72.

Zhu 2014

Zhu FC, Chen W, Hu YM, Hong Y, Li J, Zhang X. Efficacy, immunogenicity and safety of the HPV‐16/18 AS04‐adjuvanted vaccine in healthy Chinese women aged 18‐25 years: results from a randomized controlled trial. International Journal of Cancer 2014;135(1097‐0215 (Electronic), 0020‐7136 (Linking), 11):2612‐22.

Zhu 2014a

Zhu F, Li J, Hu Y, Zhang X, Yang X, Zhao H, et al. Immunogenicity and safety of the HPV‐16/18 AS04‐adjuvanted vaccine in healthy Chinese girls and women aged 9 to 45 years. Human Vaccines & Immunotherapeutics 2014;10(7):1795‐806.

Referencias de otras versiones publicadas de esta revisión

Arbyn 2011b

Arbyn M, Bryant A, Beutels P, Martin‐Hirsch PL, Paraskevaidis E, Van Hoof E, et al. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database of Systematic Reviews 2011, Issue 4. [DOI: 10.1002/14651858.CD009069]

Arbyn 2013

Arbyn M, Bryant A, Martin‐Hirsch PL, Xu L, Simoens C, Markowitz L. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database of Systematic Reviews 2013, Issue 12. [DOI: 10.1002/14651858.CD009069.pub2]

Characteristics of studies

Characteristics of included studies [author‐defined order]

Phase2 trial (ph2,1v)

Methods

Phase IIb, randomised, double‐blind, placebo‐controlled trial

Participants

2392 women (1194 in the vaccine arm and 1198 in the placebo arm) from 16 centres in the USA

Age range: 16 to 23 years

Inclusion criteria: young women who were HPV16 DNA negative at enrolment and month 7, were HPV16 seronegative at enrolment, had had no other vaccination ±1 month around each dose. Virgins were enrolled if they were seeking contraception

Exclusion criteria: pregnancy, history of abnormal Pap smears, more than 5 sexual partners

Interventions

Vaccine: monovalent HPV16 L1 virus‐like particles

Placebo: visually indistinguishable aluminium adjuvant placebo

Outcomes

Safety, immunogenicity and efficacy (persistent HPV16 infection and histological lesions of CIN 1+,2+ and 3+)

Notes

Reports: Koutsky 2002; Mao 2006 and Rowhani‐Rahbar 2009

Last report average follow‐up time: 8.5 years (Rowhani‐Rahbar 2009)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Study participants were randomised in a 1:1 ratio to receive vaccine or placebo. Permuted blocks were used to ensure similar numbers of participants in each arm

Allocation concealment (selection bias)

Low risk

Allocation sequence was generated by computer, allocation numbers were assigned at each centre. No further details were provided regarding the concealment of allocation

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants and study staff were blinded to the group assignments

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

An independent masked group of 4 pathologists reviewed the slides without knowledge of other clinical or laboratory data

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Besides the per‐protocol (PP) analysis (HPV16 DNA negative at enrolment and during vaccination, HPV16 seronegative at enrolment, 3 doses received, no protocol violations) also modified‐intention‐to‐treat (MITT‐1 [HPV16 DNA negative and seronegative at enrolment, at least 1 dose received], MITT‐2 (including also women being HPV16 DNA positive at enrolment) analyses were performed. Unrestricted susceptible population and ITT analysis done. Exclusions and reasons for exclusions were described and were balanced over the trial arms.

Selective reporting (reporting bias)

Low risk

All outcomes (safety, immunogenicity and efficacy) were presented

Japanese trial (ph2,2v)

Methods

A phase II randomised, double‐blind, controlled multicentre study in Janpan

Participants

Participants: 1040 Japanese women (519 in the vaccine arm and 521 in the placebo arm)

Age range: 20 to 25 years

Inclusion criteria: women who were not pregnant, had an intact cervix and use adequate contraception over the vaccination period

Exclusion criteria: women who had a previous vaccination with HPV vaccine or hepatitis A vaccine, previous 3‐O‐desacy l‐4'‐monophosphoral lipid A administration, hepatitis A infection and various clinically significant diseases, previous colposcopic examination for cervical cytological abnormality

Interventions

Vaccine: bivalent HPV16/18 L1 VLP vaccine

Placebo: Hepatitis A vaccine

Outcomes

Safety, immunogenicity, incident & persistent HPV16/18 infection, cytological (ASCUS+) & histopathological abnormalities (CIN1+, CIN2+) associated with vaccine and non‐vaccine oncogenic HPV types

Notes

Main reports: Konno 2010 and Konno 2010a

Maximum follow‐up time: 24 months (Konno 2010a)

For the outcome high‐grade CIN irrespective of types, the follow‐up results up to 48 months were used (Konno 2014)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Women were randomised 1:1 to receive the vaccine or placebo. No further details given

Allocation concealment (selection bias)

Unclear risk

Not described in the paper

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding was maintained for all personnel, investigators, study collaborators, and participants

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Blinding can be assumed as covering also the outcome assessment since all investigators including the statisticians were blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcomes are assessed both in the PP group (3 doses received; no protocol violations, were DNA negative for HPV vaccine types at month 0 and 6; had normal or LSIL cytology at month 0) and total vaccination group (at least one dose, were DNA negative for HPV vaccine types at month 0; had normal or LSIL cytology at month 0)

Selective reporting (reporting bias)

Low risk

Efficacy, safety and immunogenicity outcomes are reported

Phase2 trial (ph2,2v)

Methods

Phase II randomised, multicentre, double‐blind placebo‐controlled study

Participants

1113 women (560 in the vaccine arm and 553 in the placebo arm) from 32 study sites; 433 women were from a Brazilian cohort with longer follow‐up)

Age range: 15 to 25 years

Inclusion criteria: healthy women who had had no more than 6 sexual partners, no history of an abnormal Pap test, no ablative or excisional treatment of the cervix, and no ongoing treatment for external condylomata; being, at enrolment, cytologically negative, seronegative for HPV16 and HPV18 antibodies by ELISA, and HPV‐DNA negative by PCR for 14 high‐risk HPV types

Interventions

Vaccine: bivalent HPV16/18 L1 VLP vaccine

Placebo: Hepatitis A vaccine

Outcomes

Safety, tolerability, immunogenicity, incident & persistent HPV infection, cytological (ASC‐US+, LSIL+) & histopathological abnormalities (CIN1+, CIN2+) associated with vaccine and non‐vaccine oncogenic HPV types

Notes

Main reports: Harper 2004; Harper 2006; The GSK Study Group 2009 and De Carvalho 2010

Last report average follow‐up time: 7.3 years (De Carvalho 2010)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Stratified, block randomisation according to validated algorithms was centralised with an Internet‐based randomisation system

Allocation concealment (selection bias)

Low risk

Trial allocation remained concealed from investigators and the women participating throughout initial and follow‐up studies

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blinded: trial arms were masked for women and medical personal

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

A central laboratory, reported cytology results...the central histology laboratory made an initial diagnosis from the formalin‐fixed tissue specimens for clinical management

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcomes are assessed both in the PP group (3 doses received, seronegative for HPV16/18 at month 0 and negative for hrHPV DNA at month 7) and in the ITT group (at least 1 dose,, seronegative for HPV16/18, negative for hrHPV DNA at month 7, accepting HPV16/18 positive at month 0, including also protocol violations) are shown and reasons for exclusion are presented

Selective reporting (reporting bias)

Low risk

All outcomes (safety, immunogenicity and efficacy) are presented

African_2 country trial (ph3,2v)

Methods

Phase IIIb, double‐blind, randomised, placebo‐controlled, multicentre trial

Participants

Participants: 676 females (450 in the vaccine arm and 226 in the placebo arm) enrolled in Senegal or Tanzania.

Age range: 10 to 25 years

Inclusion criteria: healthy HIV‐seronegative girls and young women 10 to 25 years old at first vaccination, who were not pregnant and had fewer than 6 lifetime sexual partners

Interventions

Vaccine: HPV16/18 bivalent vaccine

Placebo: AI(OH)3 placebo

Outcomes

Immunogenicity and safety outcomes

Notes

Main report: Sow 2013

Last report average follow‐up time: 12 months

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

The randomisation list was computer generated using an Internet‐based randomisation blocking scheme

Allocation concealment (selection bias)

Low risk

Allocation was concealed until end of the study

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Investigators, study staff, and participants in each country were blinded to vaccine assignment until all participants in that country had completed the 12‐month visit

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessment was blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Safety analyses were based on the total vaccinated cohort, with at least one dose. Immunogenicity analyses were assessed in the PP cohort (3 doses received, no protocol violations). The dropout rates were low and balanced between the vaccine and placebo group

Selective reporting (reporting bias)

Low risk

All intended outcomes reported

Chinese trial (ph3,2v)_young

Methods

Phase II/III randomised, double‐blind, controlled trial

Participants

Participants: 3819 women (3026 in the vaccine arm and 3025 in the placebo arm) enrolled at four sites in JiangSu Province

Age range: 18 to 25 years

Inclusion criteria: women were agreed to use contraceptive precautions 30 days before the 1st vaccine dose and 2 months after completion of the vaccine series

Exclusion criteria: women who were pregnant or breastfeeding, had an immunosuppressive or immunodeficient condition, a history of colposcopy, an allergic disease likely to be exacerbated by any component of the vaccine or previously received HPV vaccination or adjuvant were excluded

Interventions

Vaccine: bivalent vaccine

Placebo: aluminium hydroxide placebo

Outcomes

Efficacy (incident and persistent HPV infection, CIN), safety and immunogenicity outcomes

Notes

Report: Zhu 2014.

Follow‐up of 15 months

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Women were randomised in a 1:1 ratio with an Internet‐based centralised randomisation system

Allocation concealment (selection bias)

Low risk

Treatment allocation at the investigation site were using an Internet‐based system

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

All participants, investigators and study staff were blinded to individual participant treatment assignments and results

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

All participants, investigators and study staff were blinded to individual participants treatment assignments and results

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcomes (safety and immunogenicity) were reported on the total vaccinated cohort. Reason for exclusion was noted and balanced between vaccine group and placebo group

Selective reporting (reporting bias)

Low risk

All outcomes (safety and immunogenicity) were presented

Chinese trial (ph3,2v)_ adolescent

Methods

Phase IIIb randomised, double‐blind, controlled trial

Participants

Participants: 750 girls (374 in the vaccine arm and 376 in the placebo arm) enrolled in JiangSu Province

Age range: 9 to 17 years

Inclusion criteria: healthy girls with non‐childbearing potential or who were agreed to use contraceptive precautions 30 days before the 1st vaccine dose and 2 months after completion of the vaccine series; must with written informed consent obtained from the parents

Exclusion criteria: girls who had an immunosuppressive or immunodeficient condition, concurrently participating in another clinical study, hypersensitivity to latex, had an allergic disease likely to be exacerbated by any component of the vaccine or previously received HPV vaccination or adjuvant were excluded

Interventions

Vaccine: bivalent vaccine

Placebo: aluminium hydroxide placebo

Outcomes

Safety and immunogenicity outcomes

Notes

Report: Zhu 2014a

Follow‐up of 12 months

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Women were randomised in a 1:1 ratio to receive HPV vaccine or control, using a central Internet‐based randomisation system (see Zhu 2014)

Allocation concealment (selection bias)

Unclear risk

Not described in the paper

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not described in the paper

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described in the paper

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcomes (safety and immunogenicity) were reported on the total vaccinated cohort. Reason for exclusion was noted and balanced between vaccine group and placebo group

Selective reporting (reporting bias)

Low risk

All outcomes (safety and immunogenicity) were presented

Chinese trial (ph3,2v)_mid‐adult

Methods

Phase II/III randomised, double‐blind, controlled trial

Participants

Participants: 1212 women (606 in the vaccine arm and 606 in the placebo arm) enrolled in JiangSu Province

Age range: 26 to 45 years

Inclusion criteria: women were agreed to use contraceptive precautions 30 days before the 1st vaccine dose and 2 months after completion of the vaccine series

Exclusion criteria: women who were pregnant or breastfeeding, had an immunosuppressive or immunodeficient condition, a history of colposcopy, an allergic disease likely to be exacerbated by any component of the vaccine or previously received HPV vaccination or adjuvant were excluded

Interventions

Vaccine: bivalent vaccine

Placebo: HBV vaccine

Outcomes

Safety and immunogenicity outcomes

Notes

Report: Zhu 2014a

Follow‐up of 12 months

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Women were randomised in a 1:1 ratio to receive HPV vaccine or control, using a central internet‐based randomisation system (see Zhu 2014)

Allocation concealment (selection bias)

Unclear risk

Not described in the paper

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not described in the paper

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described in the paper

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcomes (safety and immunogenicity) were reported on the total vaccinated cohort. Reason for exclusion was noted and balanced between vaccine group and placebo group

Selective reporting (reporting bias)

Low risk

All outcomes (safety and immunogenicity) were presented

Co‐vaccination_dTpa_IPV trial (ph3,2v)

Methods

Randomised, controlled, open, multicentre parallel group study

Participants

Participants: 751 healthy girls and young women were enrolled in France, Germany and Spain. Participants were randomised to receive a) HPV vaccine (n = 248), b) combined Diphtheria‐Tetanus‐Acellular Pertussis–inactivated Poliovirus vaccine (dTpa‐IPV) together with HPV vaccine at month 0 and the HPV vaccine at months 1 and 6 (n = 255) or c) dTpa‐IPV only at month 0 and HPV vaccine at months 1, 2 and 7 (n = 248)

Age range: 10 to 18 years

Inclusion criteria: healthy girls and young women who had a negative pregnancy test at the time of each vaccination, not breastfeeding, and if of child‐bearing potential, to be abstinent from sexual activity or using adequate contraceptive precautions, should have complete routine childhood vaccinations against diphtheria, tetanus, pertussis, and poliomyelitis

Exclusion criteria: girls who had received diphtheria, tetanus, pertussis vaccine, diphtheria‐tetanus booster or dTpa vaccine, and/or oral or inactivated poliovirus vaccine within the previous 5 years; had known exposure to diphtheria or household exposure to pertussis, or diphtheria, tetanus, pertussis, or polio diagnosed within 30 days before vaccination

Interventions

Vaccine: bivalent HPV vaccine

Placebo: combined Diphtheria‐Tetanus‐Acellular Pertussis–inactivated Poliovirus vaccine (dTpa‐IPV)

Outcomes

Safety and immunogenicity outcomes

Notes

Report: Garcia‐Sicilia 2010

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A randomisation list was computer generated using a standard SAS program at GSK Biological, Rixensart, Belgium

Allocation concealment (selection bias)

High risk

Treatment allocation at the investigator site was performed using a central randomisation system but not blinded

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not described in the paper

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described in the paper

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All safety outcomes were reported for the total vaccinated cohort. Immunogenicity outcomes were reported for the according‐to‐protocol cohort. Reason for exclusion was noted and balanced between vaccine group and placebo group

Selective reporting (reporting bias)

Low risk

All outcomes (safety and immunogenicity) were presented

Co‐vaccination_HepB trial (ph3, 2v)

Methods

Randomised, controlled, open, multicentre parallel group study

Participants

Participants:741 girls enrolled at seven centres in the Netherlands and Sweden. Participants were randomised to receive HPV vaccine (n = 247), Hepatitis B vaccine (n = 247) or HPV vaccine co‐administrated with Hepatitis B vaccine (n = 247)

Age range: 9 to 15 years

Inclusion criteria: healthy girls who had a negative pregnancy test at the time of each vaccination and if of child‐bearing potential, to be abstinent from sexual activity or using adequate contraceptive precautions

Exclusion criteria: girls with a history of hepatitis B infection or with known exposure to hepatitis B within 6 weeks prior to vaccination, girls with previous vaccination against HPV or hepatitis B

Interventions

Vaccine: bivalent HPV vaccine

Placebo: hepatitis B vaccine

Outcomes

Safety and immunogenicity outcomes

Notes

Report: Schmeink 2011

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A randomisation list was computer generated at GSK Biological, Rixensart, Belgium

Allocation concealment (selection bias)

High risk

This was an open study, the participants and investigators were aware of the group allocated and vaccines given

Blinding of participants and personnel (performance bias)
All outcomes

High risk

See above

Blinding of outcome assessment (detection bias)
All outcomes

High risk

See above

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All safety outcomes were reported for the total vaccinated cohort. Immunogenicity outcomes were reported on the according‐to‐protocol cohort. Reason for exclusion was noted and balanced between vaccine group and placebo group

Selective reporting (reporting bias)

Low risk

All outcomes (safety and immunogenicity) were presented

Co‐vaccination_HAB trial (Ph3, 2v)

Methods

Randomised, controlled, open, multicentre parallel group study

Participants

Participants: 813 girls enrolled in Canada, Denmark, Hungary and Sweden. Participants were randomised to receive HPV vaccine (n = 270), Hepatitis A and B vaccine (n = 271) or HPV vaccine co‐administrated with Hepatitis A and B vaccine (n = 272)

Age range: 9 to 15 years

Inclusion criteria: healthy girls with a negative pregnancy test at the time of each vaccination and if of child‐bearing potential, to be abstinent from sexual activity or using adequate contraceptive precautions

Exclusion criteria: girls with a history of hepatitis and or B infection or with known exposure to hepatitis A or B within 6 weeks prior to vaccination, girls with previous vaccination against HPV or hepatitis A or B, or planned administration of HPV, hepatitis A or B or non routine vaccines not foreseen by the study protocol were excluded

Interventions

Vaccine: bivalent vaccine

Placebo: GSK combined hepatitis A and B vaccine

Outcomes

Safety and immunogenicity outcomes

Notes

Report: Pedersen 2012

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A randomisation list was computer generated at GSK Biological, Rixensart

Allocation concealment (selection bias)

Unclear risk

Not described in the paper

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Pesonnel performing serological assays were blinded to group assignment. Not mentioned for safety outcome investigator.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

See above

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All safety outcomes were reported for the total vaccinated cohort. Immunogenicity outcomes were reported for the according‐to protocol cohort. Reason for exclusion was noted and balanced between vaccine group and placebo group

Selective reporting (reporting bias)

Low risk

All safety outcomes were presented

CVT (ph3,2v)

Methods

Phase III randomised, double‐blind, controlled trial

Participants

7466 women (3727 in the vaccine arm and 3739 in the placebo arm) from Guanacaste, Costa Rica

Age: 18 to 25 years

Inlcusion criteria: healthy women who were not pregnant, not breastfeeding and using contraception during the vaccine period. Women were enrolled regardless of past sexual behavior, HPV status, or cytology.

Exclusion criteria: women were excluded if they had history of chronic diseases, history of reactions to vaccines and history of hepatitis A vaccination

Interventions

Vaccine: bivalent HPV16/18 AS04‐adjuvant L1 VLP vaccine

Placebo: Hepatitis A vaccine‐licensed Havrix vaccine

Outcomes

Vaccine efficacy (persistent infection 6M & 12M), cross‐protection and pregnancy outcomes

Notes

Main report: Herrero 2011.

Last report average follow‐up time: 50.4 months

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

HPV vaccines and placebo were assigned random vaccine identification numbers at the time of labelling by the manufacturer. These numbers were randomised by the study Data Management Centre with a standard SAS program

Allocation concealment (selection bias)

Low risk

Codes were kept at the study's data management centre and GSK under controlled and secured access

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

All field workers were blinded to group assignment; as well as investigators from the USA and Costa Rica, participants, and medical monitors

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Analyses were conducted by an external group (Information Management Systems) under the direction of the investigators who remain masked to individuals' randomisation

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcomes are assessed in the PP cohort (3 doses received, HPV16/18 DNA negative at enrolment, no biopsy or LEEP, no protocol violations) and in the ITT cohort were assessed

Selective reporting (reporting bias)

Low risk

Efficacy, cross‐protection pregnancy and other safety outcomes were reported

Hong Kong trial (ph3,2v)

Methods

Phase III, double‐blind, randomised controlled trial

Participants

294 women (148 in the vaccine arm and 146 in the placebo arm) from Hong Kong

Age range: women aged 18 to 35 years.

Inclusion criteria: women who were healthy

Exclusion criteria: women who were receiving any investigational or non‐registered drug or vaccine, those who had received AS04‐adjuvant or HPV vaccine, those having a chronic disease or were pregnant, breastfeeding or planning to conceive were excluded

Interventions

Vaccine: HPV16/18 AS04‐adjuvant bivalent vaccine

Placebo: visually indistinguishable aluminium‐containing placebo

Outcomes

Safety and immunogenicity

Notes

Last report average follow‐up time: 7 months (Hong Kong trial (ph3,2v))

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Women were randomised in a 1:1 ratio with an Internet‐based centralised randomisation system

Allocation concealment (selection bias)

Low risk

A single treatment number was used for each patient uniquely identify the doses administered to the participant

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not described in the paper

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described in the paper

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcomes (safety and immunogenicity) were reported on the total vaccinated cohort. Reason for exclusion was noted and balanced between vaccine group and placebo group

Selective reporting (reporting bias)

Low risk

All outcomes (safety and immunogenicity) were presented

Immunobridging(ph3,2v)

Methods

Phase III, observer‐blind, randomised, controlled and multicentre trial

Participants

2067 women (1035 in the vaccine arm and 1032 in the placebo arm) recruited from Australia, Colombia, the Czech Republic, France etc.

Age range: women aged 10 to 14 years

Inclusion criteria: girls who were healthy, were not excluded based on HPV status, Pap smear history or history of sexual activity

Exclusion criteria: girls were excluded if they had immunodeficiency, history of allergic disease likely to be exacerbated by a vaccine component, known acute or chronic clinically significant neurologic, hepatic, or renal functional abnormality

Interventions

Vaccine: HPV16/18 AS04‐adjuvant bivalent vaccine

Placebo: Hepatitis A vaccine, appearance of the vaccine is different

Outcomes

Safety and immunogenicity

Notes

Last report average follow‐up time: 12 months (Medina 2010)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Girls were randomised in 1:1 ratio based on an algorithm accounted for study centre and age strata

Allocation concealment (selection bias)

High risk

Allocation was not blinded since the HPV vaccine and the control vaccine (Hepatitis A) were different in appearance

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Because of differences in vaccines appearance, study staff who administered them were not otherwise involved in study conduct;
participants and staff involved in assessment remained blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

The study staff involved in the assessment of outcomes remained blinded to the administered vaccine

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcomes (safety and immunogenicity) were reported on the total vaccinated cohort. Reasons for exclusion were noted and balanced between the vaccine group and placebo group

Selective reporting (reporting bias)

Low risk

All outcomes (safety and immunogenicity) were presented

Indian trial (ph3,2v)

Methods

Phase III, double‐blind, randomised, controlled and multicentre trial

Participants

354 women (176 in the vaccine arm and 178 in the placebo arm) from Hong Kong

Age range: women aged 18 to 35 years

Inclusion criteria: healthy women not taking any other investigational products or steroids and not pregnant or planning to become pregnant

Interventions

Vaccine: HPV16/18 AS04‐adjuvant bivalent vaccine

Placebo: visually indistinguishable aluminium‐containing placebo

Outcomes

Safety and immunogenicity

Notes

Last report average follow‐up time: 7 months (Indian trial (ph3,2v))

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Women were randomised in a 1:1 ratio with SAS analysis system

Allocation concealment (selection bias)

Low risk

Throughout the study, a single treatment number was used to uniquely identify the vaccine doses to be given to the same participant

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not described in the paper

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described in the paper

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcomes (safety and immunogenicity) were reported on the total vaccinated cohort. Reason for exclusion was noted and balanced between vaccine group and placebo group

Selective reporting (reporting bias)

Low risk

All outcomes (safety and immunogenicity) were presented

Korean trial (ph3,2v)

Methods

Phase III randomised, double‐blind, placebo‐controlled trial

Participants

Participants: 321 females (160 in the vaccine arm and 161 in the placebo arm)

Age range: 10 to 14 years.

Inclusion criteria: include healthy Korean women who were using no other investigational products or immune‐modifying drugs, not pregnant or planning to become pregnant, not breastfeeding during the study. Use effective contraception or abstinent from sexual relations

Exclusion criteria: women who had received previous HPV vaccination

Interventions

Vaccine: HPV16/18 bivalent vaccine

Placebo: hepatitis A vaccine

Outcomes

Immunogenicity and safety outcomes

Notes

Main report: Kim 2010;

Last report average follow‐up time: 7 months

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were randomly allocated to two groups in a 1:1 ratio using an Internet‐based randomisation system

Allocation concealment (selection bias)

Low risk

Syringes were prepared and administered by qualified medical personnel not otherwise involved in the study

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

See above

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

The assessment of symptoms were conducted by personnel not involved in study

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcomes (safety and immunogenicity) were reported on the total vaccinated cohort. Reason for exclusion was noted and balanced between vaccine group and placebo group

Selective reporting (reporting bias)

Low risk

All outcomes (safety and immunogenicity) were presented

Korean trial (ph3b,2v)

Methods

Phase IIIb randomised, double‐blind, placebo‐controlled, multicentre trial

Participants

Participants: 208 women (149 in the vaccine arm and 76 in the placebo arm)

Age range: 15 to 25 years

Inclusion criteria: include healthy Korean women who were not pregnant and agreed to use effective contraception during the vaccination period

Exclusion criteria: women who were used investigational or non‐registered drug or vaccines, who had a history of HPV vaccination, a history of chronic diseases or cancer were also excluded from the study

Interventions

Vaccine: HPV16/18 bivalent vaccine

Placebo: hepatitis A vaccine

Outcomes

Immunogenicity and safety outcomes

Notes

Main report: Kim 2011;

Last report average follow‐up time: 7 months

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Women were randomised in a 2:1 ratio to vaccine or placebo. Random allocation was done with standard statistical analysis system program applying an Internet‐based 2:1 blocking scheme

Allocation concealment (selection bias)

Low risk

A single treatment number was utilised in the entire study to identify the doses to be administered to the participant

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

All participants and study personnel involved in the study were blinded throughout the study until the last participant and last visit and the database was frozen

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

See above

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Immunogenecity was assessed in the PP‐cohort (initially seronegative women) and in the TVC (at least one dose, all participants randomised); safety was assessed in the TVC

Selective reporting (reporting bias)

Low risk

All intended outcomes were reported

Malaysian trial (ph3,2v)

Methods

Phase IIIb, double‐blind, randomised controlled trial

Participants

271 women (135 in the vaccine arm and 136 in the placebo arm) from Malaysia

Age range: women aged 18 to 35 years

Inclusion criteria: women who were healthy

Exclusion criteria: women who had HPV vaccine, chronic use of immunosuppressants, history of allergy to vaccine compounds, history of chronic conditions of cancer and autoimmune disease, acute disease, pregnant

Interventions

Vaccine: HPV16/18 AS04‐adjuvant bivalent vaccine

Placebo: aluminium hydroxide as placebo

Outcomes

Safety and immunogenicity

Notes

Report: Lim 2014

Last report average follow‐up time: 7 months after first dose

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Women were randomised in a 1:1 ratio with an Internet‐based centralised randomisation system

Allocation concealment (selection bias)

Low risk

A single treatment number was used for each patient uniquely identify the doses administered to the participant

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not described in the paper

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described in the paper

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcomes (safety and immunogenicity) were reported on the total vaccinated cohort. Reason for exclusion was noted and balanced between vaccine group and placebo group

Selective reporting (reporting bias)

Low risk

All outcomes (safety and immunogenicity) were presented

PATRICIA trial (ph3,2v)

Methods

Phase III randomised, double‐blind, controlled trial

Participants

18,644 women (9319 in the vaccine arm and 9325 in the placebo arm) enrolled for the study from 135 centres in 14 countries in Asia, Pacific, Europe, Latin America and North America

Age range: 15 to 25 years

Inclusion criteria: women who reported no more than six lifetime sexual partners before study enrolment, agreed to using adequate contraception over the vaccination period, and had an intact cervix were eligible. Enrolled irrespective of their HPV DNA status, HPV serostatus or cytology at baseline

Exclusion criteria: women were excluded if they had a history of colposcopy, were pregnant or breastfeeding, or had chronic or autoimmune disease or immunodeficiency

Interventions

Vaccine: HPV16/18 AS04‐adjuvant bivalent vaccine

Placebo: Hepatitis A vaccine‐licensed Havrix vaccine

Outcomes

Safety, immunogenicity, efficacy (incident infection, persistent infection, CIN1+, CIN2+, CIN3+, AIS associated with HPV16, HPV18, HPV16/18, other oncogenic HPV types, irrespective of HPV DNA) and cross‐protection

Notes

Main reports: Paavonen 2007; Paavonen 2009; Szarewski 2011 and Lehtinen 2012.

Last report average follow‐up time: 34.9 months (Lehtinen 2012)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Women were randomised in a 1:1 ratio with an Internet‐based centralised randomisation system

Allocation concealment (selection bias)

Low risk

Allocation of treatment numbers was stratified by study site and by age.The trial remained double‐blinded until all individuals had completed 48 months of follow‐up after the first immunisation

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Enrolled women and study investigators were masked to allocated vaccine

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

All CIN cases were reviewed by a panel of three pathologists who were blinded to vaccine allocation. Analysis was done by an independent statistician to maintain the trial blinding

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcomes are assessed in the PP cohort (received 3 doses, seronegative and DNA negative for the corresponding vaccine type at month 0, normal or low‐grade cytology at month 0, no protocol violations) and in the TVC‐naive cohort (at least one vaccine dose, at baseline normal cytology, DNA negative for hrHPV, seronegative for HPV‐16 and HPV‐18) and in the total vaccinated cohort (all women randomised). Reasons for exclusion were presented

Selective reporting (reporting bias)

Low risk

All outcomes (safety, immunogenicity, efficacy and cross‐protection) are presented

PATRICIA & CVT (ph3,2v)

Methods

Pooled analysis of two phase III randomised, double‐blind, controlled trials

Participants

26,130 women who enrolled for PATRICIA trial and Costa Rica trial

Interventions

Vaccine: HPV16/18 AS04‐adjuvant bivalent vaccine

Placebo: Hepatitis A vaccine‐licensed Havrix vaccine

Outcomes

Pregnancy outcomes

Notes

Main report: Wacholder 2010

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

see PATRICIA & Costa Rica trials

Allocation concealment (selection bias)

Low risk

see PATRICIA & Costa Rica trials

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

see PATRICIA & Costa Rica trials

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

see PATRICIA & Costa Rica trials

Incomplete outcome data (attrition bias)
All outcomes

Low risk

see PATRICIA & Costa Rica trials

Selective reporting (reporting bias)

Low risk

see PATRICIA & Costa Rica trials

VIVIANE trial (ph3,2v)

Methods

Phase III randomised, double‐blind, controlled trial

Participants

5752 women (2881 in the vaccine arm and 2871 in the placebo arm) from Australia, Canada, Mexico, the Netherlands, Peru, Philippines, Portugal, Russia, Singapore, Thailand, the UK and the USA

Age range: women older than 25 years old, age stratified in 26 to 35, 36 to 45 and older than 46

Inclusion criteria: Women who were older than 25 years old. Each age‐stratum had 15% of women with a history of HPV infection to represent a real‐world setting; no limits on number of lifetime sexual partners

Exclusion criteria: women were excluded if they were pregnant, breastfeeding and who had chronic or autoimmune disease or immunodeficiency

Interventions

Vaccine: HPV16/18 AS04‐adjuvant bivalent vaccine;

Placebo: visually indistinguishable aluminium‐containing placebo

Outcomes

Safety, immunogenicity, efficacy and cross‐protection

Notes

Main report: Skinner 2014

Last report average follow‐up time: 43.3 months (Skinner 2014)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Women were randomised in a 1:1 ratio with an Internet‐based centralised randomisation system

Allocation concealment (selection bias)

Low risk

The randomisation list was generated by GSK with an algorithm which used a minimisation process that accounted for region, age stratum and HPV history

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

All participants, investigators and staff involved were masked to treatment allocation and study results. The interim analysis was done by an external statistician blinded to the allocation of vaccine versus placebo

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

All CIN cases were reviewed by a panel of three pathologists who were blinded to vaccine allocation. Analysis was done by an independent statistician to maintain the trial blinding

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcomes were assessed in the PP cohort (received 3 doses, seronegative and DNA negative for the corresponding vaccine type at month 0, normal or low‐grade cytology at month 0, no protocol violations) and in the TVC‐naive cohort (at least one vaccine dose, at baseline normal cytology, DNA negative for hrHPV, seronegative for HPV‐16 and HPV‐18) and in the total vaccinated cohort (all women randomised). Reasons for exclusion were presented

Selective reporting (reporting bias)

Low risk

All outcomes (safety, immunogenicity, efficacy and cross‐protection) are presented

Japanese trial (ph2,4v)

Methods

Phase II randomised, double‐blind, controlled trial in Japan

Participants

Participants: 1021 Japanese women (509 in the vaccine arm and 512 in the placebo arm)

Age range: 18 to 26 years

Inclusion criteria: healthy women who were not pregnant, had no previous abnormal Pap smears and reported a lifetime history of four or fewer male sex partners and agreed to use effective contraception were eligible. Women with previous HPV infection were not excluded

Interventions

Vaccine: quadrivalent HPV 6/11/16/18 L1 VLP vaccine

Placebo: visually indistinguishable aluminium‐containing placebo

Outcomes

Efficacy (composite primary endpoint of persistent infection and external genital disease), immunogenicity and safety outcomes

Notes

Main report: Yoshikawa 2013

Last report average follow‐up time: 30 months

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not mentioned in the paper

Allocation concealment (selection bias)

Low risk

The prepared randomisation schedule was sealed with other corresponding randomisation listings and retained strictly until un‐blinding by the Center for Patients Allocation

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

See above

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Endpoint analysis was done by use of consensus diagnosis from a panel of pathologists who were blinded to the central laboratory diagnosis, vaccination group and HPV status

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Efficacy result only reported in PP‐cohort (received 3 doses, being naive for the relevant HPV type at enrolment, remained free of infection with the same vaccine HPV type through completion of the vaccination regimen, did not violate the protocol)

Selective reporting (reporting bias)

Low risk

All outcomes (efficacy, safety and immunogenicity) reported

Korean trial (ph2,4v)

Methods

Phase II randomised, double‐blind, placebo‐controlled trial

Participants

Participant: 176 Korean participants (117 in the vaccine arm and 59 in the placebo arm)

Age range: 9 to 23 years

Inclusion criteria: women who were not pregnant, had no fever more than 37.8*C at vaccination, age 9‐15 years must have had no sexual experience before and no plan to have sexual experience during the study period. Participants aged 16 to 23 years must have had history of fewer than 4 sexual partners and use effective contraception during the study period

Exclusion criteria: participants who were enrolled in studies of other investigation agents, history of any HPV vaccination, history of allergy to vaccine compound, thrombocytopenia, history of vaccination within 14 days from enrolment (previous 21 days for live vaccine), receipt of blood or blood‐derived products within the 6 months preceding injection, and immunosuppression. Age group 16 to 23 were required to have not had a prior Pap test showing a squamous intraepithelial lesion or worse and/or a biopsy indicating CIN or worse

Interventions

Vaccine: quadrivalent HPV 6/11/16/18 L1 VLP vaccine

Placebo: visually indistinguishable aluminium‐containing placebo

Outcomes

Immunogenicity and safety outcomes

Notes

Main report: Kang 2008

Last report average follow‐up time: 7 months

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was performed by the study centres using the block method with decreasing block sizes

Allocation concealment (selection bias)

Unclear risk

Not described in the paper

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

The trial was described as double‐blind but no further details are given

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described in the paper

Incomplete outcome data (attrition bias)
All outcomes

Low risk

The loss to follow‐up rate is low and well‐balanced for both the vaccine and the placebo groups. Participants being baseline seropositive for the concerned HPV vaccine type were excluded for the immunogenicity outcome

Selective reporting (reporting bias)

Low risk

Immunogenicity and safety outcomes reported

Phase2 trial (ph2,4v)

Methods

Phase II randomised, multicentre, double‐blind, placebo‐controlled trial

Participants

1158 women enrolled for the study, among them 52 participants were included in study part A which was a dose‐escalation study, and the 1106 remaining women were included study part B which was a dose‐ranging study. In study part B, 554 were in intermediate‐/high‐dose groups and 552 were in low‐dose groups; 277 in low‐dose vaccine group and 275 in the placebo group

Age range: 16 to 23 years

Inclusion criteria: healthy women who were not pregnant, had no previous abnormal Pap smear and reported a lifetime history of four or fewer male sex partners. The study did not exclude women with previous HPV infection.Virgins were restricted to women of 18 years or older and seeking contraception

Interventions

Vaccine: quadrivalent HPV 6/11/16/18 L1 VLP

Placebo: visually indistinguishable aluminium‐containing placebo

Outcomes

Persistent infection (≥ 4 M or at last visit) associated with HPV 6,11,16 or 18, cervical or external genital lesions (CIN 1‐3, condylomata acuminata, vulvar intraepithelial neoplasia and vaginal intraepithelial neoplasia), immunogenicity, safety and tolerability

Notes

Main reports: Villa 2005; Villa 2006 and Villa 2006a

Last report average follow‐up time: 36 months and 60 months for a subset of 241 participants (Villa 2006a)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation to the placebo or vaccine arms was applied only on a part of the enrolled women (those included in the low‐dose group). The other women were enrolled in a dose‐escalating or dose‐ranging studies. Only women from the low‐dose group were included were used for the Cochrane Review

Allocation concealment (selection bias)

Unclear risk

No further details are provided on allocation concealment

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

The placebo was visually indistinguishable from the vaccine. Both the participants and the investigator and the staff were blinded to who received vaccine and who received placebo

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Biopsies were read for endpoint determination by a blinded panel of four pathologists

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcomes were assessed in the PP cohort (3 doses and DNA negative for the relevant HPV vaccine type) and the MITTmodified‐intention‐to‐treat cohort (at least 1 dose and DNA negative for the relevant HPV vaccine type) and reasons for exclusion were presented

Selective reporting (reporting bias)

Low risk

Alll outcomes (safety, immunogenicity and efficacy) presented

African_3 country trial (ph3,4v)

Methods

Phase III randomised, partially double‐blind trial

Participants

Participants: 250 women aged 9 to 26 years enrolled in Ghana, Kenya and Senegal. Only 100 women (9 to 12 years) were randomised to receive HPV vaccine or placebo and were considered in this review.

Age range: 9 to 12 years

Inclusion criteria: healthy, HIV‐uninfected women

Exclusion criteria: women who were pregnant, were allergic to any vaccine component, had received any blood product or component in the previous 6 months, had any known immune or coagulation disorder, or had received any inactivated vaccine product within 14 days before enrolment or any live vaccine product within 21 days before enrolment

Interventions

Vaccine: quadrivalent HPV vaccine

Placebo: visually indistinguishable aluminium‐containing placebo

Outcomes

Safety and immunogenicity outcomes

Notes

Report: Mugo 2015

Follow‐up: 7 months

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Girls were randomised in a 4:1 ratio to receive HPV vaccine or placebo

Allocation concealment (selection bias)

Unclear risk

Not described in the paper

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not described in the paper

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described in the paper

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All safety outcomes were reported for the total vaccinated cohort. Immunogenicity outcomes were reported for the according‐to‐protocol cohort. Reason for exclusion was noted and balanced between vaccine group and placebo group

Selective reporting (reporting bias)

Low risk

All outcomes (immunogenicity and safety) were presented

FUTURE I trial (ph3,4v)

Methods

Phase III randomised, placebo‐controlled, double‐blind trial

Participants

Participants: 5455 women (2723 women in the vaccine arm and 2732 in the placebo arm) from 62 study centres in 16 countries

Age range: 16 to 24 years

Inclusion criteria: healthy women who were not pregnant and had no history of genital warts or abnormal results on cervical cytologic testing, had a lifetime number of no more than four sex partners and agreed to use contraception during the vaccination period

Interventions

Vaccine: quadrivalent HPV 6/11/16/18 vaccine

Placebo: visually indistinguishable aluminium‐containing placebo

Outcomes

Efficacy (CIN of any grade, AIS, cervical cancer, VIN, VaIN, GW, vulvar‐vaginal cancer, Pap abnormalities), immunogenicity and safety

Notes

Main reports: Garland 2007;

Last report average follow‐up time: 4.9 years (Munoz 2010)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A computer‐based randomised allocation schedule provided by the statistician was used for sequence allocation

Allocation concealment (selection bias)

Low risk

An interactive voice response system was used to randomise participants within each study centre

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

The participants, investigator and sponsor were blinded to the allocated trial arm

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Central laboratory was unaware of treatment‐group assignment and HPV status. A panel of 4 pathologists was unaware of diagnosis made at the central laboratory, clinical findings, treatment group, and HPV status

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcomes are assessed in the PP cohort (received 3 doses without protocol violations, being HPV DNA negative for the relevant HPV vaccine type from enrolment to 1 month after dose 3), in the unrestricted susceptible group (all women who were negative on HPV DNA and serology negative for the relevant HPV vaccine type at enrolment) and in the ITT cohort (all participants who had undergone randomisation, regardless of baseline HPV status or presence of HPV‐associated an\anogenital disease). Reasons for exclusion were presented

Selective reporting (reporting bias)

Low risk

All outcomes (efficacy, safety and immunogenicity) reported

FUTURE II trial (ph3,4v)

Methods

Phase III randomised, placebo‐controlled, double‐blind trial.

Participants

Participants: 12167 women (6087 women in vaccine arm and 6080 women in the placebo arm) from 90 study centres in 13 countries.

Age range: 15 to 26 years.

Inclusion criteria: healthy women with an intact uterus, who were not pregnant and had no history of genital warts or abnormal results on cervical cytologic testing, had a lifetime number of no more than four sex partners and agreed to use contraception during the vaccination period

Interventions

Vaccine: Quadrivalent HPV6/11/16/18 vaccine

Placebo: visually indistinguishable aluminium‐containing placebo

Outcomes

Efficacy (CIN of any grade, AIS, cervical cancer, VIN, VaIN, GW, vulvar‐vaginal cancer, Pap abnormalities), safety and immunogenicity

Notes

Main reports: FUTURE‐II 2007 and Munoz 2010

Last report average follow‐up time: 4.9 years (Munoz 2010)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A computer‐based randomised allocation schedule provided by the statistician.was used for sequence allocation

Allocation concealment (selection bias)

Low risk

An interactive voice response system was used to randomise participants within each study centre

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

The participants, investigator and sponsor were blinded to the allocated trial arm

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Central laboratory was unaware of treatment‐group assignment and HPV status. A panel of 4 pathologists was unaware of diagnosis made at the central laboratory, clinical findings, treatment group, and HPV status

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcomes were assessed in the PP cohort (received 3 doses without protocol violations, being HPV DNA negative for the relevant HPV vaccine type from enrolment to 1 month after dose 3), in the unrestricted susceptible group (all women who were negative on HPV DNA and serology negative for the relevant HPV vaccine type at enrolment) and in the ITT cohort (all participants who had undergone randomisation, regardless of baseline HPV status or presence of HPV‐associated anogenital disease). Reasons for exclusion were presented

Selective reporting (reporting bias)

Low risk

All outcomes (efficacy, safety and immunogenicity) reported

FUT I/II trials (ph3,4v)

Methods

Pooling of two phase III randomised, placebo‐controlled, double‐blind trials

Participants

Participants: 17,622 women (see FUTURE I and FUTURE II trials for more details)

Age range: 16 to 26 years

Interventions

Vaccine: Quadrivalent HPV6/11/16/18 vaccine

Placebo: visually indistinguishable aluminium‐containing placebo

Outcomes

Efficacy (CIN of any grade, AIS, cervical cancer, VIN, VaIN, GW, vulvar‐vaginal cancer, Pap abnormalities), safety and immunogenicity

Notes

Main report: Munoz 2010

Last report average follow‐up time: 4.9 years

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

See FUTURE I & II trials

Allocation concealment (selection bias)

Low risk

See FUTURE I & II trials

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

See FUTURE I & II trials

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

See FUTURE I & II trials

Incomplete outcome data (attrition bias)
All outcomes

Low risk

See FUTURE I & II trials

Selective reporting (reporting bias)

Low risk

All outcomes (efficacy, safety and immunogenicity) reported

FUTURE III trial (ph3,4v)

Methods

Phase III randomised, double‐blind, controlled trial

Participants

Participants: 3819 women (1911 in the vaccine arm and 1908 in the placebo arm) enrolled in 38 international study sites from 7 countries.

Age range: 24 to 45 years

Inclusion criteria: women were not pregnant, who had not undergone hysterectomy and agreed to use effective contraception until month 7 of the study

Exclusion criteria: women were excluded if they have a history of surgical cervical procedure, had biopsy less than 5 years ago, had history of genital warts and cervical disease. Women infected with HIV and those who were immunocompromised were not eligible for enrolment

Interventions

Vaccine: quadrivalent vaccine

Placebo: visually indistinguishable aluminium‐containing placebo

Outcomes

Efficacy (persistent HPV infection, CIN, condyloma, VIN or VaIN), safety and immunogenicity outcomes

Notes

Main reports: Munoz 2009 and Castellsagué 2011

Last report average follow‐up time: 48 months ( Castellsagué 2011)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A computer‐generated allocation schedule was generated by the sponsor's Clinical Biostatistics department

Allocation concealment (selection bias)

Low risk

Randomised to a vaccination group using an interactive Voice Response System

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

All study‐site investigators and personnel, study participants, monitors, and central laboratory personnel were blinded to treatment allocation throughout the study

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Biopsy material was first read for clinical management by pathologists at a central laboratory, and then read for endpoint determination by a blinded panel of 4 pathologists

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcomes were assessed in the PP cohort (received 3 doses, seronegative at day 1 and HPV DNA negative for the HPV vaccine types from day 0 until month 7, no protocol violations), in the naive to the relevant type (NRT) cohort (at least 1 dose, seronegative at day 1 and HPV DNA negative for the HPV vaccine types on day 1) and in the ITT‐cohort (at least 1 dose, irrespective of initial HPV status, protocol violators included)

Selective reporting (reporting bias)

Low risk

All outcomes (safety, immunogenicity and efficacy) are presented

AIS: adenocarcinoma in situ
ASC: atypical squamous cells
ASC‐US: atypical squamous cells of undetermined significance
CIN: cervical intraepithelial neoplasia
DNA: Desoxyribo‐nucleic acid
ELISA: enzyme‐linked immunosorbent assay
GSK: GlaxoSmithKline
GW: genital wart
HPV: human papillomavirus
ITT: intention‐to‐treat
LEEP: loop electrosurgical excision procedure
LSIL: low‐grade squamous intraepithelial lesion
MITT: modified intention‐to‐treat
PATRICIA: PApiloma TRIal against Cancer In young Adults
PCR: polymerase chain reaction
PP: per‐protocol
TVC: total vaccinated cohort
VAIN: Vaginal intra‐epithelial neoplasia,
VIN: vaginal intraepithelial neoplasia
VLP: virus‐like particles

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Angelo 2014

Post‐licensure safety surveillance over more than 4 years of routine use of HPV bivalent vaccine. Not a randomised controlled trial.

Arguedas 2010

Randomised trial to evaluate Novartis vaccines co‐administrated with Tdap vaccine and HPV vaccine. No HPV alone group.

Ault 2004

Phase I trial.

Ault 2007

Pooled analysis of 4 RCTs on both bivalent and quadrivalent vaccine. No new original data were presented.

Basu 2013

A review of evidence from phase III trials and national immunisation programs regarding efficacy and safety of HPV vaccines.

Beachler 2016

Efficacy of the bivalent vaccine against cervical, anal and oral infection in a sub‐cohort nested in the CVT trial. Cervical outcomes already included.

Brown 2004

Post hoc analysis using combined data from two Phase I tolerability/immunogenicity trials.

Couto 2014

Systemactic review and meta‐analysis of protection of HPV vaccines against CIN, VIN, VAIN, and genital warts in catch‐up populations. No Original data, not a randomised controlled trial.

D'Addario 2017

Systematic review and meta‐analysis of the immunogenicity of the 2‐dose vaccination schedule versus 3‐dose schedule.

D'Souza 2013

A case‐study on HPV vaccination national programme in Australia for future innovation prevention.

De Vincenzo 2014

Review of the long‐term efficacy and safety of HPV vaccines. No original data.

Delere 2013

Assessment of HPV vaccine update and post‐vaccination cervical cancer prevention in Germany. Not a randomised controlled trial.

Denny 2013

Randomised trial assessing safety and immunogenicity in HIV‐positive women (N = 120 randomised to bivalent vaccine or placebo). 30 HIV seronegative women all received the bivalent vaccine.

Descamps 2009

Pooled analysis on safety of the bivalent vaccine including 11 studies. Not all were randomised trials.

Dobson 2013

Randomised phase III trial assessing immunogenicity after two versus three doses of the quadrivalent vaccine. No vaccine efficacy data.

Draper 2011

Non randomised study assessing presence of neutralising antibodies of non‐vaccine HPV types in girls vaccinated with the bivalent vaccine.

Draper 2013

Randomised trial comparing generation of cross‐protecting antibodies in serum and vaginal mucus among girls receiving bivalent versus quadrivalent vaccine. No vaccine efficacy data. No placebo group included in the RCT.

Einstein 2009

Randomised trial comparing safety and generation of antiHPV16/18 antibodies in serum and vaginal mucus among girls receiving bivalent versus quadrivalent vaccine (7 months after 3rd dose). No vaccine efficacy data. No placebo group included in the RCT.

Einstein 2011

Randomised trial comparing safety and generation of antiHPV16/18 antibodies in serum and vaginal mucus among girls receiving bivalent versus quadrivalent vaccine (12 months after 3rd dose). No vaccine efficacy data. No placebo group included in the RCT.

Evans 2001

Dose‐escalation phase I trial addressing immunological response and safety after administration of an L1 HPV11 vaccine.

Forinash 2011

Systematic review on pregnancy outcomes of bi‐ and quadrivalent vaccines using data from RCTs and post‐marketing surveillance.

Garland 2016

Post‐hoc analysis of the bivalent HPV vaccine against the recurrent of the high‐grade CIN after surgical therapy.

Giuliano 2007

Pooled analysis of phase II/III trials assessing immunogenicity according to baseline covariates. No original data. No vaccine‐efficacy or safety data.

Giuliano 2011

Phase III trial assessing safety and efficacy of vaccination with the quadrivalent vaccine in men.

Giuliano 2015

Immunogenicity and safety of Gardasil vaccine among mid‐adult aged men of 27 to 45 years. No data on women.

Goldstone 2013

Quadrivalent HPV vaccine efficacy against disease related to vaccine and non‐vaccine HPV types in men.

Harro 2001

Phase I dose‐escalation trial assessing immunogenicity and safety of a mono‐valent HPV16 vaccine.

Haupt 2011

Pooled analysis of 2 RCTs assessing the incidence of CIN2+/AIS+ related to HPV 16/18 in women who received the quadrivalent vaccine or placebo and who were HPV16/18 DNA and seropositive. The data of the separate studies are already included in the review.

Heijstek 2014

Cohort study on immunogenicity and safety of the bivalent HPV vaccines in female patients with juvenile idiopathic arthritis. Not a randomised controlled trial.

Hernandez‐Avila 2016

Non randomised trial to evaluate the immunogenicity of the quadrivalent HPV vaccine using 2 versus 3 doses, An observational surveillance study to evaluate alternative vaccination schedules.

Herrero 2013

Report from the Costa Rica vaccination trial assessing effect of the bivalent vaccine on oral HPV infection.

Hildesheim 2007

Report of the Costa Rica trial assessing the effect of the bivalent vaccine on clearance of existing HPV infection.

Hillman 2011

Phase III randomised trial assessing immunogenicity of the quadrivalent vaccine in men.

Joura 2007

Pooled analyses of three randomised trials assessing protection of the quadrivalent vaccine against vulval and vaginal intraepithelial lesions. Protection against cervical lesions was not addressed.

Kahn 2013

Immunogenicity and safety of the human papillomavirus 6, 11, 16, 18 vaccine in HIV‐infected young women.

Kang 2013

Non randomised study assessing effect of the quadrivalent vaccine on the incidence of recurrence of CIN in women treated by excision for high‐grade CIN.

Khatun 2012

Girls randomised to the experimental arm received the bivalent vaccine, those in the control arm did not receive anything. The trial was not placebo‐controlled. Observation of effects were restricted to participants in the experimental arm.

Kjaer 2009

A pooled analysis of efficacy of quadrivalent HPV vaccines against cervical and genital lesions. No separate data on FUTURE I and FUTURE II trials. The data of the separate studies are already included in the review.

Kreimer 2015

Discussion about conducting a randomised clinical trial to assess the efficacy of a single dose of prophylactic HPV vaccines among adolescent. No original data.

Lamontagne 2013

Immunogenicity of quadrivalent HPV vaccine among girls aged 11 to 13 years of age vaccinated using alternative dosing schedules.

Lang 2014

A nested analysis of CVT trial on vaccine efficacy against vulvar HPV infection. Cervical outcomes from the trial have been included in the review.

Lazcano‐Ponce 2014

Non‐inferiority of antibody response to human papillomavirus 16/18 vaccine in adolescents vaccinated with alternative dosing schedules.

Lehtinen 2016

Phase IV RCT to evaluate the effectiveness, safety and immunogenicity of Cervarix in boys and girls aged 12‐15 years in Finland.

Leroux‐Roels 2011

Randomised trial assessing safety and immunogenicity of vaccination with the hepatitis‐B vaccine alone versus co‐administration of the hepatitis‐B vaccine with the bivalent HPV vaccine. No HPV alone group.

Leung 2015

Non RCT to compare immunogenicity and safety of 2‐dose bivalent, 2‐dose quadrivalent and 3‐dose quadrivalent vaccination schedule among girls aged 9‐14 years.

Li 2012

Randomised trial assessing safety and immunogenicity of the quadrivalent vaccine in a group of Chinese women and men. Outcomes are presented jointly. Data separated by gender were requested from the authors with no response.

Lin 2014

Randomised controlled trial of two dosing schedules for human papillomavirus vaccination among college‐age men.

Lu 2011

Systematic review and meta‐analysis of vaccine efficacy and safety of the bivalent vaccine.

Luna 2013

Follow‐up report (up to 6 years after dose 1) of the Columbian cohort of the FUTURE III trial, assessing the safety, immunogenicity and protection against the joint ocutome of CIN and extra‐genital lesions combined of the quadrivalent vaccine. No separated data for protection against CIN2+ were reported.

Malagon 2012

Systematic review and meta‐analysis on cross‐protection of the bi‐ and quadrivalent vaccines.

McCormack 2011

Review paper on the efficacy of the quadrivalent vaccine.

McKeage 2011

Review paper on the efficacy of the bivalent vaccine.

Money 2016

Not a randomised trial. Only HIV+ girls or women enrolled.

Moreira 2011

Randomised trial assessing the safety of vaccination with the quadrivalent vaccine in men

Nakalembe 2015

Review of safety, immunogenicity and efficacy of HPV vaccines in low‐ and middle‐income countries. No original data.

Nelson 2013

Randomised comparison of safety and immunogenicity of the bi‐ and quadrivalent vaccine administered by intra‐muscular versus intradermal injection. No placebo comparison group.

Neuzil 2011

Randomised trial assessing safety and immunogenicity of four alternative schedules of administration of the quadrivalent vaccine in Vietnamese girls. No placebo group.

Olsson 2009

A pooled analysis of efficacy and safety of quadrivalent HPV vaccines on women with previous HPV infection. No separate data on FUTURE I and FUTURE II trials. The data of the separate studies are already included in the review.

Palefsky 2011

Randomised trial assessing the effect of vaccination with the quadrivalent vaccine on anal HPV infection and AIN in men

Pedersen 2007

Immunobridging study assessing immunogenicity and safety of the bivalent HPV vaccines in women aged 15‐25 years and 10‐14 years. Not a randomised controlled trial and all participants received the bivalent vaccines.

Perez 2008

Pooled analysis of RCTs of the efficacy of the quadrivalent vaccine regarding protection against HPV‐related lesions, restricted to the Latin‐American cohorts included in the phase II and III trials (FUTURE II trial (ph3,4v); FUTURE I trial (ph3,4v); Phase2 trial (ph2,4v)). The data of the separate studies are already included in the review.

Petaja 2009

Randomised trial assessing the immunogenicity and safety of vaccination with the bivalent vaccine in boys.

Petaja 2011

Trial assessing long‐term (at 48 months) safety and immunogenicity (antibodies in serum and cervicovaginal secretions) of the bivalent vaccine. No placebo group.

Poland 2005

Dose‐ranging study assessing safety and immunogenicity of a monovalent HPV16 vaccine.

Puthanakit 2016

Randomised open trial to compare 2‐dose versus 3‐dose regimens of the bivalent vaccine in terms of immunogenicity and safety. No placebo group.

Ramanakumar 2016

Incidence and duration of type‐specific human papillomavirus infection in high‐risk HPV‐naive women. Post study results of Phase2 trial (ph2,2v) trial.

Read 2011

Surveillance of the incidence of genital warts before and after introduction of HPV vaccination in Australia. Not a randomised controlled trial.

Reisinger 2007

Randomised controlled trial assessing the safety and persistent immunogenicity of quadrivalent HPV vaccine in a group of boys and girls. Outcomes were presented jointly. Author was contacted to request data separated by gender. The author responded that separated data were not available.

Reisinger 2010

Randomised open‐label study to assess the safety, tolerability and immunogenicity of quadrivalent vaccine co‐administrated with enactra and Adacel vaccine. No quadrivalent only group and no separate data between girls and boys.

Romanowski 2016

Five‐year sustained immunogenicity of the bivalent vaccine administered as a 2‐dose schedule in girls aged 9‐14 years. No placebo group.

Rowhani‐Rahbar 2012

Trial demonstrating immune memory after administration of a dose of quadrivalent vaccine to women enrolled 8.5 years before in a phase II trial assessing the effects of the monovalent HPV16 vaccine.

Safaeian 2013

Cross‐protection efficacy against HPV 31 of bivalent vaccine, results from Costa Rica trials.

Schwarz 2008

Review of the immunological response, including the induction of immune memory after vaccination with the bivalent vaccine. No original data.

Schwarz 2009

Non randomised trial assessing immunogenicity and tolerability of the bivalent vaccine in female participants aged 15‐55 years from Germany and Poland.

Schwarz 2010

Non randomised trial assessing presence of HPV antibodies in serum and cervicovaginal secretions of induced by the bivalent vaccine in female participants aged 15‐55 years from Germany and Poland.

Schwarz 2011

Follow‐up study to the Schwarz 2009 report.

Schwarz 2014

An open follow‐up study of an RCT on safety and immunogenicity of bivalent vaccine in girls aged 10‐13 years. Medina 2010 trial.

Sengupta 2011

Correspondence about HPV vaccine trials in India. No extractable original data.

Singhal 2011

Correspondence about HPV vaccine trials in India. No extractable original data.

Skinner 2016

Systematic review on the efficacy of bivalent vaccine summarized from 6 RCTs. No original data.

Smith‐McCune 2010

Short review on pregnancy outcomes after vaccination against HPV. No original data.

Srinivasan 2011

Review article. No original data.

Toft 2014

RCT to compare of the immunogenicity and reactogenicity of Cervarix and Gardasil human papillomavirus vaccines in HIV‐infected adults.

Van Klooster 2011

Surveillance study assessing occurrence of adverse effects reported after HPV vaccination in the Netherlands.

Vesikari 2010

Randomised open‐label study to assess the safety, tolerability and immunogenicity of quadrivalent vaccine co‐administrated with REPEVAX vaccine. No quadrivalent only group and no separate data between girls and boys.

Wheeler 2008

Randomised open‐label study to assess the safety, tolerability and immunogenicity of quadrivalent vaccine co‐administrated with Hepatitis B vaccine. No quadrivalent only group.

Wheeler 2011

Trial assessing reactogenicity and immunogenicity of Tdap (tetanosdiphteria, pertussis) and MCV4 (meningococcal polysaccharide & diphtheria toxoid) vaccines when given alone or co‐administrated with the bivalent HPV vaccine. Not a randomised controlled trial.

Yancey 2010

Systematic review on vaccine immunogenicity and efficacy in men.

Zhu 2011

Non randomised phase I trial on safety and immunogenicity of the bivalent vaccine,conducted in China (female participants aged 15‐45 years).

Zimmerman 2010

Randomised trial assessing the immunogenicity of the quadrivalent vaccine with two alternative schedules (months 0,2 & 6, versus months 0, 2 & 12).

AIS: adenocarcinoma in situ
CIN: cervical intraepithelial neoplasia
CVT: Costa Rica Vaccination Trial
HPV: human papillomavirus
RCT: randomised controlled trial
Tdap: tetanosdiphteria, pertussis
VAIN: Vaginal intra‐epithelial neoplasia,
VIN: vaginal intraepithelial neoplasia

Data and analyses

Open in table viewer
Comparison 1. High‐grade cervical lesions in hrHPV DNA negative women at baseline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 CIN2+ associated with HPV16/18, at least 1 dose Show forest plot

3

23676

Risk Ratio (IV, Random, 95% CI)

0.01 [0.00, 0.05]

Analysis 1.1

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 1 CIN2+ associated with HPV16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 1 CIN2+ associated with HPV16/18, at least 1 dose.

2 CIN2+ associated with HPV6/11/16/18, at least 1 dose Show forest plot

1

9296

Risk Ratio (IV, Random, 95% CI)

0.01 [0.00, 0.09]

Analysis 1.2

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 2 CIN2+ associated with HPV6/11/16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 2 CIN2+ associated with HPV6/11/16/18, at least 1 dose.

3 CIN3+ associated with HPV16/18, at least 1 dose Show forest plot

2

20214

Risk Ratio (IV, Random, 95% CI)

0.01 [0.00, 0.10]

Analysis 1.3

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 3 CIN3+ associated with HPV16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 3 CIN3+ associated with HPV16/18, at least 1 dose.

4 CIN3+ associated with HPV6/11/16/18, at least 1 dose Show forest plot

1

9296

Risk Ratio (IV, Random, 95% CI)

0.01 [0.00, 0.18]

Analysis 1.4

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 4 CIN3+ associated with HPV6/11/16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 4 CIN3+ associated with HPV6/11/16/18, at least 1 dose.

5 AIS associated with HPV16/18, at least 1 dose Show forest plot

2

20214

Risk Ratio (IV, Random, 95% CI)

0.10 [0.01, 0.82]

Analysis 1.5

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 5 AIS associated with HPV16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 5 AIS associated with HPV16/18, at least 1 dose.

6 AIS associated with HPV6/11/16/18, at least 1 dose Show forest plot

1

9296

Risk Ratio (IV, Random, 95% CI)

0.14 [0.01, 2.80]

Analysis 1.6

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 6 AIS associated with HPV6/11/16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 6 AIS associated with HPV6/11/16/18, at least 1 dose.

7 Any CIN2+ irrespective of HPV types, at least 1 dose Show forest plot

5

25180

Risk Ratio (IV, Random, 95% CI)

0.37 [0.25, 0.55]

Analysis 1.7

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 7 Any CIN2+ irrespective of HPV types, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 7 Any CIN2+ irrespective of HPV types, at least 1 dose.

7.1 Bivalent vaccine

4

15884

Risk Ratio (IV, Random, 95% CI)

0.33 [0.25, 0.43]

7.2 Quadrivalent vaccine

1

9296

Risk Ratio (IV, Random, 95% CI)

0.57 [0.44, 0.76]

8 Any CIN3+ irrespective of HPV types, at least 1 dose Show forest plot

3

20719

Risk Ratio (IV, Random, 95% CI)

0.21 [0.04, 1.10]

Analysis 1.8

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 8 Any CIN3+ irrespective of HPV types, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 8 Any CIN3+ irrespective of HPV types, at least 1 dose.

8.1 Bivalent vaccine

2

11423

Risk Ratio (IV, Random, 95% CI)

0.08 [0.03, 0.23]

8.2 Quadrivalent vaccine

1

9296

Risk Ratio (IV, Random, 95% CI)

0.54 [0.36, 0.82]

9 Any AIS irrespective of HPV types, at least 1 dose Show forest plot

2

20214

Risk Ratio (IV, Random, 95% CI)

0.10 [0.01, 0.76]

Analysis 1.9

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 9 Any AIS irrespective of HPV types, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 9 Any AIS irrespective of HPV types, at least 1 dose.

Open in table viewer
Comparison 2. High‐grade cervical lesions in HPV16/18 DNA negative women at baseline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 CIN2+ associated with HPV16/(18), 3 doses Show forest plot

8

43376

Risk Ratio (IV, Random, 95% CI)

0.08 [0.04, 0.16]

Analysis 2.1

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 1 CIN2+ associated with HPV16/(18), 3 doses.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 1 CIN2+ associated with HPV16/(18), 3 doses.

1.1 Age group 15‐26 years

6

36579

Risk Ratio (IV, Random, 95% CI)

0.07 [0.03, 0.15]

1.2 Age group 24‐45 years

2

6797

Risk Ratio (IV, Random, 95% CI)

0.16 [0.04, 0.74]

2 CIN2+ associated with HPV16/(18), at least 1 dose Show forest plot

8

42030

Risk Ratio (IV, Random, 95% CI)

0.10 [0.05, 0.20]

Analysis 2.2

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 2 CIN2+ associated with HPV16/(18), at least 1 dose.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 2 CIN2+ associated with HPV16/(18), at least 1 dose.

2.1 Age group 15‐26 years

6

34478

Risk Ratio (IV, Random, 95% CI)

0.05 [0.03, 0.10]

2.2 Age group 24‐45 years

2

7552

Risk Ratio (IV, Random, 95% CI)

0.30 [0.11, 0.81]

3 CIN2+ associated with HPV16/(18), 1 or 2 doses (post hoc analysis) Show forest plot

7

3713

Risk Ratio (IV, Random, 95% CI)

0.19 [0.07, 0.51]

Analysis 2.3

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 3 CIN2+ associated with HPV16/(18), 1 or 2 doses (post hoc analysis).

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 3 CIN2+ associated with HPV16/(18), 1 or 2 doses (post hoc analysis).

3.1 women age 15‐26 years

5

2958

Risk Ratio (IV, Random, 95% CI)

0.10 [0.04, 0.26]

3.2 women age 24‐45 years

2

755

Risk Ratio (IV, Random, 95% CI)

0.61 [0.14, 2.67]

4 CIN2+ associated with HPV6/11/16/18, 3 doses Show forest plot

2

7664

Risk Ratio (IV, Random, 95% CI)

0.06 [0.01, 0.61]

Analysis 2.4

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 4 CIN2+ associated with HPV6/11/16/18, 3 doses.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 4 CIN2+ associated with HPV6/11/16/18, 3 doses.

4.1 Age group 15‐26 years

1

4499

Risk Ratio (IV, Random, 95% CI)

0.02 [0.00, 0.25]

4.2 Age group 24‐45 years

1

3165

Risk Ratio (IV, Random, 95% CI)

0.17 [0.02, 1.39]

5 CIN2+ associated with HPV6/11/16/18, at least 1 dose Show forest plot

2

8980

Risk Ratio (IV, Random, 95% CI)

0.08 [0.00, 2.41]

Analysis 2.5

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 5 CIN2+ associated with HPV6/11/16/18, at least 1 dose.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 5 CIN2+ associated with HPV6/11/16/18, at least 1 dose.

5.1 Age group 15‐26 years

1

5351

Risk Ratio (IV, Random, 95% CI)

0.01 [0.00, 0.19]

5.2 Age group 24‐45 years

1

3629

Risk Ratio (IV, Random, 95% CI)

0.37 [0.10, 1.41]

6 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses (post hoc analysis) Show forest plot

2

1316

Risk Ratio (IV, Random, 95% CI)

0.24 [0.01, 5.00]

Analysis 2.6

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 6 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses (post hoc analysis).

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 6 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses (post hoc analysis).

6.1 Age group 15‐26 years

1

852

Risk Ratio (IV, Random, 95% CI)

0.04 [0.00, 0.74]

6.2 Age group 24‐45 years

1

464

Risk Ratio (IV, Random, 95% CI)

0.97 [0.14, 6.80]

7 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 3 doses Show forest plot

3

29720

Risk Ratio (IV, Random, 95% CI)

0.07 [0.02, 0.29]

Analysis 2.7

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 7 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 3 doses.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 7 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 3 doses.

8 CIN3+ associated with HPV 16/18 or HPV6/11/16/18, at least 1 dose Show forest plot

3

33199

Risk Ratio (IV, Random, 95% CI)

0.05 [0.02, 0.14]

Analysis 2.8

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 8 CIN3+ associated with HPV 16/18 or HPV6/11/16/18, at least 1 dose.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 8 CIN3+ associated with HPV 16/18 or HPV6/11/16/18, at least 1 dose.

9 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis) Show forest plot

3

3479

Risk Ratio (IV, Random, 95% CI)

0.06 [0.01, 0.24]

Analysis 2.9

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 9 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis).

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 9 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis).

10 AIS associated with HPV16/18 or HPV6/11/16/18, 3 doses Show forest plot

3

29707

Risk Ratio (IV, Random, 95% CI)

0.12 [0.02, 0.70]

Analysis 2.10

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 10 AIS associated with HPV16/18 or HPV6/11/16/18, 3 doses.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 10 AIS associated with HPV16/18 or HPV6/11/16/18, 3 doses.

11 AIS associated with HPV16/18 or 6/11/16/18, at least 1 dose Show forest plot

2

17079

Risk Ratio (IV, Random, 95% CI)

0.09 [0.01, 0.72]

Analysis 2.11

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 11 AIS associated with HPV16/18 or 6/11/16/18, at least 1 dose.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 11 AIS associated with HPV16/18 or 6/11/16/18, at least 1 dose.

12 AIS associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis) Show forest plot

2

2015

Risk Ratio (IV, Random, 95% CI)

0.15 [0.01, 2.97]

Analysis 2.12

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 12 AIS associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis).

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 12 AIS associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis).

13 Any CIN2+ irrespective of HPV types, 3 doses Show forest plot

3

7320

Risk Ratio (IV, Random, 95% CI)

0.40 [0.25, 0.64]

Analysis 2.13

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 13 Any CIN2+ irrespective of HPV types, 3 doses.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 13 Any CIN2+ irrespective of HPV types, 3 doses.

14 Any CIN2+ irrespective of HPV types, at least 1 dose Show forest plot

3

19143

Risk Ratio (IV, Random, 95% CI)

0.41 [0.32, 0.52]

Analysis 2.14

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 14 Any CIN2+ irrespective of HPV types, at least 1 dose.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 14 Any CIN2+ irrespective of HPV types, at least 1 dose.

15 Any CIN2+ irrespective of HPV types, 1 or 2 doses (post hoc analysis) Show forest plot

1

34

Risk Ratio (IV, Random, 95% CI)

0.71 [0.15, 3.38]

Analysis 2.15

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 15 Any CIN2+ irrespective of HPV types, 1 or 2 doses (post hoc analysis).

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 15 Any CIN2+ irrespective of HPV types, 1 or 2 doses (post hoc analysis).

Open in table viewer
Comparison 3. High‐grade cervical lesions in women regardless of baseline HPV DNA status

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 CIN2+ associated with HPV16/18, at least 1 dose Show forest plot

5

44052

Risk Ratio (IV, Random, 95% CI)

0.52 [0.41, 0.67]

Analysis 3.1

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 1 CIN2+ associated with HPV16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 1 CIN2+ associated with HPV16/18, at least 1 dose.

1.1 Age group 15‐26 years

3

34852

Risk Ratio (IV, Random, 95% CI)

0.46 [0.37, 0.57]

1.2 Age group 24‐45 years

2

9200

Risk Ratio (IV, Random, 95% CI)

0.74 [0.52, 1.05]

2 CIN2+ associated with HPV6/11/16/18, at least 1 dose Show forest plot

2

20883

Risk Ratio (IV, Random, 95% CI)

0.57 [0.38, 0.86]

Analysis 3.2

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 2 CIN2+ associated with HPV6/11/16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 2 CIN2+ associated with HPV6/11/16/18, at least 1 dose.

2.1 Age group 15‐26 years

1

17160

Risk Ratio (IV, Random, 95% CI)

0.50 [0.42, 0.59]

2.2 Age group 24‐45 years

1

3723

Risk Ratio (IV, Random, 95% CI)

0.78 [0.44, 1.37]

3 CIN3+ associated with HPV16/18, at least 1 dose Show forest plot

2

34562

Risk Ratio (IV, Random, 95% CI)

0.55 [0.45, 0.67]

Analysis 3.3

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 3 CIN3+ associated with HPV16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 3 CIN3+ associated with HPV16/18, at least 1 dose.

4 CIN3+ associated with HPV6/11/16/18, at least 1 dose Show forest plot

1

17160

Risk Ratio (IV, Random, 95% CI)

0.54 [0.43, 0.68]

Analysis 3.4

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 4 CIN3+ associated with HPV6/11/16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 4 CIN3+ associated with HPV6/11/16/18, at least 1 dose.

5 AIS associated with HPV16/18, at least 1 dose Show forest plot

2

34562

Risk Ratio (IV, Random, 95% CI)

0.36 [0.17, 0.78]

Analysis 3.5

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 5 AIS associated with HPV16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 5 AIS associated with HPV16/18, at least 1 dose.

6 AIS associated with HPV6/11/16/18, at least 1 dose Show forest plot

2

20830

Risk Ratio (IV, Random, 95% CI)

0.40 [0.16, 0.98]

Analysis 3.6

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 6 AIS associated with HPV6/11/16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 6 AIS associated with HPV6/11/16/18, at least 1 dose.

7 Any CIN2+ irrespective of HPV types, at least 1 dose Show forest plot

6

45066

Risk Ratio (IV, Random, 95% CI)

0.79 [0.65, 0.97]

Analysis 3.7

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 7 Any CIN2+ irrespective of HPV types, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 7 Any CIN2+ irrespective of HPV types, at least 1 dose.

7.1 Age group 15‐26 years

4

35779

Risk Ratio (IV, Random, 95% CI)

0.70 [0.58, 0.85]

7.2 Age group 24‐45 years

2

9287

Risk Ratio (IV, Random, 95% CI)

1.04 [0.83, 1.30]

8 Any CIN3+ HPV type, at least 1 dose Show forest plot

3

35489

Risk Ratio (IV, Random, 95% CI)

0.67 [0.49, 0.93]

Analysis 3.8

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 8 Any CIN3+ HPV type, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 8 Any CIN3+ HPV type, at least 1 dose.

8.1 Bivalent vaccine

2

18329

Risk Ratio (IV, Random, 95% CI)

0.55 [0.43, 0.71]

8.2 Quadrivalent vaccine

1

17160

Risk Ratio (IV, Random, 95% CI)

0.81 [0.69, 0.96]

9 Any AIS irrespective of HPV types, at least 1 dose Show forest plot

2

34562

Risk Ratio (IV, Random, 95% CI)

0.32 [0.15, 0.67]

Analysis 3.9

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 9 Any AIS irrespective of HPV types, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 9 Any AIS irrespective of HPV types, at least 1 dose.

Open in table viewer
Comparison 4. Infection with HPV vaccine types in hrHPV DNA negative women at baseline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Incident HPV16/18 infection, 3 doses Show forest plot

1

368

Risk Ratio (IV, Random, 95% CI)

0.06 [0.02, 0.20]

Analysis 4.1

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 1 Incident HPV16/18 infection, 3 doses.

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 1 Incident HPV16/18 infection, 3 doses.

2 Persistent HPV16/18 infection (6M), 3 doses Show forest plot

1

368

Risk Ratio (IV, Random, 95% CI)

0.02 [0.00, 0.35]

Analysis 4.2

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 2 Persistent HPV16/18 infection (6M), 3 doses.

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 2 Persistent HPV16/18 infection (6M), 3 doses.

3 Persistent HPV16/18 infection (6M), at least 1 dose Show forest plot

1

10826

Risk Ratio (IV, Random, 95% CI)

0.07 [0.05, 0.09]

Analysis 4.3

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 3 Persistent HPV16/18 infection (6M), at least 1 dose.

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 3 Persistent HPV16/18 infection (6M), at least 1 dose.

4 Persistent HPV16/18 infection(12M), 3 doses Show forest plot

1

368

Risk Ratio (IV, Random, 95% CI)

0.04 [0.00, 0.73]

Analysis 4.4

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 4 Persistent HPV16/18 infection(12M), 3 doses.

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 4 Persistent HPV16/18 infection(12M), 3 doses.

5 Persistent HPV16/18 infection (12M), at least 1 dose Show forest plot

2

14153

Risk Ratio (IV, Random, 95% CI)

0.08 [0.05, 0.12]

Analysis 4.5

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 5 Persistent HPV16/18 infection (12M), at least 1 dose.

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 5 Persistent HPV16/18 infection (12M), at least 1 dose.

Open in table viewer
Comparison 5. HPV16/18 infection in HPV16/18 DNA negative women at baseline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Incident HPV16/18 infection, 3 doses Show forest plot

4

8034

Risk Ratio (IV, Random, 95% CI)

0.17 [0.10, 0.31]

Analysis 5.1

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 1 Incident HPV16/18 infection, 3 doses.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 1 Incident HPV16/18 infection, 3 doses.

2 Incident HPV16/18 infection, at least 1 dose Show forest plot

5

23872

Risk Ratio (IV, Random, 95% CI)

0.23 [0.14, 0.37]

Analysis 5.2

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 2 Incident HPV16/18 infection, at least 1 dose.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 2 Incident HPV16/18 infection, at least 1 dose.

3 Incident HPV16/18 infection, 1 or 2 doses (post hoc analysis) Show forest plot

3

331

Risk Ratio (IV, Random, 95% CI)

0.47 [0.26, 0.84]

Analysis 5.3

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 3 Incident HPV16/18 infection, 1 or 2 doses (post hoc analysis).

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 3 Incident HPV16/18 infection, 1 or 2 doses (post hoc analysis).

4 Persistent HPV16/18 infection (6M), 3 doses Show forest plot

8

34113

Risk Ratio (IV, Random, 95% CI)

0.07 [0.06, 0.09]

Analysis 5.4

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 4 Persistent HPV16/18 infection (6M), 3 doses.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 4 Persistent HPV16/18 infection (6M), 3 doses.

4.1 Age group 15‐26 years

6

27385

Risk Ratio (IV, Random, 95% CI)

0.06 [0.05, 0.08]

4.2 Age group 24‐45 years

2

6728

Risk Ratio (IV, Random, 95% CI)

0.11 [0.06, 0.20]

5 Persistent HPV16/18 infection (6M), at least 1 dose Show forest plot

6

30323

Risk Ratio (IV, Random, 95% CI)

0.12 [0.08, 0.17]

Analysis 5.5

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 5 Persistent HPV16/18 infection (6M), at least 1 dose.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 5 Persistent HPV16/18 infection (6M), at least 1 dose.

5.1 Age group 15‐26 years

4

22803

Risk Ratio (IV, Random, 95% CI)

0.10 [0.08, 0.12]

5.2 Age group 24‐45 years

2

7520

Risk Ratio (IV, Random, 95% CI)

0.17 [0.10, 0.29]

6 Persistent HPV16/18 infection (6M), 1 or 2 doses (post hoc analysis) Show forest plot

4

1229

Risk Ratio (IV, Random, 95% CI)

0.26 [0.16, 0.44]

Analysis 5.6

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 6 Persistent HPV16/18 infection (6M), 1 or 2 doses (post hoc analysis).

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 6 Persistent HPV16/18 infection (6M), 1 or 2 doses (post hoc analysis).

6.1 Age group 15‐26 years

2

437

Risk Ratio (IV, Random, 95% CI)

0.12 [0.03, 0.42]

6.2 Age group 24‐45 years

2

792

Risk Ratio (IV, Random, 95% CI)

0.31 [0.18, 0.54]

7 Persistent HPV6/11/16/18 infection (6M), 3 doses Show forest plot

2

4008

Risk Ratio (IV, Random, 95% CI)

0.12 [0.06, 0.21]

Analysis 5.7

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 7 Persistent HPV6/11/16/18 infection (6M), 3 doses.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 7 Persistent HPV6/11/16/18 infection (6M), 3 doses.

8 Persistent HPV6/11/16/18 infection (6M), at least 1 dose Show forest plot

2

4129

Risk Ratio (IV, Random, 95% CI)

0.13 [0.05, 0.37]

Analysis 5.8

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 8 Persistent HPV6/11/16/18 infection (6M), at least 1 dose.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 8 Persistent HPV6/11/16/18 infection (6M), at least 1 dose.

9 Persistent HPV16/18 infection (12M), 3 doses Show forest plot

4

22267

Risk Ratio (IV, Random, 95% CI)

0.09 [0.06, 0.13]

Analysis 5.9

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 9 Persistent HPV16/18 infection (12M), 3 doses.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 9 Persistent HPV16/18 infection (12M), 3 doses.

10 Persistent HPV16/18 infection (12M), at least 1 dose Show forest plot

5

29464

Risk Ratio (IV, Random, 95% CI)

0.16 [0.12, 0.20]

Analysis 5.10

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 10 Persistent HPV16/18 infection (12M), at least 1 dose.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 10 Persistent HPV16/18 infection (12M), at least 1 dose.

11 Persistent HPV16/18 infection (12M), 1 or 2 doses (post hoc analysis) Show forest plot

3

3912

Risk Ratio (IV, Random, 95% CI)

0.13 [0.06, 0.33]

Analysis 5.11

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 11 Persistent HPV16/18 infection (12M), 1 or 2 doses (post hoc analysis).

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 11 Persistent HPV16/18 infection (12M), 1 or 2 doses (post hoc analysis).

Open in table viewer
Comparison 6. Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Incident HPV16/18 infection, at least 1 dose Show forest plot

1

4210

Risk Ratio (IV, Random, 95% CI)

0.24 [0.17, 0.33]

Analysis 6.1

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 1 Incident HPV16/18 infection, at least 1 dose.

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 1 Incident HPV16/18 infection, at least 1 dose.

2 Persistent HPV16/18 infection (6M), at least 1 dose Show forest plot

4

33847

Risk Ratio (IV, Random, 95% CI)

0.48 [0.41, 0.57]

Analysis 6.2

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 2 Persistent HPV16/18 infection (6M), at least 1 dose.

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 2 Persistent HPV16/18 infection (6M), at least 1 dose.

2.1 Age group 15‐26 years

2

25199

Risk Ratio (IV, Random, 95% CI)

0.44 [0.38, 0.51]

2.2 Age group 24‐45 years

2

8648

Risk Ratio (IV, Random, 95% CI)

0.57 [0.47, 0.69]

3 Persistent HPV6/11/16/18 infection (6M), at least 1 dose Show forest plot

1

3713

Risk Ratio (IV, Random, 95% CI)

0.52 [0.42, 0.65]

Analysis 6.3

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 3 Persistent HPV6/11/16/18 infection (6M), at least 1 dose.

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 3 Persistent HPV6/11/16/18 infection (6M), at least 1 dose.

4 Persistent HPV16/18 infection (12M), at least 1 dose Show forest plot

2

24785

Risk Ratio (IV, Random, 95% CI)

0.46 [0.40, 0.54]

Analysis 6.4

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 4 Persistent HPV16/18 infection (12M), at least 1 dose.

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 4 Persistent HPV16/18 infection (12M), at least 1 dose.

5 Persistent HPV16/18 infection (12M) by dose (post hoc analysis) Show forest plot

1

7153

Risk Ratio (IV, Random, 95% CI)

0.18 [0.12, 0.27]

Analysis 6.5

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 5 Persistent HPV16/18 infection (12M) by dose (post hoc analysis).

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 5 Persistent HPV16/18 infection (12M) by dose (post hoc analysis).

Open in table viewer
Comparison 7. Adverse events

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall local/injection site adverse events Show forest plot

8

18113

Risk Ratio (IV, Fixed, 95% CI)

1.18 [1.16, 1.20]

Analysis 7.1

Comparison 7 Adverse events, Outcome 1 Overall local/injection site adverse events.

Comparison 7 Adverse events, Outcome 1 Overall local/injection site adverse events.

1.1 Bivalent vaccine

2

6503

Risk Ratio (IV, Fixed, 95% CI)

1.29 [1.26, 1.33]

1.2 Quadrivalent vaccine

6

11610

Risk Ratio (IV, Fixed, 95% CI)

1.14 [1.12, 1.16]

2 Pain at injection site Show forest plot

13

25691

Risk Ratio (IV, Random, 95% CI)

1.35 [1.23, 1.49]

Analysis 7.2

Comparison 7 Adverse events, Outcome 2 Pain at injection site.

Comparison 7 Adverse events, Outcome 2 Pain at injection site.

2.1 Monovalent vaccine

1

2280

Risk Ratio (IV, Random, 95% CI)

1.05 [1.01, 1.09]

2.2 Bivalent vaccine

8

16897

Risk Ratio (IV, Random, 95% CI)

1.49 [1.26, 1.75]

2.3 Quadrivalent vaccine

4

6514

Risk Ratio (IV, Random, 95% CI)

1.13 [1.07, 1.19]

3 Swelling at injection site Show forest plot

9

22106

Risk Ratio (IV, Random, 95% CI)

1.73 [1.32, 2.27]

Analysis 7.3

Comparison 7 Adverse events, Outcome 3 Swelling at injection site.

Comparison 7 Adverse events, Outcome 3 Swelling at injection site.

3.1 Bivalent vaccine

7

16603

Risk Ratio (IV, Random, 95% CI)

1.62 [1.15, 2.29]

3.2 Quadrivalent vaccine

2

5503

Risk Ratio (IV, Random, 95% CI)

2.79 [0.85, 9.15]

4 Redness at injection site Show forest plot

6

19996

Risk Ratio (IV, Random, 95% CI)

1.72 [1.50, 1.97]

Analysis 7.4

Comparison 7 Adverse events, Outcome 4 Redness at injection site.

Comparison 7 Adverse events, Outcome 4 Redness at injection site.

4.1 Quadrivalent vaccine

1

5345

Risk Ratio (IV, Random, 95% CI)

1.46 [1.32, 1.63]

4.2 Bivalent vaccine

5

14651

Risk Ratio (IV, Random, 95% CI)

1.80 [1.53, 2.11]

5 Overall systemic event and general symptoms Show forest plot

8

18191

Risk Ratio (IV, Random, 95% CI)

1.02 [0.98, 1.07]

Analysis 7.5

Comparison 7 Adverse events, Outcome 5 Overall systemic event and general symptoms.

Comparison 7 Adverse events, Outcome 5 Overall systemic event and general symptoms.

5.1 Bivalent vaccine

2

6503

Risk Ratio (IV, Random, 95% CI)

1.07 [0.97, 1.19]

5.2 Quadrivalent vaccine

6

11688

Risk Ratio (IV, Random, 95% CI)

1.01 [0.98, 1.04]

6 Serious adverse events Show forest plot

23

71597

Risk Ratio (IV, Random, 95% CI)

0.98 [0.92, 1.05]

Analysis 7.6

Comparison 7 Adverse events, Outcome 6 Serious adverse events.

Comparison 7 Adverse events, Outcome 6 Serious adverse events.

6.1 Monovalent vaccine

1

2387

Risk Ratio (IV, Random, 95% CI)

0.95 [0.51, 1.78]

6.2 Bivalent vaccine

15

46231

Risk Ratio (IV, Random, 95% CI)

1.01 [0.96, 1.07]

6.3 Quadrivalent vaccine

7

22979

Risk Ratio (IV, Random, 95% CI)

0.81 [0.65, 1.02]

7 Deaths Show forest plot

23

71176

Risk Ratio (IV, Random, 95% CI)

1.29 [0.85, 1.98]

Analysis 7.7

Comparison 7 Adverse events, Outcome 7 Deaths.

Comparison 7 Adverse events, Outcome 7 Deaths.

7.1 Monovalent vaccine

1

2280

Risk Ratio (IV, Random, 95% CI)

0.0 [0.0, 0.0]

7.2 Bivalent vaccine

15

46231

Risk Ratio (IV, Random, 95% CI)

1.21 [0.66, 2.22]

7.3 Quadrivalent vaccine

7

22665

Risk Ratio (IV, Random, 95% CI)

1.54 [0.73, 3.23]

Open in table viewer
Comparison 8. Pregnancy outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Normal infant Show forest plot

8

8782

Risk Ratio (IV, Random, 95% CI)

1.00 [0.97, 1.02]

Analysis 8.1

Comparison 8 Pregnancy outcomes, Outcome 1 Normal infant.

Comparison 8 Pregnancy outcomes, Outcome 1 Normal infant.

2 Spontaneous abortion/miscarriage Show forest plot

9

8618

Risk Ratio (IV, Random, 95% CI)

0.88 [0.68, 1.14]

Analysis 8.2

Comparison 8 Pregnancy outcomes, Outcome 2 Spontaneous abortion/miscarriage.

Comparison 8 Pregnancy outcomes, Outcome 2 Spontaneous abortion/miscarriage.

3 Elective termination/induced abortion Show forest plot

9

10909

Risk Ratio (IV, Random, 95% CI)

0.90 [0.80, 1.02]

Analysis 8.3

Comparison 8 Pregnancy outcomes, Outcome 3 Elective termination/induced abortion.

Comparison 8 Pregnancy outcomes, Outcome 3 Elective termination/induced abortion.

4 Stillbirth Show forest plot

6

8754

Risk Ratio (IV, Random, 95% CI)

1.12 [0.68, 1.83]

Analysis 8.4

Comparison 8 Pregnancy outcomes, Outcome 4 Stillbirth.

Comparison 8 Pregnancy outcomes, Outcome 4 Stillbirth.

5 Abnormal infant Show forest plot

5

9252

Risk Ratio (IV, Random, 95% CI)

1.22 [0.88, 1.69]

Analysis 8.5

Comparison 8 Pregnancy outcomes, Outcome 5 Abnormal infant.

Comparison 8 Pregnancy outcomes, Outcome 5 Abnormal infant.

Flow diagram summarising the retrieval, inclusion and exclusion of relevant reports of randomised trials assessing the safety and effects of prophylactic HPV vaccines.
Figuras y tablas -
Figure 1

Flow diagram summarising the retrieval, inclusion and exclusion of relevant reports of randomised trials assessing the safety and effects of prophylactic HPV vaccines.

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
 V1 = Random sequence generation; V2 = Allocation concealment; V3 = Blinding participants & personnel; V4 = Blinding of outcome assessment; V5 = Incomplete outcomes; V6 = Selective reporting.
Figuras y tablas -
Figure 2

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
V1 = Random sequence generation; V2 = Allocation concealment; V3 = Blinding participants & personnel; V4 = Blinding of outcome assessment; V5 = Incomplete outcomes; V6 = Selective reporting.

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.
Figuras y tablas -
Figure 3

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
Figuras y tablas -
Figure 4

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.

Protection against CIN2+ irrespective of presence of HPV types in women, aged 15‐26 years, regardless of their HPV DNA status at baseline, who received at least one dose.
Figuras y tablas -
Figure 5

Protection against CIN2+ irrespective of presence of HPV types in women, aged 15‐26 years, regardless of their HPV DNA status at baseline, who received at least one dose.

Summary of vaccine efficacy estimates, by age group, outcome and HPV DNA status at enrolment (for women who received at least one dose). [REFS BETWEEN SQUARE BRACKETS MUST BE ADAPTED][
Figuras y tablas -
Figure 6

Summary of vaccine efficacy estimates, by age group, outcome and HPV DNA status at enrolment (for women who received at least one dose). [REFS BETWEEN SQUARE BRACKETS MUST BE ADAPTED][

Summary of vaccine efficacy estimates by age group, outcome and number of received doses (for women who were HPV16/18 DNA negative at enrolment). [REFS BETWEEN SQUARE BRACKETS MUST BE ADAPTED][
Figuras y tablas -
Figure 7

Summary of vaccine efficacy estimates by age group, outcome and number of received doses (for women who were HPV16/18 DNA negative at enrolment). [REFS BETWEEN SQUARE BRACKETS MUST BE ADAPTED][

Modified Cates plot: Number of cases of CIN2+ associated with HPV16/18 occurring in women who were all hrHPV DNA negative at baseline. 16 out of 1000 non‐vaccinated women developed the lesion (left) whereas fewer than one (0.2) out 1000 vaccinated women developed the lesion (right). Relative risk= 0.01 (95% CI: 0.01 to 0.05).
Figuras y tablas -
Figure 8

Modified Cates plot: Number of cases of CIN2+ associated with HPV16/18 occurring in women who were all hrHPV DNA negative at baseline. 16 out of 1000 non‐vaccinated women developed the lesion (left) whereas fewer than one (0.2) out 1000 vaccinated women developed the lesion (right). Relative risk= 0.01 (95% CI: 0.01 to 0.05).

Modified Cates plot: Number of cases of CIN2+ irrespective of HPV types occurring in women who were all hrHPV DNA negative at baseline. 28 out of 1000 non‐vaccinated women developed the lesion (left) whereas 11 out 1000 vaccinated women developed the lesion (right). Relative risk= 0.37 (95% CI: 0.25 to 0.55).
Figuras y tablas -
Figure 9

Modified Cates plot: Number of cases of CIN2+ irrespective of HPV types occurring in women who were all hrHPV DNA negative at baseline. 28 out of 1000 non‐vaccinated women developed the lesion (left) whereas 11 out 1000 vaccinated women developed the lesion (right). Relative risk= 0.37 (95% CI: 0.25 to 0.55).

Sensitivity analysis of Analysis 7.6 on severe adverse effects restricting to data extracted from publications in peer‐reviewed journals.
Figuras y tablas -
Figure 10

Sensitivity analysis of Analysis 7.6 on severe adverse effects restricting to data extracted from publications in peer‐reviewed journals.

Sensitivity analysis of Analysis 7.7 on deaths restricting to data extracted from publications in peer‐reviewed journals.
Figuras y tablas -
Figure 11

Sensitivity analysis of Analysis 7.7 on deaths restricting to data extracted from publications in peer‐reviewed journals.

Protection against CIN2+ associated with HPV16/18 in women, aged 15‐26 years, who were HPV DNA 16/18 negative at baseline, by number of doses.
Figuras y tablas -
Figure 12

Protection against CIN2+ associated with HPV16/18 in women, aged 15‐26 years, who were HPV DNA 16/18 negative at baseline, by number of doses.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 1 CIN2+ associated with HPV16/18, at least 1 dose.
Figuras y tablas -
Analysis 1.1

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 1 CIN2+ associated with HPV16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 2 CIN2+ associated with HPV6/11/16/18, at least 1 dose.
Figuras y tablas -
Analysis 1.2

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 2 CIN2+ associated with HPV6/11/16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 3 CIN3+ associated with HPV16/18, at least 1 dose.
Figuras y tablas -
Analysis 1.3

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 3 CIN3+ associated with HPV16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 4 CIN3+ associated with HPV6/11/16/18, at least 1 dose.
Figuras y tablas -
Analysis 1.4

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 4 CIN3+ associated with HPV6/11/16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 5 AIS associated with HPV16/18, at least 1 dose.
Figuras y tablas -
Analysis 1.5

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 5 AIS associated with HPV16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 6 AIS associated with HPV6/11/16/18, at least 1 dose.
Figuras y tablas -
Analysis 1.6

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 6 AIS associated with HPV6/11/16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 7 Any CIN2+ irrespective of HPV types, at least 1 dose.
Figuras y tablas -
Analysis 1.7

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 7 Any CIN2+ irrespective of HPV types, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 8 Any CIN3+ irrespective of HPV types, at least 1 dose.
Figuras y tablas -
Analysis 1.8

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 8 Any CIN3+ irrespective of HPV types, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 9 Any AIS irrespective of HPV types, at least 1 dose.
Figuras y tablas -
Analysis 1.9

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 9 Any AIS irrespective of HPV types, at least 1 dose.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 1 CIN2+ associated with HPV16/(18), 3 doses.
Figuras y tablas -
Analysis 2.1

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 1 CIN2+ associated with HPV16/(18), 3 doses.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 2 CIN2+ associated with HPV16/(18), at least 1 dose.
Figuras y tablas -
Analysis 2.2

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 2 CIN2+ associated with HPV16/(18), at least 1 dose.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 3 CIN2+ associated with HPV16/(18), 1 or 2 doses (post hoc analysis).
Figuras y tablas -
Analysis 2.3

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 3 CIN2+ associated with HPV16/(18), 1 or 2 doses (post hoc analysis).

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 4 CIN2+ associated with HPV6/11/16/18, 3 doses.
Figuras y tablas -
Analysis 2.4

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 4 CIN2+ associated with HPV6/11/16/18, 3 doses.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 5 CIN2+ associated with HPV6/11/16/18, at least 1 dose.
Figuras y tablas -
Analysis 2.5

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 5 CIN2+ associated with HPV6/11/16/18, at least 1 dose.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 6 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses (post hoc analysis).
Figuras y tablas -
Analysis 2.6

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 6 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses (post hoc analysis).

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 7 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 3 doses.
Figuras y tablas -
Analysis 2.7

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 7 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 3 doses.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 8 CIN3+ associated with HPV 16/18 or HPV6/11/16/18, at least 1 dose.
Figuras y tablas -
Analysis 2.8

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 8 CIN3+ associated with HPV 16/18 or HPV6/11/16/18, at least 1 dose.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 9 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis).
Figuras y tablas -
Analysis 2.9

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 9 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis).

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 10 AIS associated with HPV16/18 or HPV6/11/16/18, 3 doses.
Figuras y tablas -
Analysis 2.10

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 10 AIS associated with HPV16/18 or HPV6/11/16/18, 3 doses.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 11 AIS associated with HPV16/18 or 6/11/16/18, at least 1 dose.
Figuras y tablas -
Analysis 2.11

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 11 AIS associated with HPV16/18 or 6/11/16/18, at least 1 dose.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 12 AIS associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis).
Figuras y tablas -
Analysis 2.12

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 12 AIS associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis).

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 13 Any CIN2+ irrespective of HPV types, 3 doses.
Figuras y tablas -
Analysis 2.13

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 13 Any CIN2+ irrespective of HPV types, 3 doses.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 14 Any CIN2+ irrespective of HPV types, at least 1 dose.
Figuras y tablas -
Analysis 2.14

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 14 Any CIN2+ irrespective of HPV types, at least 1 dose.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 15 Any CIN2+ irrespective of HPV types, 1 or 2 doses (post hoc analysis).
Figuras y tablas -
Analysis 2.15

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 15 Any CIN2+ irrespective of HPV types, 1 or 2 doses (post hoc analysis).

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 1 CIN2+ associated with HPV16/18, at least 1 dose.
Figuras y tablas -
Analysis 3.1

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 1 CIN2+ associated with HPV16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 2 CIN2+ associated with HPV6/11/16/18, at least 1 dose.
Figuras y tablas -
Analysis 3.2

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 2 CIN2+ associated with HPV6/11/16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 3 CIN3+ associated with HPV16/18, at least 1 dose.
Figuras y tablas -
Analysis 3.3

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 3 CIN3+ associated with HPV16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 4 CIN3+ associated with HPV6/11/16/18, at least 1 dose.
Figuras y tablas -
Analysis 3.4

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 4 CIN3+ associated with HPV6/11/16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 5 AIS associated with HPV16/18, at least 1 dose.
Figuras y tablas -
Analysis 3.5

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 5 AIS associated with HPV16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 6 AIS associated with HPV6/11/16/18, at least 1 dose.
Figuras y tablas -
Analysis 3.6

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 6 AIS associated with HPV6/11/16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 7 Any CIN2+ irrespective of HPV types, at least 1 dose.
Figuras y tablas -
Analysis 3.7

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 7 Any CIN2+ irrespective of HPV types, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 8 Any CIN3+ HPV type, at least 1 dose.
Figuras y tablas -
Analysis 3.8

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 8 Any CIN3+ HPV type, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 9 Any AIS irrespective of HPV types, at least 1 dose.
Figuras y tablas -
Analysis 3.9

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 9 Any AIS irrespective of HPV types, at least 1 dose.

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 1 Incident HPV16/18 infection, 3 doses.
Figuras y tablas -
Analysis 4.1

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 1 Incident HPV16/18 infection, 3 doses.

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 2 Persistent HPV16/18 infection (6M), 3 doses.
Figuras y tablas -
Analysis 4.2

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 2 Persistent HPV16/18 infection (6M), 3 doses.

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 3 Persistent HPV16/18 infection (6M), at least 1 dose.
Figuras y tablas -
Analysis 4.3

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 3 Persistent HPV16/18 infection (6M), at least 1 dose.

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 4 Persistent HPV16/18 infection(12M), 3 doses.
Figuras y tablas -
Analysis 4.4

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 4 Persistent HPV16/18 infection(12M), 3 doses.

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 5 Persistent HPV16/18 infection (12M), at least 1 dose.
Figuras y tablas -
Analysis 4.5

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 5 Persistent HPV16/18 infection (12M), at least 1 dose.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 1 Incident HPV16/18 infection, 3 doses.
Figuras y tablas -
Analysis 5.1

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 1 Incident HPV16/18 infection, 3 doses.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 2 Incident HPV16/18 infection, at least 1 dose.
Figuras y tablas -
Analysis 5.2

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 2 Incident HPV16/18 infection, at least 1 dose.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 3 Incident HPV16/18 infection, 1 or 2 doses (post hoc analysis).
Figuras y tablas -
Analysis 5.3

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 3 Incident HPV16/18 infection, 1 or 2 doses (post hoc analysis).

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 4 Persistent HPV16/18 infection (6M), 3 doses.
Figuras y tablas -
Analysis 5.4

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 4 Persistent HPV16/18 infection (6M), 3 doses.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 5 Persistent HPV16/18 infection (6M), at least 1 dose.
Figuras y tablas -
Analysis 5.5

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 5 Persistent HPV16/18 infection (6M), at least 1 dose.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 6 Persistent HPV16/18 infection (6M), 1 or 2 doses (post hoc analysis).
Figuras y tablas -
Analysis 5.6

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 6 Persistent HPV16/18 infection (6M), 1 or 2 doses (post hoc analysis).

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 7 Persistent HPV6/11/16/18 infection (6M), 3 doses.
Figuras y tablas -
Analysis 5.7

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 7 Persistent HPV6/11/16/18 infection (6M), 3 doses.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 8 Persistent HPV6/11/16/18 infection (6M), at least 1 dose.
Figuras y tablas -
Analysis 5.8

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 8 Persistent HPV6/11/16/18 infection (6M), at least 1 dose.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 9 Persistent HPV16/18 infection (12M), 3 doses.
Figuras y tablas -
Analysis 5.9

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 9 Persistent HPV16/18 infection (12M), 3 doses.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 10 Persistent HPV16/18 infection (12M), at least 1 dose.
Figuras y tablas -
Analysis 5.10

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 10 Persistent HPV16/18 infection (12M), at least 1 dose.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 11 Persistent HPV16/18 infection (12M), 1 or 2 doses (post hoc analysis).
Figuras y tablas -
Analysis 5.11

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 11 Persistent HPV16/18 infection (12M), 1 or 2 doses (post hoc analysis).

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 1 Incident HPV16/18 infection, at least 1 dose.
Figuras y tablas -
Analysis 6.1

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 1 Incident HPV16/18 infection, at least 1 dose.

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 2 Persistent HPV16/18 infection (6M), at least 1 dose.
Figuras y tablas -
Analysis 6.2

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 2 Persistent HPV16/18 infection (6M), at least 1 dose.

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 3 Persistent HPV6/11/16/18 infection (6M), at least 1 dose.
Figuras y tablas -
Analysis 6.3

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 3 Persistent HPV6/11/16/18 infection (6M), at least 1 dose.

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 4 Persistent HPV16/18 infection (12M), at least 1 dose.
Figuras y tablas -
Analysis 6.4

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 4 Persistent HPV16/18 infection (12M), at least 1 dose.

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 5 Persistent HPV16/18 infection (12M) by dose (post hoc analysis).
Figuras y tablas -
Analysis 6.5

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 5 Persistent HPV16/18 infection (12M) by dose (post hoc analysis).

Comparison 7 Adverse events, Outcome 1 Overall local/injection site adverse events.
Figuras y tablas -
Analysis 7.1

Comparison 7 Adverse events, Outcome 1 Overall local/injection site adverse events.

Comparison 7 Adverse events, Outcome 2 Pain at injection site.
Figuras y tablas -
Analysis 7.2

Comparison 7 Adverse events, Outcome 2 Pain at injection site.

Comparison 7 Adverse events, Outcome 3 Swelling at injection site.
Figuras y tablas -
Analysis 7.3

Comparison 7 Adverse events, Outcome 3 Swelling at injection site.

Comparison 7 Adverse events, Outcome 4 Redness at injection site.
Figuras y tablas -
Analysis 7.4

Comparison 7 Adverse events, Outcome 4 Redness at injection site.

Comparison 7 Adverse events, Outcome 5 Overall systemic event and general symptoms.
Figuras y tablas -
Analysis 7.5

Comparison 7 Adverse events, Outcome 5 Overall systemic event and general symptoms.

Comparison 7 Adverse events, Outcome 6 Serious adverse events.
Figuras y tablas -
Analysis 7.6

Comparison 7 Adverse events, Outcome 6 Serious adverse events.

Comparison 7 Adverse events, Outcome 7 Deaths.
Figuras y tablas -
Analysis 7.7

Comparison 7 Adverse events, Outcome 7 Deaths.

Comparison 8 Pregnancy outcomes, Outcome 1 Normal infant.
Figuras y tablas -
Analysis 8.1

Comparison 8 Pregnancy outcomes, Outcome 1 Normal infant.

Comparison 8 Pregnancy outcomes, Outcome 2 Spontaneous abortion/miscarriage.
Figuras y tablas -
Analysis 8.2

Comparison 8 Pregnancy outcomes, Outcome 2 Spontaneous abortion/miscarriage.

Comparison 8 Pregnancy outcomes, Outcome 3 Elective termination/induced abortion.
Figuras y tablas -
Analysis 8.3

Comparison 8 Pregnancy outcomes, Outcome 3 Elective termination/induced abortion.

Comparison 8 Pregnancy outcomes, Outcome 4 Stillbirth.
Figuras y tablas -
Analysis 8.4

Comparison 8 Pregnancy outcomes, Outcome 4 Stillbirth.

Comparison 8 Pregnancy outcomes, Outcome 5 Abnormal infant.
Figuras y tablas -
Analysis 8.5

Comparison 8 Pregnancy outcomes, Outcome 5 Abnormal infant.

Summary of findings for the main comparison. HPV vaccine effects on cervical lesions in adolescent girls and women negative for hrHPV DNA at baseline

HPV vaccine effects on cervical lesions in adolescent girls and women who are hrHPV DNA negative at baseline

Patient or population: adolescent girls and women aged 15 to 26 years who are hrHPV negative before vaccination

Setting: Europe, Asia Pacific countries, South & North America
Intervention: HPV vaccines (at least one dose of bivalent or quadrivalent vaccines)

Comparison: Placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with HPV vaccination1

Cervical cancer ‐ not measured

CIN2+ associated with HPV16/18.

Follow‐up: 3 to 5 years

164 per 10,000

2 per 10,000
(0 to 8)

RR 0.01
(0.00 to 0.05)

23,676
(3 RCTs)

⊕⊕⊕⊕
HIGH

CIN3+ associated with HPV16/18

Follow‐up: 3 to 5 years

70 per 10,000

0 per 10,000
(0 to 7)

RR 0.01
(0.00 to 0.10)

20,214
(2 RCTs)

⊕⊕⊕⊕
HIGH

Continuity correction

AIS associated with HPV16/18

Follow‐up: 3 to 5 years

9 per 10,000

0 per 10,000
(0 to 7)

RR 0.10
(0.01 to 0.82)

20,214
(2 RCTs)

⊕⊕⊕⊝
MODERATE 2

Continuity correction

Any CIN2+ irrespective of HPV type, bivalent or quadrivalent vaccine

Follow‐up: 2 to 6 years

287 per 10,000

106 per 10,000
(72 to 158)

RR 0.37
(0.25 to 0.55)

25,180
(5 RCTs)

⊕⊕⊕⊕
HIGH

Substantial subgroup heterogeneity was observed (I2= 84.3%) for bi‐ and quadrivalent vaccines. So results are reported separately for the 2 vaccines (see next 2 rows).

Any CIN2+ irrespective of HPV type

Follow‐up (bivalent): 3.5 to 6 years

Follow‐up (quadrivalent): 3.5 years

Bivalent vaccine

RR 0.33

(0.25 to 0.43)

15,884

(4 RCTs)

⊕⊕⊕⊕
HIGH

285 per 10,000

94 per 10,000

(71 to 122)

Quadrivalent vaccine

RR 0.57

(0.44 to 0.76)

9296

(1 RCT)

⊕⊕⊕⊝
MODERATE3

291 per 10,000

166 per 10,000

(128 to 221)

Any CIN3+ irrespective of HPV type, bivalent or quadrivalent vaccine

Follow‐up: 3.5 to 4 years

109 per 10,000

23 per 10,000
(4 to 120)

RR 0.21
(0.04 to 1.10)

20,719
(3 RCTs)

⊕⊕⊕⊝
MODERATE 3

Substantial subgroup heterogeneity was observed (I2 = 84.3%) for bi‐ and quadrivalent vaccines. So results are reported separately for the 2 vaccines (see next 2 rows).

Any CIN3+ irrespective of HPV type

Follow‐up (bivalent): 4 years

Follow‐up (quadrivalent): 3.5 years

Bivalent vaccine

RR 0.08

(0.03 to 0.23)

11,423

(2 RCTs)

⊕⊕⊕⊕
HIGH

81 per 10,000

6 per 10,000

(3 to 19)

Quadrivalent vaccine

RR 0.54

(0.36 to 0.82)

9296

(1 RCT)

⊕⊕⊕⊝
MODERATE3

143 per 10,000

77 per 10,000

(51 to 117 )

Any AIS irrespective of HPV type

Follow‐up: 3 to 5 years

10 per 10,000

0 per 10,000
(0 to 8)

RR 0.10
(0.01 to 0.76)

20,214
(2 RCTs)

⊕⊕⊕⊝
MODERATE 2

Continuity correction

1The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). When risk in vaccine group is zero, the 95% CI is computed using an exact binomial method.

AIS: adenocarcinoma in situ; CI: Confidence interval; CIN: cervical intraepithelial neoplasia; RR: Risk ratio

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Assumed risk calculated from the sum of control group event rates.

2 Downgraded due to serious imprecision in effect estimate (width 95% CI around RR > 0.6).

3 Downgraded one level due to serious imprecision. Few events observed in the two studies (9 in placebo arms and 0 in vaccination arms for the outcome of AIS HPV16/18 and 7 in placebo arms and 0 in vaccination arms for outcome of AIS of any type).

Figuras y tablas -
Summary of findings for the main comparison. HPV vaccine effects on cervical lesions in adolescent girls and women negative for hrHPV DNA at baseline
Summary of findings 2. HPV vaccine effects on cervical lesions in adolescent girls and women negative for HPV16/18 DNA at baseline

HPV vaccine effects on cervical lesions in adolescent girls and women negative for HPV16/18 DNA at baseline

Patient or population: adolescent girls and women aged 15 to 45 years who were HPV16/18 negative before vaccination
Setting: Europe, Asia Pacific countries, South & North America
Intervention: HPV vaccines (at least one dose of bivalent or quadrivalent vaccines)
Comparison: Placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with HPV vaccination1

Cervical cancer ‐ not measured

CIN2+ associated with HPV16/18

Follow‐up (age 15 to 26 years): 1 to 8.5 years

Follow‐up (age 24 to 45 years): 4 to 6 years

15 to 26 years

RR 0.05
(0.03 to 0.10)

34,478
(6 RCTs)

⊕⊕⊕⊕
HIGH

113 per 10,000

6 per 10,000
(3 to 11)

24 to 45 years

RR 0.30

(0.11 to 0.81)

7552

(2 RCTs)

⊕⊕⊕⊝

MODERATE 2

45 per 10,000

14 per 10,000

(5 to 37)

CIN3+ associated with HPV16/18 (age 15 to 26 years)

Follow‐up: 3 years

57 per 10,000

3 per 10,000

(1 to 8)

RR 0.05

(0.02 to 0.14)

33,199

(3 studies)

⊕⊕⊕⊕
HIGH

AIS associated with HPV16/18 or 6/11/16/18 (age 15 to 26 years)

Follow‐up: 3 years

12 per 10,000

0 per 10,000
(0 to 8)

RR 0.09
(0.01 to 0.72)

17,079
(2 RCTs)

⊕⊕⊕⊝

MODERATE 2

Continuity

correction

Any CIN2+ irrespective of HPV type (age 15 to 26 years)

Follow‐up: 2 to 6.5 years

231 per 10,000

95 per 10,000
(74 to 120)

RR 0.41
(0.32 to 0.52)

19,143
(3 RCTs)

⊕⊕⊕⊕
HIGH

Any CIN3+ irrespective of HPV type ‐ not measured

Any AIS irrespective of HPV type ‐ not measured

1The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Exception: when risk in vaccine group is zero, the 95% CI is computed using an exact binomial method..

AIS: adenocarcinoma in situ; CI: Confidence interval; CIN: cervical intraepithelial neoplasia; RR: Risk ratio

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Assumed risk calculated from the sum of control group event rates.

2 Downgraded due to serious imprecision in effect estimate (width 95% CI around RR > 0.6).

Figuras y tablas -
Summary of findings 2. HPV vaccine effects on cervical lesions in adolescent girls and women negative for HPV16/18 DNA at baseline
Summary of findings 3. HPV vaccine effects in adolescent girls and women regardless of HPV DNA status at baseline

HPV vaccine effects on cervical lesions in adolescent girls and women unselected for HPV DNA status at baseline

Patient or population: adolescent girls and women aged 15 to 45 years regardless of HPV DNA status at baseline
Setting: Europe, Asia Pacific countries, South & North America and Africa
Intervention: HPV vaccines (at least one dose of bivalent or quadrivalent vaccines)
Comparison: Placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with HPV vaccination1

Cervical cancer ‐ not measured

CIN2+ associated with HPV16/18

Follow‐up (age 15 to 26 years): 3.5 to 8.5 years

Follow‐up (age 24 to 45 years): 3.5 years

15 to 26 years

RR 0.46

(0.37 to 0.57

34,852
(3 RCTs)

⊕⊕⊕⊕
HIGH

341 per 10,000

157 per 10,000
(126 to 194)

24 to 45 years

RR 0.74

(0.52 to 1.05)

9200

(2 studies)

⊕⊕⊕⊝
MODERATE 2

145 per 10,000

107 per 10,000

(76 to 152)

CIN3+ associated with HPV16/18

Follow‐up: 3.5 years

165 per 10,000

91 per 10,000

(74 to 127)

RR 0.55

(0.45 to 0.67)

34,562

(2 RCTs)

⊕⊕⊕⊕
HIGH

Adeno carcinoma in situ (AIS) associated with HPV16/18

Follow‐up: 3.5 years

14 per 10,000

5 per 10,000
(3 to 11)

RR 0.36
(0.17 to 0.78)

34,562
(2 RCTs)

⊕⊕⊕⊕
HIGH

Any CIN2+ irrespective of HPV type

Follow‐up (age 15 to 26 years): 3.5 to 8.5 years

Follow‐up (age 24 to 45 years): 3.5 to 6 years

15 to 26 years

RR 0.70
(0.58 to 0.85)

35,779
(4 RCTs)

⊕⊕⊕⊕
HIGH

559 per 10,000

391 per 10,000
(324 to 475)

24 to 45 years

RR 1.04
(0.83 to 1.30)

9287
(2 RCTs)

⊕⊕⊕⊝
MODERATE 2

343 per 10,000

356 per 10,000
(284 to 445)

Any CIN3+ irrespective of HPV type (age 15 to 26 years)

Follow‐up: 3.5 to 4 years

266 per 10,000

178 per 10,000

(231 to 247)

RR 0.67

(0.49 to 0.93)

35,489

(3 RCTs)

⊕⊕⊕⊝
MODERATE

Substantial subgroup heterogeneity was observed (I2 = 84.3%) for bivalent and quadrivalent vaccines. So results are reported separately for two vaccines.

Any CIN3+ irrespective of HPV type (age 15 to 26 years),

Follow‐up (bivalent): 3.5 to 4 years

Follow‐up (quadrivalent): 3.5 years

Bivalent vaccine

RR 0.55

(0.43 to 0.71)

18,329

(2 RCTs)

⊕⊕⊕⊕
HIGH

188 per 10,000

104 per 10,000

(81 to 134)

Quadrivalent vaccine

0.81

(0.69 to 0.96)

17,160

(1 RCT)

⊕⊕⊕⊝
MODERATE 3

349 per 10,000

283 per 10,000

(241 to 335)

Any AIS irrespective of HPV type (age 15 to 26 years)

Follow‐up: 3.5 years

17 per 10,000

5 per 10,000
(3 to 11)

RR 0.32
(0.15 to 0.67)

34,562
(2 RCTs)

⊕⊕⊕⊕
HIGH

Serious adverse events

Follow‐up: 6 months to 7 years

669 per 10,000

656 per 10,000
(616 to 703)

RR 0.98
(0.92 to 1.05)

71,597
(23 RCTs)

⊕⊕⊕⊕
HIGH

Deaths

Follow‐up: 7 months to 10 years. Most of the information in the analysis comes from studies with follow‐up ranging from 5‐10 years.

11 per 10,000

14 per 10,000
(9 to 22)

RR 1.29
(0.85 to 1.98)

71,176
(23 RCTs)

⊕⊕⊝⊝
LOW 4 5

Older women had higher fatality rate (RR 2.36, 95% CI 1.10 to 5.03). Assessment of the deaths in the studies has not been able to identify a pattern in the cause or timing of death.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

AIS: adenocarcinoma in situ; CI: Confidence interval; CIN: cervical intraepithelial neoplasia; RR: Risk ratio

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Assumed risk calculated from the sum of control group event rates for all outcomes unless otherwise stated.

2 Downgraded due to serious imprecision. Confidence interval is wide and includes large decrease and small increase in lesions with vaccination group in the older age group.

3 Downgraded one level due to serious inconsistency. Reduction in lesions was greater in younger women than in older women (RR 0.46 in 15 to 26 years versus RR 0.74 in 24 to 45 years; P = 0.02 for interaction).

4 Downgraded one level due to serious imprecision. Confidence interval includes potentially meaningful increase in risk of mortality.

5 Downgraded one level due to serious inconsistency. Despite limited evidence of statistical variation, sub grouping studies by age showed higher fatality rate with vaccines in older age group. There is no clear pattern in causes or timing of deaths.

Figuras y tablas -
Summary of findings 3. HPV vaccine effects in adolescent girls and women regardless of HPV DNA status at baseline
Summary of findings 4. HPV vaccine effects on pregnancy outcomes

HPV vaccine adverse pregnancy outcomes (regardless of DNA status and age)

Patient or population: adolescent girls and women aged 15 to 45 years who became pregnant during the study
Setting: Europe, Asia Pacific, North, Central and South America
Intervention: HPV vaccines (bivalent or quadrivalent vaccines)
Comparison: Placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with HPV vaccines

Spontaneous abortion/miscarriage

Follow‐up: 1 to 7 years

Study population

RR 0.88
(0.68 to 1.14)

8618
(9 RCTs)

⊕⊕⊕⊕
HIGH

1618 per 10,000

1,424 per 10,000
(1,100 to 1844)

Elective termination/induced abortion

Follow‐up: 1 to 7 years

Study population

RR 0.90
(0.80 to 1.02)

10,909
(9 RCTs)

⊕⊕⊕⊕
HIGH 1

931 per 10,000

838 per 10,000
(745 to 950)

Stillbirth

Follow‐up: 1 to 3.5 years

Study population

RR 1.12
(0.68 to 1.83)

8754
(6 RCTs)

⊕⊕⊕⊝
MODERATE 2

70 per 10,000

78 per 10,000
(48 to 128)

Babies born with congenital malformations

Follow‐up: 3 to 7 years

Study population

RR 1.22
(0.88 to 1.69)

9252
(5 RCTs)

⊕⊕⊕⊝
MODERATE 2

205 per 10,000

250 per 10,000
(180 to 346)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Confidence interval rules out an increased risk of termination so there is no downgrade for imprecision.

2 Downgraded one level due to serious imprecision. Confidence intervals for both outcomes include meaningful increase and reduction in risk of stillbirth or abnormal infants following vaccination.

Figuras y tablas -
Summary of findings 4. HPV vaccine effects on pregnancy outcomes
Table 1. Listing of included trials

Valency

Phase

Number of trials

Appelation

N

Outcomes

Main References

Monovalent

II

1

Phase2 trial (ph2,1v)

2392

Efficacy, safety

Koutsky 2002

Mao 2006

Rowhani‐Rahbar 2009

Bivalent

II

2

Japanese trial (ph2,2v)

1040

Efficacy, safety

Konno 2010

Konno 2010a

Konno 2014

Phase2 trial (ph2,2v)

1113

Efficacy, safety

Harper 2004

Harper 2006

The GSK Study Group 2009

De Carvalho 2010

III

16

African_2 country trial (ph3,2v)

676

Safety

Sow 2013

Chinese trial (ph3,2v)_young

6051

Efficacy, safety

Zhu 2014

Chinese trial (ph3,2v)_ adolescent

750

Safety

Zhu 2014a

Chinese trial (ph3,2v)_mid‐adult

1212

Safety

Zhu 2014a

Co‐vaccination_dTpa_IPV trial (ph3,2v)

494

Safety

Garcia‐Sicilia 2010

Co‐vaccination_HAB trial (Ph3, 2v)

494

Safety

Pedersen 2012

Co‐vaccination_HepB trial (ph3, 2v)

541

Safety

Schmeink 2011

CVT (ph3,2v)

7466

Efficacy, safety

Herrero 2011

Kreimer 2011

Hong Kong trial (ph3,2v)

294

Safety

Ngan 2010

Immunobridging(ph3,2v)

2067

Safety

Medina 2010

Indian trial (ph3,2v)

354

Safety

Bhatla 2010

Korean trial (ph3,2v)

208

Safety

Kim 2010

Korean trial (ph3b,2v)

321

Safety

Kim 2011

Malaysian trial (ph3,2v)

271

Safety

Lim 2014

PATRICIA trial (ph3,2v)

18,644

Efficacy, safety

Paavonen 2007

Paavonen 2009

Szarewski 2011

Wheeler 2011

Lehtinen 2012

VIVIANE trial (ph3,2v)

5752

Efficay, safety,

Skinner 2014

Wheeler 2016

Quadrivalent

II

3

Japanese trial (ph2,4v)

1021

Safety

Yoshikawa 2013

Korean trial (ph2,4v)

176

Safety

Kang 2008

Phase2 trial (ph2,4v)

552

Efficacy, safety

Villa 2005

Villa 2006

Villa 2006a

Olsson 2009

III

4

African_3 country trial (ph3,4v)

98

Safety

Mugo 2015

FUTURE I trial (ph3,4v)

5455

Efficacy, safety

Garland 2007

FUTURE II trial (ph3,4v)

12,167

Efficacy, safety

FUTURE‐II 2007

FUTURE III trial (ph3,4v)

3819

Efficacy, safety

Munoz 2009

Castellsagué 2011

Total

26

73,428

Figuras y tablas -
Table 1. Listing of included trials
Table 2. Results of all the efficacy outcomes

Outcomes and exposure subgroups

Absolute risk / per 10,000

Relative risk
(95% CI)

Vaccine

efficacy

(95% CI)

Risk difference/ per 10,000

(95% CI)

No of Participants
(studies)

Certainty of evidence
(GRADE)*

Placebo

Vaccinated

1. High‐grade cervical lesions in women who were hrHPV DNA negative at baseline

Analysis 1.1 CIN2+ associated with HPV16/18, at least 1 dose, age 15‐26 years

164

2

0.01

(0.00 to 0.05)

99%

(95% to 100%)

162

(157 to 164)

23,676
(3 studies)

⊕⊕⊕⊕

high

Analysis 1.2 CIN2+ associated with HPV6/11/16/18, at least 1 dose, age 15‐26 years

197

2

0.01

(0.00 to 0.09)

99%

(91% to 100%)

195

(179 to 197)

9296

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 1.3 CIN3+ associated with HPV16/18, at least 1 dose, age 15‐26 years

70

0*

0.01

(0.00 to 0.10)

99%

(90% to 100%)

70

(63 to 70)

20,214

(2 studies)

⊕⊕⊕⊕

high

Analysis 1.4 CIN3+ associated with HPV6/11/16/18, at least 1 dose, age 15‐26 years

94

0*

0.01

(0.00 to 0.18)

99%

(82% to 100%)

94

(77 to 94)

9296

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 1.5 AIS associated with HPV16/18, at least 1 dose, age 15‐26 years

9

0*

0.10

(0.01 to 0.82)

90%

(18% to 99%)

9

(2 to 9)

20,214
(2 studies)

⊕⊕⊕⊝
moderate4

Analysis 1.6 AIS associated with HPV6/11/16/18m at least 1 dose, age 15‐26 years

6

0*

0.14

(0.01 to 2.8)

86%

(‐180% to 99%)

6

(‐12 to 6)

9296

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 1.7.1 Any CIN2+ irrespective of HPV types, at least 1 dose of the bivalent vaccine, age 15‐26 years

285

94

0.33

(0.25 to 0.43)

67%

(57% to 75%)

191

(163 to 214)

15,884

(4 studies)

⊕⊕⊕⊕

high

Analysis 1.7.2 Any CIN2+ irrespective of HPV types, at least 1 dose of the quadrivalent vaccine, age 15‐26 years

291

166

0.57

(0.44 to 0.76)

43%

(24 to 56%)

125

(70 to 163)

9296

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 1.8.1 Any CIN3+ irrespective of HPV types, at least 1 dose of the bivalent vaccine, age 15‐26 years

81

6

0.08

(0.03 to 0.23)

92%

(77% to 97%)

74

(62 to 78)

11,423

(2 studies)

⊕⊕⊕⊕
high

Analysis 1.8.2 Any CIN3+ irrespective of HPV types, at least 1 dose of the quadrivalent vaccine, age 15‐26 years

143

77

0.54

(0.36 to 0.82)

46%

(17% to 64%)

66

(26 to 92)

9296

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 1.9 Any AIS irrespective of HPV types, at least 1 dose

10

0*

0.10

(0.01 to 0.76)

90%

(24% to 99%)

10

(2 to 10)

20,214
(2 studies)

⊕⊕⊕⊝
moderate4

2. High‐grade cervical lesions in women who were HPV16/18 negative at baseline

Analysis 2.1.1 CIN2+ associated with HPV16/18, 3 doses, age 15‐26 years

74

5

0.07

(0.03 to 0.15)

93%

(85% to 97%)

69

(63 to 72)

36,579

(6 studies)

⊕⊕⊕⊕

high

Analysis 2.1.2 CIN2+ associated with HPV16/18, 3 doses, 24‐45 years

36

6

0.16

(0.04 to 0.74)

84%

(26% to 96%)

30

(9 to 34)

6797

(2 studies)

⊕⊕⊕⊝
moderate4

Analysis 2.2.1 CIN2+ associated with HPV16/18, at least 1 dose, 15‐26 years

113

6

0.05

(0.03 to 0.10)

95%

(90% to 97%)

107

(102 to 110)

34,478

(6 studies)

⊕⊕⊕⊕

high

Analysis 2.2.2 CIN2+ associated with HPV16/18, at least 1 dose, age 24‐45 years

45

14

0.30

(0.11 to 0.81)

70%

(19% to 89%)

32

(9 to 40)

7552

(2 studies)

⊕⊕⊕⊝
moderate4

Analysis 2.3.1 CIN2+ associated with HPV16/18, 1 or 2 doses, 15‐26 years***

436

44

0.10

(0.04 to 0.26)

90%

(74% to 96%)

392

(323 to 418)

2958

(5 studies)

⊕⊕⊝⊝

low1$

Analysis 2.3.2 CIN2+ associated with HPV16/18, 1 or 2 doses, age 24‐45 years***

134

82

0.61

(0.14 to 2.67)

39%

(‐167% to 86%)

52

(‐2245 to 115)

755

(2 studies)

⊕⊝⊝⊝
very low1$,4

Analysis 2.4 CIN2+ associated with HPV6/11/16/18, 3 doses, age 15‐45 years

99

6

0.06

(0.01 to 0.61)

94%

(39% to 99%)

93

(39 to 98)

7664

(2 studies)

⊕⊕⊕⊝
moderate4

Analysis 2.4.1 CIN2+ associated with HPV6/11/16/18, 3 doses, age 15‐26 years

142

0*

0.02

(0.00 to 0.25)

98%

(75% to 100%)

142

(93 to 190)

4499

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 2.4.2 CIN2+ associated with HPV6/11/16/18, 3 doses, age 24‐45 years

38

6

0.17

(0.02 to 1.39)

83%

(‐39% to 98%)

32

(‐1 to 32)

3165

(1 study)

⊕⊕⊝⊝
low3,4

Analysis 2.5.1 CIN2+ associated with HPV6/11/16/18, at least 1 dose, age 15‐26 years

160

0*

0.01

(0.00 to 0.19)

99%

(81% to 100%)

160

(130 to 159)

5351

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 2.5.2 CIN2+ associated with HPV6/11/16/18, at least 1 dose, age 24‐45 years

44

16

0.37

(0.10 to 1.41)

63%

(‐41% to 90%)

28

(‐18 to 40)

3629

(1 study)

⊕⊕⊕⊝
moderate3,4

Analysis 2.6 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses, age 15‐45 years***

199

48

0.24

(0.01 to 5)

76%

(‐400% to 99%)

151

(‐795 to 197)

1316

(2 studies)

⊕⊝⊝⊝
very low1$,4

Analysis 2.6.1 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses, age 15‐26 years***

258

0*

0.04

(0.00 to 0.74)

96%

(26% to 100%))

258

(108 to 409)

852

(1 study)

⊕⊝⊝⊝
very low1$,3,4

Analysis 2.6.2 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses, age 24‐45 years***

88

85

0.97

(0.14 to 6.80)

3%

(‐580% to 86%)

3

(‐165 to 171)

464

(1 study)

⊕⊝⊝⊝
very low1$,3,4

Analysis 2.7 CIN3+ associated with HPV16/18, 3 doses, age 15‐26 years

40

3

0.07

(0.02 to 0.29)

93%

(71% to 98%)

37

(28 to 39)

29,720

(3 studies)

⊕⊕⊕⊕
high

Analysis 2.8 CIN3+ associated with HPV16/18, at least 1 dose, age 15‐26 years

57

3

0.05

(0.02 to 0.14)

95%

(86% to 98%)

54

(49 to 56)

33,199

(3 studies)

⊕⊕⊕⊕

high

Analysis 2.9 CIN3+ associated with HPV16/18, 1 or 2 doses, age 15‐26 years***

200

12

0.06

(0.01 to 0.24)

94%

(26% to 100%)

188

(152 to 198)

3479

(3 studies)

⊕⊕⊝⊝

low1$

Analysis 2.10 AIS+ associated with HPV16/18, 3 doses, age 15‐26 years

8

0*

0.12

(0.02 to 0.70)

88%

(36% to 99%)

8

(2 to 8)

29,707

(3 studies)

⊕⊕⊕⊝
moderate4

Analysis 2.11 AIS+ associated with HPV16/18, at least 1 dose, age 15‐26 years

12

0*

0.09

(0.01 to 0.72)

81%

(28% to 99%)

12

(3 to 12)

17,079

(2 studies)

⊕⊕⊕⊝
moderate4

Analysis 2.12 AIS+ associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses, age 15‐26 years***

29

0*

0.15

(0.01 to 2.97)

85%

(‐197% to 99%)

29

(‐57 to 29)

2015

(2 studies)

⊕⊝⊝⊝
very low1$,4

Analysis 2.13 CIN2+ irrespective of HPV types, 3 doses, age 15‐26 years

166

66

0.40

(0.25 to 0.64)

60%

(36% to 75%)

99

(60 to 124)

7320

(3 studies)

⊕⊕⊕⊕

high

Analysis 2.14 CIN2+ irrespective of HPV types, at least 1 dose, age 15‐26 years

231

95

0.41

(0.32 to 0.52)

58%

(46% to 67%)

136

(111 to 157)

19,143

(3 studies)

⊕⊕⊕⊕

high

Analysis 2.15 CIN2+ irrespective of HPV types, 1 or 2 doses, age 20‐25 years***

1000

710

0.71

(0.15 to 3.38)

29%

(‐238% to 85%)

290

(‐2,380 to 850)

34

(1 study)

⊕⊝⊝⊝
very low1$,3,4

3. High‐grade cervical lesions in all women regardless of HPV DNA status at baseline**

Analysis 3.1.1 CIN2+ associated with HPV16/18, at least 1 dose, age 15‐26 years

341

157

0.46

(0.37 to 0.57)

54%

(43% to 63%)

184

(147 to 215)

34,852
(3 studies)

⊕⊕⊕⊕

high

Analysis 3.1.2 CIN2+ associated with HPV16/18, at least 1 dose, age 24‐45 years

157

116

0.74

(0.52 to 1.05)

26%

(‐5% to 48%)

41

(‐8 to 75)

9200

(2 studies)

⊕⊕⊕⊝

moderate4

Analysis 3.2.1 CIN2+ associated with HPV6/11/16/18, at least 1 dose, age 15‐26 years

436

217

0.50

(0.42 to 0.59)

50%

(41% to 58%)

219

(166 to 272)

17,160

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 3.2.2 CIN2+ associated with HPV6/11/16/18, at least 1 dose, age 24‐45 years

145

113

0.78

(0.44 to 1.37)

22%

(‐37% to 56%)

143

(72 to 204

3723

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 3.3 CIN3+ associated with HPV16/18, at least 1 dose, age 15‐26 years

165

91

0.55

(0.43 to 0.68)

74%

(55% to 91%)

74

(55 to 91)

34,562
(2 studies)

⊕⊕⊕⊕

high

Analysis 3.4 CIN3+ associated with HPV16/18, 1 or 2 doses, age 15‐26 years***

230

124

0.54

(0.43 to 0.68)

46%

(32% to 57%)

106

(74 to 131)

17,160

(1 study)

⊕⊕⊝⊝
low1,3

Analysis 3.5 AIS associated with HPV16/18, at least 1 dose, age 15‐26 years

14

5

0.36

(0.17 to 0.78)

64%

(22% to 83%)

9

(3 to 12)

34,562
(2 studies)

⊕⊕⊕⊕

high

Analysis 3.6 AIS associated with HPV6/11/16/18, at least 1 dose, age 15‐45 years

15

6

0.40

(0.16 to 0.98)

60%

(2% to 84%)

9

(0 to 13)

20,830

(1 study)

⊕⊕⊕⊝
moderate3,4

Analysis 3.7.1 Any CIN2+ irrespective of HPV types, at least 1 dose, age 15‐26 years

559

391

0.70

(0.58 to 0.85)

30%

(15% to 42%)

168

(84 to 235)

35,779
(4 studies)

⊕⊕⊕⊕

high

Analysis 3.7 2 Any CIN2+ irrespective of HPV types, at least 1 dose, age 24‐45 years

342

356

1.04

(0.83 to 1.30)

‐4%

(‐30% to 17%)

‐14

(‐103 to 58)

9287

(2 studies)

⊕⊕⊝⊝
moderate4

Analysis 3.8 Any CIN3+ irrespective of HPV types, at least 1 dose, age 18‐26 years, bivalent vaccine

188

103

0.55

(0.43 to 0.71)

45%

(29% to 57%)

84

(54 to 1107)

18,329

(2 studies)

⊕⊕⊕⊕

high

Analysis 3.8 Any CIN3+ irrespective of HPV types, at least 1 dose, age 15‐26 years, quadrivalent vaccine

349

283

0.81

(0.69 to 0.96)

19%

(4% to 31%)

66

(14 to 108)

17,160

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 3.9 Any AIS irrespective of HPV types, at least 1 dose, age 15‐26 years

17

5

0.32

(0.15 to 0.67)

68%

(33% to 0.85%)

11

(6 to 14)

34,562
(2 studies)

⊕⊕⊕⊕

high

4. HPV16/18 infection in women who were hrHPV DNA negative at baseline

Analysis 4.1 Incident HPV16/18 infection, 3 doses, age 18‐26 years

2,457

147

0.06

(0.02 to 0.20)

94%

(80% to 98%)

2,310

(1,966 to 2,408)

368

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 4.2 Persistent HPV16/18 infection(6M), 3 doses, age 15‐26 years

971

29

0.02

(0.00 to 0.35)

97%

(57% to 100%)

942

(554 to 971)

368

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 4.3 Persistent HPV16/18 infection(6M), at least 1 dose, age 18‐25 years

96

7

0.07

(0.05 to 0.09)

93%

(81% to 95%)

90

(88 to 91)

10,826

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 4.4 Persistent HPV16/18 infection(12M), 3 doses, age 15‐26 years

571

23

0.04

(0.00 to 0.73)

96%

(27% to 100%)

549

(154 to 571)

368

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 4.5 Persistent HPV16/18 infection(12M), at least 1 dose, age 15‐26 years

462

37

0.08

(0.05 to 0.12)

92%

(88% to 95%)

425

(406 to 439)

14,153

( 2 studies)

⊕⊕⊕⊕

high

5. HPV16/18 infection in women who were HPV16/18 negative at baseline

Analysis 5.1 Incident HPV16/18 infection, 3 doses, age 15‐26 years

474

81

0.17

(0.10 to 0.31)

87%

(78% to 92%)

412

(369 to 436)

8,034

(4 studies)

⊕⊕⊕⊕

high

Analysis 5.2 Incident HPV16/18 infection, at least 1 dose, age 15‐26 years

1,326

305

0.23

(0.14 to 0.37)

81%

(71% to 88%)

1,074

(941 to 1,167)

23,872

(5 studies)

⊕⊕⊕⊕

high

Analysis 5.3 Incident HPV16/18 infection, 1 or 2 dose, age 15‐26 years***

2,568

1207

0.47

(0.26 to 0.84)

74%

(31% to 90%)

1,901

(796 to 2,311)

331

(3 studies)

⊕⊕⊕⊝

moderate1

Analysis 5.4.1 Persistent HPV16/18 infection (6M), 3 doses, age 15‐26 years

581

35

0.06

(0.05 to 0.08)

94%

(91% to 95%)

546

(534 to 552)

27,385

(6 studies)

⊕⊕⊕⊕

high

Analysis 5.4.2 Persistent HPV16/18 infection (6M), 3 doses, age 24‐45 years

350

38

0.11

(0.06 to 0.20)

89%

(80% to 94%)

311

(280 to 329)

6728

(2 studies)

⊕⊕⊕⊝
moderate4

Analysis 5.5.1 Persistent HPV16/18 infection (6M), at least 1 dose, age 15‐26 years

657

66

0.10

(0.08 to 0.13)

90%

(87% to 92%)

591

(572 to 605)

22,803

(4 studies)

⊕⊕⊕⊕

high

Analysis 5.5.2 Persistent HPV16/18 infection (6M), at least 1 dose, age 24‐45 years

441

75

0.17

(0.10 to 0.29)

83%

(71% to 90%)

366

(313 to 397)

7520

(2 studies)

⊕⊕⊕⊕

high

Analysis 5.6.1 Persistent HPV16/18 infection (6M), 1 or 2 doses, age 15‐26 years***

996

119

0.12

(0.03 to 0.42)

88%

(58% to 97%)

876

(577 to 966)

437

(2 studies)

⊕⊕⊝⊝
low1,4

Analysis 5.6.2 Persistent HPV16/18 infection (6M), 1 or 2 doses, age 24‐45 years***

1,221

379

0.31

(0.18 to 0.54)

69%

(46% to 82%)

843

(562 to 1002)

792

(2 studies)

⊕⊕⊕⊝

moderate1

Analysis 5.7 Persistent HPV6/11/16/18 infection (6M), 3 doses

518

62

0.12

(0.06 to 0.21)

88%

(79% to 94%)

456

(409 to 487)

4008

(2 studies)

⊕⊕⊕⊕

high

Analysis 5.8 Persistent HPV6/11/16/18 infection (6M), at least 1 dose

907

118

0.13

(0.05 to 0.37)

87%

(63% to 95%)

789

(571 to 862)

4129

(2 studies)

⊕⊕⊕⊕

high

Analysis 5.9 Persistent HPV16/18 infection (12M), 3 doses

297

27

0.09

(0.06 to 0.13)

91%

(87% to 94%)

270

(258 to 279)

22,267

(4 studies)

⊕⊕⊕⊕

high

Analysis 5.10 Persistent HPV16/18 infection (12M), at least 1 dose

365

58

0.16

(0.01 to 0.13)

84%

(87% to 99%)

306

(292 to 361)

29,464

(5 studies)

⊕⊕⊕⊕

high

Analysis 5.11 Persistent HPV16/18 infection (12M), 1 or 2 doses***

205

27

0.13

(0.06 to 0.33)

87%

(67% to 94%)

178

(137 to 193)

3912

(3 studies)

⊕⊕⊕⊝

moderate1

6. HPV16/18 infection regardless of HPV DNA status at baseline**

Analysis 6.1 Incident HPV16/18 infection, at least 1 dose, age 15‐26 years

807

194

0.24

(0.17 to 0.33)

76%

(67% to 83%)

613

(541 to 670)

4210

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 6.2.1 Persistent HPV16/18 infection (6M), at least 1 dose, age 15‐26 years

1,359

598

0.44

(0.38 to 0.51)

56%

(49% to 62%)

761

(666 to 842)

25,199

(2 studies)

⊕⊕⊕⊕

high

Analysis 6.2.2 Persistent HPV16/18 infection (6M), at least 1 dose, age 24‐45 years

642

366

0.57

(0.47 to 0.69)

43%

(31% to 53%)

276

(199 to 341)

8648

(2 studies)

⊕⊕⊕⊕

high

Analysis 6.3 Persistent HPV6/11/16/18 infection (6M), at least 1 dose, age 24‐45 years

1,136

591

0.52

(0.42 to 0.65)

48%

(35% to 58%)

545

(398 to 659)

3713

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 6.4 Persistent HPV16/18 infection (12M), at least 1 dose, age 15‐26 years

861

396

0.46

(0.40 to 0.54)

54%

(46% to 60%)

465

(396 to 516)

24,785

(2 studies)

⊕⊕⊕⊕

high

CI: Confidence interval; RR: Risk Ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect. *The attribution of "high quality" depends on the following conditions: well‐conducted randomised trials, with consistent findings, direct outcome, precise estimates (narrow confidence intervals), absence of reporting bias (Guyatt 2008).

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1In case of study flaws as assessed by the Cochrane Collaboration's tool for assessing risk of bias in randomised trials (Higgins 2011b), not observed but calculated outcome;

2 Substantial heterogeneity defined as I2 >30%, when multiple studies were available for the considered outcome;

3When only one study was retrieved for the outcome;

4Imprecision, when the width of the 95% confidence interval around RR >0.60.

0* When zero events occurred in the vaccine group a continuity correction was applied to compute the RR and its confidence interval. Nevertheless, in this case the absolute risks in the vaccine arms in Table 2 were computed considering an exact binomal distribution.

** Relative and absolute effects in women regardless of HPV DNA status at baseline (headings 3 and 6) must be interpreted with care since influenced by the prevalence of HPV infection at enrolment in the respective trials.

*** Post hoc analysis for women who received <3 doses.

$ For the precancer endpoints (CIN2/3 and AIS),a higher risk in the placebo arms was observed if <3 doses were received compared to those who received 3 doses Therefore the quality of evidence was downgraded to low or very low.

Figuras y tablas -
Table 2. Results of all the efficacy outcomes
Table 3. Number needed to vaccinate (NNV) to prevent one outcome event (in young women aged 15‐26 years)

Outcome

Initial HPV status at enrolment

hrHPV negative

Regardless of HPV status

Lesions associated with HPV16/18

NNV (95% CI)

NNV (95% CI)

CIN2+

62 (61 to 64)

54 (46 to 68)

CIN3+

204 (149 to 333)

135 (110 to 263)

AIS+

1111 (714 to 5000)

1111 (625 to 3333)

Lesions irrespective of HPV types

NNV (95% CI)

NNV (95% CI)

CIN2+

60 (50 to 76)

68 (52 to 97)

CIN3+

141 (106 to 208)

133 (94 to 227)

AIS+

1000 (556 to 10,000)

833 (526 to 2000)

AIS: adenocarcinoma in situ, CIN: cervical intraepithelial neoplasia, CIN2+: CIN of degree II or worse, CIN3+: CIN of degree 3 or worse, hrHPV: high‐risk human papillomavirus types, NNV: number needed to vaccinate.

Figuras y tablas -
Table 3. Number needed to vaccinate (NNV) to prevent one outcome event (in young women aged 15‐26 years)
Table 4. Results of all the safety outcomes (adverse events, pregnancy outcomes)

Outcomes

Absolute risk/ per 10,000

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

placebo

vaccinated

Analysis 7.1Overall local/injection site adverse events

6847

8080

1.18

(1.16 to 1.20)

18,113
(8 studies)

⊕⊕⊕⊝
moderate2

Analysis 7.2Pain at injection site

6505

8782

1.35

(1.23 to 1.49)

25,691
(13 studies)

⊕⊕⊕⊝
moderate2

Analysis 7.3Swelling at injection site

1582

2737

1.73

(1.32 to 2.27)

22,106
(9 studies)

⊕⊕⊕⊝
moderate2

Analysis 7.4Redness at injection site

1938

3333

1.72

(1.50 to 1.97)

19,996
(6 studies)

⊕⊕⊕⊝
moderate2

Analysis 7.5Overall systematic event and general symptoms

6102

6224

1.02

(0.98 to 1.07)

18,191
(8 studies)

⊕⊕⊕⊝
moderate2

Analysis 7.6Serious adverse events

605

611

1.01

(0.95 to 1.07)

6978
(21studies)

⊕⊕⊕⊕
high

Analysis 7.7Deaths

11

13

1.25

(0.81 to 1.93)

71,452

(23 studies)

⊕⊕⊝⊝
low2,4,†

Analysis 8.1Normal infant

7171

7171

1.00

(0.97 to 1.02)

8782
(8 studies)

⊕⊕⊕⊕
high

Analysis 8.2Spontaneous abortion/miscarriage

1618

1424

0.88

(0.68 to 1.14)

8618
(9 studies)

⊕⊕⊕⊕
high

Analysis 8.3Elective termination/induced abortion

931

838

0.90

(0.80 to 1.02)

10.909
(9 studies)

⊕⊕⊕⊕
high

Analysis 8.4Stillbirth

70

78

1.12

(0.68 to 1.83)

8754
(6 studies)

⊕⊕⊕⊝4
moderate

Analysis 8.5Abnormal infant

205

250

1.22

(0.88 to 1.69)

9252
(5 studies)

⊕⊕⊕⊝4
moderate

CI: Confidence interval; RR: Risk Ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect. *The attribution of "high quality" depends on the following conditions: well‐conducted randomized trials, with consistent findings, direct outcome, precise estimates (narrow confidence intervals), absence of reporting bias (Guyatt 2008).

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1In case of study flaws as assessed by Cochrane's tool for assessing risk of bias in randomised trials (Higgins 2011b), not observed but calculated outcome

2 Substantial heterogeneity defined as I2 > 30%, when multiple studies were available for the considered outcome

3When only one study was retrieved for the outcome

4Imprecision, when the width of the 95% confidence interval around RR > 0.60

† inter‐age group heterogeneity, absence of pattern in causes of deaths

Figuras y tablas -
Table 4. Results of all the safety outcomes (adverse events, pregnancy outcomes)
Table 5. Deaths observed in the FUTURE III trial (quadrivalent vaccine, phase 3, women aged 24‐45 years)

ID

Group

Death causes

1

C

Pulmonary thromboembolism with background of acute lymphoblastic leukaemia

2

V

Breast cancer

3

V

Pulmonary tuberculosis

4

V

Thyrotoxicosis

5

V

Cerebral haemorrhage subsequent to hypertension

6

V

Pericarditis on a background of lupus erythematosus

7

V

Nasopharyngeal cancer with metastases to brain

8

V

Pulmonary embolism after intervention for uterine myoma

RR of deaths in vaccine vs placebo arm (7 over 1,890 vs 1 over 1888): RR = 6.99 (95% CI 0.86 to 56.78), 2‐sided pexact=0.070.

The age at death varied between 29 and 45 years, seven of the deaths occurred in the Philippines and one in Columbia.

All participants received three doses of HPV vaccine or placebo except one who received only two doses of vaccine. The time interval between last dose and date at death ranged between 6 and 37 months.

Group:V = vaccinated against HPV, C = control group.

Source: end‐of‐study analysis after a median follow‐up of four years (Castellsagué 2011) and personal communication with Alfred Saah (MSD, 6/05/2016).

Figuras y tablas -
Table 5. Deaths observed in the FUTURE III trial (quadrivalent vaccine, phase 3, women aged 24‐45 years)
Table 6. Deaths observed in the VIVIANE trial (bivalent vaccine, phase 3 trial, women aged >25 years)

Patient

Cause of death

Group

Age

Country

Source

1

Breast cancer metastatic

V

47

Canada

1

2

Suicide

V

47

Mexico

1

3

Lower respiratory tract infection and sepsis*

C

55

Mexico

1

4

Cervix cancer metastatic**

V

45

Mexico

1

5

Interstitial lung disease

V

41

Mexico

1

6

Breast cancer

***

32

Mexico

1***

7

Suicide

V

41

Mexico

1

8

Cardiac valve disease and liver disorder*

C

38

Mexico

1

9

Drug hypersensitivity and acute renal failure*

V

46

Peru

1

10

Cardiorespiratory arrest

C

44

Phillipines

1

11

Acute myocardial infarction

V

31

Phillipines

1

12

Multiple myeloma and pulmonary embolism*

V

50

Phillipines

1

13

Homicide

V

32

Phillipines

1

14

Bronchopneumonia

V

40

Singapore

1

15

Lung neoplasm malignant

V

41

Thailand

1

16

Suicide

V

28

USA

1

17

Glioblastoma multiforme

V

45

USA

1

18

Anaplastic astrocytoma

C

43

****

2

19

Nasopharyngeal cancer

C

41

****

2

Remarks

*

Multiple death causes

**

This woman had normal cytology but was HPV‐18 DNA‐positive at study entry (May 2006). At the next scheduled cytology testing at Month 12 (April 2007), the cytology finding was atypical squamous cells cannot exclude high‐grade squamous intraepithelial lesion. She was diagnosed with metastatic cervical cancer in May 2007 (approximately 7 months after receiving the third dose of vaccine or control) and died in July 2008

***

One case of death due to breast cancer reported in the 48 month report (Skinner 2014) had to be excluded from the analysis (Wheeler 2016).

****

Two additional cases of death occurring in the control arm were reported in the 84‐month report (Wheeler 2016). The country for these two cases was not reported.

Source: 1) interim analysis after 48 months of follow‐up (Skinner 2014); 2) report at 84 months of follow‐up (Wheeler 2016)

The 84‐month follow‐up report revealed 13 deaths in the HPV arm (N = 2877) versus 5 (N = 2870), with death causes allocated to the trial arms (vaccine versus placebo arm) the RR was 2.59 (95% CI 0.93 to 7.27), 2‐sided pexact=0.0957. No pattern was noticed which could indicate a causal role attributed to HPV vaccination.

Figuras y tablas -
Table 6. Deaths observed in the VIVIANE trial (bivalent vaccine, phase 3 trial, women aged >25 years)
Table 7. Trials for which vaccine efficacy is reported by smaller age subgroups

Trial

Target age group

Age category

Reported age sub‐groups

Phase2 trial (ph2,1v)

16‐23

younger

none

Phase2 trial (ph2,2v)

15‐25

younger

none

Phase2 trial (ph2,4v)

16‐23

younger

none

Japanese trial (ph2,2v)

20‐25

younger

none

PATRICIA trial (ph3,2v)

15‐25

younger

15‐17, 18‐20, 21‐25

CVT (ph3,2v)

18‐25

younger

18‐19, 20‐21, 22‐23, 24‐25

VIVIANE trial (ph3,2v)

26+

older

26‐35, 36‐45, 46+

FUTURE I trial (ph3,4v)

16‐24

younger

none

FUTURE II trial (ph3,4v)

15‐26

younger

none

FUTURE III trial (ph3,4v)

25‐45

older

none

Figuras y tablas -
Table 7. Trials for which vaccine efficacy is reported by smaller age subgroups
Table 8. Influence of age (PATRICIA trial)

Outcome

Age

Event/N

Vaccine

Event/N

Placebo

Relative risk

(95% CI)

Vaccine efficacy

% (95% CI)

P value for linear effect of age

In women with hrHPV DNA negative status at baseline

CIN2+ associated with HPV16/18

15‐17

1/1997

53/2022

0.02 (0.00 to 0.14)

98% (86 to 100%)

0.995

18‐20

0/1096

27/1144

0.02 (0.00 to 0.32)

98% (68 to 100%)

21‐25

0/2363

17/2281

0.03 (0.00 to 0.47)

97% (53 to 100%)

CIN2+ irrespective of HPV types

15‐17

34/1997

101/2022

0.34 (0.23 to 0.50)

66% (50 to 77%)

0.355

18‐20

10/1096

38/1144

0.27 (0.14 to 0.55)

73% (45 to 86%)

21‐25

17/2363

33/2281

0.50 (0.28 to 0.89)

50% (11 to 72%)

CIN3+ associated with HPV16/18

15‐17

0/1997

14/2022

0.04 (0.00 to 0.61)

96% (39 to100%)

1.000

18‐20

0/1096

8/1144

0.07 (0.00 to 1.13)

93% (‐13 to 100%)

21‐25

0/2363

5/2281

0.10 (0.00 to 1.74)

90%(‐74 to 100%)

CIN3+ irrespective of HPV types

15‐17

2/1997

24/2022

0.08 (0.02 to 0.36)

92% (64 to 98%)

0.488

18‐20

1/1096

11/1144

0.09 (0.01 to 0.73)

91% (27 to 99%)

21‐25

0/2363

9/2281

0.05 (0.00 to 0.92)

95% (8 to 100%)

Persistent HPV16/18 infection (6M)

15‐17

14/1989

303/2020

0.05 (0.03 to 0.08)

95% (92 to 97%)

0..042

18‐20

9/1090

110/1125

0.08 (0.04 to 0.17)

92%(83 to 96%)

21‐25

12/2338

108/2249

0.11 (0.06 to 0.19)

89% (81 to 94%)

Regardless of women’s baseline HPV DNA status

CIN2+ associated with HPV16/18

15‐17

21/2882

100/2892

0.21 (0.13 to 0.24)

79% (66 to 87%)

0.000

18‐20

23/1871

66/1908

0.36 (0.22 to 0.57)

64% (43 to 78%)

21‐25

46/3929

62/3898

0.74 (0.50 to 1.08)

26% (‐8 to 50%)

CIN2+ irrespective of HPV types

15‐17

112/2882

200/2892

0.56 (0.45 to 0.70)

44% (30 to 55%)

0.006

18‐20

62/1871

105/1908

0.60 (0.44 to 0.82)

40% (18 to 56%)

21‐25

113/3929

123/3898

0.91 (0.09 to 1.17)

9% (‐17 to 29%)

CIN3+ associated with HPV16/18

15‐17

7/2882

36/2892

0.20 (0.09 to 0.44)

80% (56 to 91%)

0.000

18‐20

13/1871

30/1908

0.44 (0.23 to 0.84)

56% (16 to 77%)

21‐25

31/3929

28/3898

1.10 (0.66 to 1.83)

‐10% (‐83 to 34%)

CIN3+ irrespective of HPV types

15‐17

21/2882

61/2892

0.35 (0.21 to 0.57)

65% (43 to 79%)

0.008

18‐20

22/1871

44/1908

0.51 (0.31 to 0.85)

49% (15 to 69%)

21‐25

43/3929

53/3898

0.80 (0.54 to 1.20)

20% (‐20 to 46%)

Persistent HPV16/18 infection (6M)

15‐17

167/2916

588/2920

0.28 (0.24 to 0.34)

72% (66 to 76%)

0.000

18‐20

143/1925

283/1961

0.51 (0.43 to 0.62)

49% (38 to 57%)

21‐25

194/4009

356/3979

0.54 (0.46 to 0.64)

46% (36 to 54% )

Source: Lehtinen 2012.

CIN: cervical intraepithelial neoplasia, CIN2+: CIN of degree II or worse, CIN3+: CIN of degree 3 or worse, HPV: human papillomavirus types..

Figuras y tablas -
Table 8. Influence of age (PATRICIA trial)
Table 9. Influence of age (CVT trial)

Outcome

Age

Vaccine

Placebo

Relative risk

(95% CI)

Vaccine efficacy

(95% CI)

P value for linear effect of age

In women with HPV16/18 DNA negative status at baseline cohort

Persistent HPV16/18 infection (6M)

18‐19

1/825

51/870

0.02 (0.00 to 0.10)

98% (90% to 100%)

0.145

20‐21

3/659

36/649

0.08 (0.02 to 0.24)

92% (76% to 98%)

22‐23

2/588

36/625

0.06 (0.00 to 0.20)

94% (80% to 100%)

24‐25

3/563

20/533

0.14 (0.03 to 0.44)

86% (56% to 97%)

Regardless if women’s baseline HPV DNA status

Persistent HPV16/18 infection (6M)

18‐19

47/1193

165/1,244

0.30 (0.21 to 0.41)

70% (59% to 79%)

0.000

20‐21

64/946

134/905

0.46 (0.34 to 0.61)

54% (39% to 66%)

22‐23

59/818

112/848

0.55 (0.40 to 0.75)

45% (25% to 60%)

24‐25

61/770

75/742

0.78 (0.56 to 1.99)

22 %(‐9.9 to 44%)

Source: Herrero 2011.

Figuras y tablas -
Table 9. Influence of age (CVT trial)
Table 10. Influence of age (VIVIANE trial)

Outcome

Age

Event/NVaccine

Event/NPlacebo

Relative risk

(95% CI)

Vaccine efficacy

(95% CI)

P value for linear effect of age

In women with HPV16/18 DNA negative status at baseline cohort

Persistent HPV16/18 infection (6M)

26‐35

3/834

22/800

0.13 (0.04 to 0.44)

87% (56% to 96%)

0.532

36‐45

3/816

12/809

0.25 (0.07 to 0.88)

75%(12% to 93%)

46+

0/219

0/213

N.A.

N.A.

Regardless if women’s baseline HPV DNA status

Persistent HPV16/18 infection (6M)

26‐35

48/1221

78/1242

0.63 (0.44 to 0.89)

37% (11% to 56%)

0.177

36‐45

19/1244

43/1228

0.44 (0.26 to 0.74)

56% (26% to 74%)

46+

4/300

11/306

0.37 (0.12 to 1.15)

63% (‐15% to 88%)

Source: Skinner 2014.

Figuras y tablas -
Table 10. Influence of age (VIVIANE trial)
Table 11. Influence of the initial serological status on vaccine efficacy against cervical lesions associated with HPV16/18

Initial HPV DNA/ status

Serology

status

Vaccine

Placebo

Relative Risk

(95% CI)

Relative Risk ratio

FUTURE I trial (ph3,4v) (Garland 2007)*

DNA(‐)

Sero‐

0/2,241

32/2258

0.00 (0.02 to 0.26)

15.93

Sero+

0/377

2/379

0.25 (0.01 to 5.20)

DNA(+)

Sero‐

27/232

31/213

0.80 (0.49 to 1.29)

1.50

Sero+

41/156

30/137

1.20 (0.80 to 1.81)

FUTURE II trial (ph3,4v) (FUTURE‐II 2007)**

DNA(‐)

Sero‐

0/5,305

28/5260

0.02(0.00 to 0.14)

7.41

Sero+

0/498

4/524

0.13 (0.01 to 2.43)

DNA(+)

Sero‐

33/423

35/402

0.90 (0.57 to 1.41)

1.12

Sero+

47/298

52/332

1.01 (0.70 to 1.45

PATRICIA trial (ph3,2v) (Paavonen 2009)**

DNA(‐)

Sero‐

5/8709

92/8112

0.05 (0.02 to 0.12)

6.16

Sero+

3/1710

10/1777

0.31 (0.09 to 1.13)

DNA(+)

Sero‐

20/309

29/293

0.65 (0.38 to 1.13)

1.70

Sero+

53/333

44/307

1.11 (0.77 to 1.61)

Pooled results for CIN2+ associated with HPV16/18

(FUTURE II trial (ph3,4v) and PATRICIA trial (ph3,2v)***

DNA(‐)

Sero‐

5/14,014

120/13,372

0.03 (0.02 to 0.09)

5.85

(0.53 to 65.10)

Sero+

3/2205

14/2301

0.19 (0.09 t0 o.77)

DNA(+)

Sero‐

53/679

64/695

0.79 (0.60 to 1.05

1.37

(0.97 to 1.93)

Sero+

100/531

96/639

1.10 (0.88 to 1.36)

*RR against HPV 6/11/16/18 related cervical lesions

** RR against HPV16/18 related CIN2+

*** Pooled only for FUTURE II and PATRIACIA, since, in the FUTURE I trial, the endpoints were cervical lesions and not CIN2+ associated with HPV16/18

Figuras y tablas -
Table 11. Influence of the initial serological status on vaccine efficacy against cervical lesions associated with HPV16/18
Table 12. Influence of the study quality and the involvement of vaccine manufacturers

Outcome

P value

V1

V2

V3

V4

V5

V6

V7

Persistent HPV16/18 infection (6M), in women being baseline HPV16/18 negative 3 doses

0.70

0.60

np

np

0.90

np

0.42

Persistent HPV16/18 infection (6M), in women being baseline HPV16/18 negative at least 1 dose

0.56

0.56

np

np

np

np

np

Persistent HPV16/18 infection (12M), in women being baseline HPV16/18 negative 3 doses

0.94

0.94

np

np

np

np

0.73

Persistent HPV16/18 infection (12M), in women being baseline HPV16/18 negative at least 1 dose

0.67

0.67

np

np

np

np

np

Influence of study quality (items V1‐V6) and independence of the research team towards the vaccine manufacturer (V7) on protection against persistent HPV16/18 infection assessed by meta‐regression.

The P values correspond with the statistical significance of the incorporation of each item in the meta‐regression.

V1: Random sequence generation; V2: Allocation concealment; V3: Blinding participants and personnel; V4: Blinding of outcome; V5: Incomplete outcomes; V6: Selective reporting; V7: Involvement of manufacturer,

np: meta‐regression not possible because of collinearity.

Figuras y tablas -
Table 12. Influence of the study quality and the involvement of vaccine manufacturers
Table 13. Influence of the number of administered doses: one, two or three in two RCTs with four years of follow‐up

Outcome

No. of doses

Vaccine

arm

Placebo

arm

Relative Risk

(95%CI)

P value for linear

dose‐effect relation

12‐month

persistent HPV16/18

infection

in women being

HPV16/18 negative at baseline

3

84/11,104

627/11,203

0.135 (0.108 to 0.169)

0.303

2

3/611

26/574

0.108 (0.033 to 0.356)

1

1/292

17/249

0.050 (0.007 to 0.374)

6‐month

persistent HPV16/18

infection

in women being

HPV16/18 negative at baseline

3

114/11,104

1000/11,209

0.115 (0.095 to 0.139)

0.269

2

4/611

35/574

0.107 (0.038 to 0.300)

1

1/292

24/250

0.036 (0.005 to 0.261)

Incident HPV16/18 infection

in women being HPV16/18

negative at baseline

3

529/11,110

2172/11,217

0.246 (0.224 to 0.269)

0.337

2

22/611

82/574

0.252 (0.160 to 0.398)

1

8/292

45/251

0.153 (0.073 to 0.318)

12‐month

persistent HPV16/18

infection

in women being

hrHPV negative at baseline

3

27/6634

351/6656

0.077 (0.052 to 0.114)

0.996

2

2/273

12/276

0.168 (0.038 to 0.746)

1

0/138

5/99

0.071 (0.004 to 1.289)

6‐month

persistent HPV16/18

infection

in women being

hrHPV negative at baseline

3

38/6634

567/6660

0.067 (0.049 to 0.093)

0.809

2

2/273

16/276

0.126 (0.029 to 0.544)

1

0/138

8/100

0.045 (0.003 to 0.774)

Incident HPV16/18 infection

in women being hrHPV

negative at baseline

3

38/6634

567/6660

0.067 (0.049 to 0.093)

0.809

2

2/273

16/276

0.126 (0.029 to 0.544)

1

0/138

8/100

0.045 (0.003 to 0.774)

Figuras y tablas -
Table 13. Influence of the number of administered doses: one, two or three in two RCTs with four years of follow‐up
Table 14. Influence of the number of administered doses in the CVT trial (seven years of follow‐up)

Outcome

No. of doses

n events

N vaccinated

% (95%CI)

P* for difference with 3 doses

Cumulative

incidence

HPV16/18

infections

3

88

2023

4.3 (3.5 to 5.3)

2 (at months 0 & 6)

3

78

3.8 (1.0 to 10.1)

1.00

2 (at months 0 & 1)

7

192

3.6 (1.6 to 7.1)

0.85

1

2

133

1.5 (0.3 to 4.9)

0.17

Source: Safaeian 2018.

* two‐sided exact test for difference between proportions.

Figuras y tablas -
Table 14. Influence of the number of administered doses in the CVT trial (seven years of follow‐up)
Table 15. Influence of the number of administered doses: all three versus less than three doses

Outcomes

Age

Group

(years)

Studies

RR if 3 doses

(95% CI)

RR if 1‐2 doses

(95% CI)

CIN2+

due to HPV16/18

15‐26

5 (FUTURE II trial (ph3,4v); Japanese trial (ph2,2v);

PATRICIA trial (ph3,2v); Phase2 trial (ph2,1v); Chinese trial (ph3,2v)_young)

0.07 (0.03 to 0.14)*

0.10 (0.04 to 0.26)*

24‐45

2 (FUTURE III trial (ph3,4v); VIVIANE trial (ph3,2v))

0.14 (0.03 to 0.79)*

0.98 (0.20 to 4.83)

CIN3+

due to HPV16/18

15‐26

1 (PATRICIA trial (ph3,2v))

0.20 (0.04 to 0.91)*

0.04 (0.01 to 0.74)*

Incident HPV16/18 infection

15‐26

3 (Japanese trial (ph2,2v); Phase2 trial (ph2,1v);Chinese trial (ph3,2v)_young)

0.20 (0.10 to 0.41)*

0.47 (0.26 to 0.84)*

6‐month persistent HPV16/18 infection

15‐26

2 (Japanese trial (ph2,2v);Chinese trial (ph3,2v)_young)

0.05 (0.01 to 0.27)*

0.12 (0.03 to 0.42)*

24‐45

2 (FUTURE III trial (ph3,4v);VIVIANE trial (ph3,2v))

0.15 (0.09 to 0.27)*

0.34 (0.19 to 0.61)*

12‐month persistent HPV16/18 infection

15‐26

3 (Japanese trial (ph2,2v);CVT (ph3,2v); Chinese trial (ph3,2v)_young)

0.09 (0.05 to 0.19)*

0.13 (0.06 to 0.33)*

*Vaccine efficacy in women being HPV16/18 DNA negative at enrolment and having received all three or less than three doses (computed from trials where per‐protocol [all doses administered] and intention‐to‐treat analyses [at least one dose administered] are reported).

Figuras y tablas -
Table 15. Influence of the number of administered doses: all three versus less than three doses
Table 16. Influence of follow‐up time

Outcomes

Study

Report

(duration of follow‐up)

Vaccine

Placebo

Relative Risk

(95%CI)

P value for linear difference

of follow‐up time effect

CIN2+ associated with HPV16/18

in women being HPV negative at baseline

PATRICIA

Paavonen 2007

14.8 moths

2/7788

21/7838

0.096 (0.007 to 0.466)

0.512

Paavonen 2009

34.9 months

5/8040

91/8080

0.054 (0.016 to 0.137)

Szarewski 2011

39.4 months

5/8079

92/8112

0.054 (0.016 to 0.137)

Lehtinen 2011

43.7 months

5/7338

97/7305

0.051 (0.016 to 0.123)

FUTURE

The FUTURE II study group 2007

36 months

3/5865

87/5836

0.039 (0.011 to 0.109)

0.994

Munoz 2010*

43 months

0/4616

89/4680

0.006 (0.000 to 0.092)

CIN2+ irrespective of HPV types

regardless of women’s initial HPV DNA status

PATRICIA

Paavonen 2009

34.9 months

224/8667

322/8682

0.696 (0.579 to 0.8369)

0.750

Lehtinen 2011

43.7 months

287/8694

428/8708

0.669 (0.574 to 0.778)

FUTURE

The FUTURE II study group 2007

36 months

281/6087

361/6080

0.780 (0.668 to 0.905)

0.665

Munoz 2010

43 months

421/8562

520/8598

0.807 (0.690 to 0.943)

Assessment of the influence of duration of follow‐up on study outcomes using meta‐regression. p‐values correspond with the statistical significance of incorporating average follow‐up time as a continuous variable.

Figuras y tablas -
Table 16. Influence of follow‐up time
Table 17. Influence of the number of sexual partners

Number of sex partners

Vaccine

Placebo

Relative Risk

(95% CI)

P value of number of sexual partners effect

In women being HPV16/18 DNA negative at baseline cohort

Virgin

1/566

17/615

0.064 (0.003 to 0.352)

0.7448

1 partner

3/904

27/915

0.112 (0.007 to 0.335)

2 partners

1/544

17/519

0.056 (0.003 to 0.309)

3+ partners

3/621

28/628

0.108 (0.026 to 0.321)

Regardless of women’s baseline HPV DNA status

Virgin

4/733

21/819

0.202 (0.059 to 0.551)

< 0.0001

1 partner

40/1237

83/1256

0.489 (0.333 to 0.711)

2 partners

38/777

81/753

0.455 (0.307 to 0.665)

3+ partners

71/940

116/911

0.593 (0.440 to 0.796)

The influence of the number of lifetime sexual partners on vaccine efficacy was assessed by Poisson regression. The P value corresponds with the likelihood ratio test comparing a Poisson model with and without inclusion of the sexual history with 3 possible categories.

Source: CVT (ph3,2v) (Herrero 2011).

Figuras y tablas -
Table 17. Influence of the number of sexual partners
Table 18. Influence of the study size

Outcomes

Study

Number of

participants

Study size

Vaccine

Placebo

Relative

Risk

(95%CI)

P value

CIN2+ associated with

HPV16/18

in women being

HPV16/18 negative at baseline

Phase2 trial (V1)

2392

S

0/126

8/127

0.062*

(0.004 to 1.071)

0.598

Phase2 trial (V2)

1113

S

0/219

3/212

0.161*

(0.008 to 3.091)

Japanese trial (ph2,2v)

1040

S

0/422

2/427

0.252*

(0.012 to 5.241)

PATRICIA trial (ph3,2v)

18,644

L

5/8040

91/8080

0.055

(0.022 to 0.136)

FUTURE II trial (ph3, 4v)

12,167

L

3/5865

87/5863

0.034

(0.011 to 0.109)

Chinese trial (ph3,2V)

6051

L

0/2543

4/2554

0.125

(0.001 to 8.681)

CIN2+ irrespective of

HPV types and

regardless of women’s

initial HPV DNA status

FUTURE I/II trial (ph3,4v)

17,622

L

421/8562

520/8598

0.813

(0.718 to 0.921)

0.703

PATRICIA trial (ph3,2v)

18,644

L

287/8694

428/8708

0.672

(0.582 to 0.778)

Phase2 trial (v1)

2392

S

8/148

12/142

0.640

(0.269 to 1.568)

Assesment of the influence of the study size on the protection against CIN2+ associated with HPV16/18 according to study size (S = small, < 3000 participants, L = large >= 3000 participants) in women aged 15‐26 years and received at least 1 dose.

* P values correspond with the statistical significance of a meta‐regression with vs without study size category.

Figuras y tablas -
Table 18. Influence of the study size
Table 19. Vaccine efficacy endpoints derived from phase 2 trials with longest follow‐up time

Analysis

Endpoint

Initial HPV status

Doses

Relative Risk

Monovalent vaccine (Rowhani‐Rahbar, 2009): 102 months of follow‐up

3.1

CIN2+ associated with HPV16

HPV16‐

3

0.00

3.2

CIN2+ associated with HPV16

HPV16‐

>= 1

0.00

3.3

CIN2+ associated with HPV16

HPV16‐

1‐2

0.00

4.1

Incident HPV16 infection

HPV16‐

3

0.05

4.3

Incident HPV16 infection

HPV16‐

>= 1

0.11

4.3

Incident HPV16 infection

HPV16‐

1‐2

0.25

5.1

CIN2+ associated with HPV16

regardless of HPV infection

>= 1

0.36

5.3

CIN2+ irrespective of HPV types

regardless of HPV infection

>= 1

0.64

Bivalent vaccine (De Calvaho, 2012): 88 months of follow‐up

2.2

6M persistent HPV16/18 infection

hrHPV‐

3

0.00

2.4

12M persistent HPV16/18 infection

hrHPV‐

3

0.00

3.2

CIN2+ associated with HPV16/18

HPV16/18‐

>= 1

0.00

Quadrivalent vaccine (Villa, 2006): 60 months of follow‐up

4.8

Persistent HPV6/11/16/18 infection

HPV16/18‐

>= 1

0.07

Figuras y tablas -
Table 19. Vaccine efficacy endpoints derived from phase 2 trials with longest follow‐up time
Table 20. Cross‐protective efficacy of the bivalent and quadrivalent vaccine

Trials

Ref

Endpoint

Relative Risk (95% CI)

P value for

difference in VE

Bivalent

Quadrivalent

FUT I/II trials (ph3,4v)

Malagon 2012

6‐month persistent HPV31 infection

0.229 (0.156 to 0.228)

0.538 (0.336 to 0.847)

0.003

PATRICIA trial (ph3,2v)

6‐month persistent HPV45 infection

0.210 (0.106 to 0.387)

0.922 (0.507 to 1.670)

0.0003

Phase2 trial (ph2,2v)

CIN2+ associated with HPV33

0.177 (0.053 to 0.466)

0.760 (0.328 to 1.712)

0.02

Phase2 trial (ph2,4v)

CIN2+ associated with HPV45

0.000 (0.000 to 0.583)

0.481 (0.174 to 1.177)

0.04

CVT (ph3,2v)

Hildesheim 2014

CIN2+ associated with other hrHPV

0.401 (0.192 to 0.793)

VIVIANE trial (ph3,2v)

Skinner 2014

6‐month persistent HPV31 infection

0.209 (0.041 to 0.724)

6‐month persistent HPV45 infection

0.221 (0.044 to 0.914)

Figuras y tablas -
Table 20. Cross‐protective efficacy of the bivalent and quadrivalent vaccine
Table 21. Relative risk ratio of adverse effects associated with the bivalent versus the quadrivalent vaccine, adjusted for age group and products administered in the control group

Adverse effect

Relative risk

Relative risk ratio

p value

Quadrivalent vs placebo

Bivalent/Quadrivalent

1

Overall adverse effects at injection site

1.19 (0.89 to 1.59)

1.69 (0.96 to 2.96)

0.061

2

Pain at injection site

1.20 (0.78 to 1.85)

1.19 (0.67 to 2.12)

0.501

3

Swelling at injection site

2.72 (0.77to 9.61)

0.62 (0.16 to 2.41)

0.427

4

Redness at injection site

1.46 (1.23 to 1.74)

1.08 (0.88 to 1.32)

0.307

5

Overall systemic events

0.99 (0.91 to 1.07)

1.06 (0.95 to 1.19)

0.210

6

Serious adverse events

0.94 (0.70 to 1.26)

1.08 (0.80 to 1.45)

0.583

7

Deaths

1.18 (0.25 to 5.62)

0.84 (0.14 to 4.91)

0.775

Relative risks of the quadrivalent vaccine versus placebo and the relative risk ratios were computed by meta‐regression including vaccine, age group and type of product injected in the control group (aluminium adjuvants alone or other vaccine such as Hepatitis A vaccine) as covariate. The relative risk ratio reflects how much more an adverse effect is observed after vaccination with the bivalent versus the quadrivalent vaccine.

Figuras y tablas -
Table 21. Relative risk ratio of adverse effects associated with the bivalent versus the quadrivalent vaccine, adjusted for age group and products administered in the control group
Comparison 1. High‐grade cervical lesions in hrHPV DNA negative women at baseline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 CIN2+ associated with HPV16/18, at least 1 dose Show forest plot

3

23676

Risk Ratio (IV, Random, 95% CI)

0.01 [0.00, 0.05]

2 CIN2+ associated with HPV6/11/16/18, at least 1 dose Show forest plot

1

9296

Risk Ratio (IV, Random, 95% CI)

0.01 [0.00, 0.09]

3 CIN3+ associated with HPV16/18, at least 1 dose Show forest plot

2

20214

Risk Ratio (IV, Random, 95% CI)

0.01 [0.00, 0.10]

4 CIN3+ associated with HPV6/11/16/18, at least 1 dose Show forest plot

1

9296

Risk Ratio (IV, Random, 95% CI)

0.01 [0.00, 0.18]

5 AIS associated with HPV16/18, at least 1 dose Show forest plot

2

20214

Risk Ratio (IV, Random, 95% CI)

0.10 [0.01, 0.82]

6 AIS associated with HPV6/11/16/18, at least 1 dose Show forest plot

1

9296

Risk Ratio (IV, Random, 95% CI)

0.14 [0.01, 2.80]

7 Any CIN2+ irrespective of HPV types, at least 1 dose Show forest plot

5

25180

Risk Ratio (IV, Random, 95% CI)

0.37 [0.25, 0.55]

7.1 Bivalent vaccine

4

15884

Risk Ratio (IV, Random, 95% CI)

0.33 [0.25, 0.43]

7.2 Quadrivalent vaccine

1

9296

Risk Ratio (IV, Random, 95% CI)

0.57 [0.44, 0.76]

8 Any CIN3+ irrespective of HPV types, at least 1 dose Show forest plot

3

20719

Risk Ratio (IV, Random, 95% CI)

0.21 [0.04, 1.10]

8.1 Bivalent vaccine

2

11423

Risk Ratio (IV, Random, 95% CI)

0.08 [0.03, 0.23]

8.2 Quadrivalent vaccine

1

9296

Risk Ratio (IV, Random, 95% CI)

0.54 [0.36, 0.82]

9 Any AIS irrespective of HPV types, at least 1 dose Show forest plot

2

20214

Risk Ratio (IV, Random, 95% CI)

0.10 [0.01, 0.76]

Figuras y tablas -
Comparison 1. High‐grade cervical lesions in hrHPV DNA negative women at baseline
Comparison 2. High‐grade cervical lesions in HPV16/18 DNA negative women at baseline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 CIN2+ associated with HPV16/(18), 3 doses Show forest plot

8

43376

Risk Ratio (IV, Random, 95% CI)

0.08 [0.04, 0.16]

1.1 Age group 15‐26 years

6

36579

Risk Ratio (IV, Random, 95% CI)

0.07 [0.03, 0.15]

1.2 Age group 24‐45 years

2

6797

Risk Ratio (IV, Random, 95% CI)

0.16 [0.04, 0.74]

2 CIN2+ associated with HPV16/(18), at least 1 dose Show forest plot

8

42030

Risk Ratio (IV, Random, 95% CI)

0.10 [0.05, 0.20]

2.1 Age group 15‐26 years

6

34478

Risk Ratio (IV, Random, 95% CI)

0.05 [0.03, 0.10]

2.2 Age group 24‐45 years

2

7552

Risk Ratio (IV, Random, 95% CI)

0.30 [0.11, 0.81]

3 CIN2+ associated with HPV16/(18), 1 or 2 doses (post hoc analysis) Show forest plot

7

3713

Risk Ratio (IV, Random, 95% CI)

0.19 [0.07, 0.51]

3.1 women age 15‐26 years

5

2958

Risk Ratio (IV, Random, 95% CI)

0.10 [0.04, 0.26]

3.2 women age 24‐45 years

2

755

Risk Ratio (IV, Random, 95% CI)

0.61 [0.14, 2.67]

4 CIN2+ associated with HPV6/11/16/18, 3 doses Show forest plot

2

7664

Risk Ratio (IV, Random, 95% CI)

0.06 [0.01, 0.61]

4.1 Age group 15‐26 years

1

4499

Risk Ratio (IV, Random, 95% CI)

0.02 [0.00, 0.25]

4.2 Age group 24‐45 years

1

3165

Risk Ratio (IV, Random, 95% CI)

0.17 [0.02, 1.39]

5 CIN2+ associated with HPV6/11/16/18, at least 1 dose Show forest plot

2

8980

Risk Ratio (IV, Random, 95% CI)

0.08 [0.00, 2.41]

5.1 Age group 15‐26 years

1

5351

Risk Ratio (IV, Random, 95% CI)

0.01 [0.00, 0.19]

5.2 Age group 24‐45 years

1

3629

Risk Ratio (IV, Random, 95% CI)

0.37 [0.10, 1.41]

6 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses (post hoc analysis) Show forest plot

2

1316

Risk Ratio (IV, Random, 95% CI)

0.24 [0.01, 5.00]

6.1 Age group 15‐26 years

1

852

Risk Ratio (IV, Random, 95% CI)

0.04 [0.00, 0.74]

6.2 Age group 24‐45 years

1

464

Risk Ratio (IV, Random, 95% CI)

0.97 [0.14, 6.80]

7 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 3 doses Show forest plot

3

29720

Risk Ratio (IV, Random, 95% CI)

0.07 [0.02, 0.29]

8 CIN3+ associated with HPV 16/18 or HPV6/11/16/18, at least 1 dose Show forest plot

3

33199

Risk Ratio (IV, Random, 95% CI)

0.05 [0.02, 0.14]

9 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis) Show forest plot

3

3479

Risk Ratio (IV, Random, 95% CI)

0.06 [0.01, 0.24]

10 AIS associated with HPV16/18 or HPV6/11/16/18, 3 doses Show forest plot

3

29707

Risk Ratio (IV, Random, 95% CI)

0.12 [0.02, 0.70]

11 AIS associated with HPV16/18 or 6/11/16/18, at least 1 dose Show forest plot

2

17079

Risk Ratio (IV, Random, 95% CI)

0.09 [0.01, 0.72]

12 AIS associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis) Show forest plot

2

2015

Risk Ratio (IV, Random, 95% CI)

0.15 [0.01, 2.97]

13 Any CIN2+ irrespective of HPV types, 3 doses Show forest plot

3

7320

Risk Ratio (IV, Random, 95% CI)

0.40 [0.25, 0.64]

14 Any CIN2+ irrespective of HPV types, at least 1 dose Show forest plot

3

19143

Risk Ratio (IV, Random, 95% CI)

0.41 [0.32, 0.52]

15 Any CIN2+ irrespective of HPV types, 1 or 2 doses (post hoc analysis) Show forest plot

1

34

Risk Ratio (IV, Random, 95% CI)

0.71 [0.15, 3.38]

Figuras y tablas -
Comparison 2. High‐grade cervical lesions in HPV16/18 DNA negative women at baseline
Comparison 3. High‐grade cervical lesions in women regardless of baseline HPV DNA status

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 CIN2+ associated with HPV16/18, at least 1 dose Show forest plot

5

44052

Risk Ratio (IV, Random, 95% CI)

0.52 [0.41, 0.67]

1.1 Age group 15‐26 years

3

34852

Risk Ratio (IV, Random, 95% CI)

0.46 [0.37, 0.57]

1.2 Age group 24‐45 years

2

9200

Risk Ratio (IV, Random, 95% CI)

0.74 [0.52, 1.05]

2 CIN2+ associated with HPV6/11/16/18, at least 1 dose Show forest plot

2

20883

Risk Ratio (IV, Random, 95% CI)

0.57 [0.38, 0.86]

2.1 Age group 15‐26 years

1

17160

Risk Ratio (IV, Random, 95% CI)

0.50 [0.42, 0.59]

2.2 Age group 24‐45 years

1

3723

Risk Ratio (IV, Random, 95% CI)

0.78 [0.44, 1.37]

3 CIN3+ associated with HPV16/18, at least 1 dose Show forest plot

2

34562

Risk Ratio (IV, Random, 95% CI)

0.55 [0.45, 0.67]

4 CIN3+ associated with HPV6/11/16/18, at least 1 dose Show forest plot

1

17160

Risk Ratio (IV, Random, 95% CI)

0.54 [0.43, 0.68]

5 AIS associated with HPV16/18, at least 1 dose Show forest plot

2

34562

Risk Ratio (IV, Random, 95% CI)

0.36 [0.17, 0.78]

6 AIS associated with HPV6/11/16/18, at least 1 dose Show forest plot

2

20830

Risk Ratio (IV, Random, 95% CI)

0.40 [0.16, 0.98]

7 Any CIN2+ irrespective of HPV types, at least 1 dose Show forest plot

6

45066

Risk Ratio (IV, Random, 95% CI)

0.79 [0.65, 0.97]

7.1 Age group 15‐26 years

4

35779

Risk Ratio (IV, Random, 95% CI)

0.70 [0.58, 0.85]

7.2 Age group 24‐45 years

2

9287

Risk Ratio (IV, Random, 95% CI)

1.04 [0.83, 1.30]

8 Any CIN3+ HPV type, at least 1 dose Show forest plot

3

35489

Risk Ratio (IV, Random, 95% CI)

0.67 [0.49, 0.93]

8.1 Bivalent vaccine

2

18329

Risk Ratio (IV, Random, 95% CI)

0.55 [0.43, 0.71]

8.2 Quadrivalent vaccine

1

17160

Risk Ratio (IV, Random, 95% CI)

0.81 [0.69, 0.96]

9 Any AIS irrespective of HPV types, at least 1 dose Show forest plot

2

34562

Risk Ratio (IV, Random, 95% CI)

0.32 [0.15, 0.67]

Figuras y tablas -
Comparison 3. High‐grade cervical lesions in women regardless of baseline HPV DNA status
Comparison 4. Infection with HPV vaccine types in hrHPV DNA negative women at baseline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Incident HPV16/18 infection, 3 doses Show forest plot

1

368

Risk Ratio (IV, Random, 95% CI)

0.06 [0.02, 0.20]

2 Persistent HPV16/18 infection (6M), 3 doses Show forest plot

1

368

Risk Ratio (IV, Random, 95% CI)

0.02 [0.00, 0.35]

3 Persistent HPV16/18 infection (6M), at least 1 dose Show forest plot

1

10826

Risk Ratio (IV, Random, 95% CI)

0.07 [0.05, 0.09]

4 Persistent HPV16/18 infection(12M), 3 doses Show forest plot

1

368

Risk Ratio (IV, Random, 95% CI)

0.04 [0.00, 0.73]

5 Persistent HPV16/18 infection (12M), at least 1 dose Show forest plot

2

14153

Risk Ratio (IV, Random, 95% CI)

0.08 [0.05, 0.12]

Figuras y tablas -
Comparison 4. Infection with HPV vaccine types in hrHPV DNA negative women at baseline
Comparison 5. HPV16/18 infection in HPV16/18 DNA negative women at baseline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Incident HPV16/18 infection, 3 doses Show forest plot

4

8034

Risk Ratio (IV, Random, 95% CI)

0.17 [0.10, 0.31]

2 Incident HPV16/18 infection, at least 1 dose Show forest plot

5

23872

Risk Ratio (IV, Random, 95% CI)

0.23 [0.14, 0.37]

3 Incident HPV16/18 infection, 1 or 2 doses (post hoc analysis) Show forest plot

3

331

Risk Ratio (IV, Random, 95% CI)

0.47 [0.26, 0.84]

4 Persistent HPV16/18 infection (6M), 3 doses Show forest plot

8

34113

Risk Ratio (IV, Random, 95% CI)

0.07 [0.06, 0.09]

4.1 Age group 15‐26 years

6

27385

Risk Ratio (IV, Random, 95% CI)

0.06 [0.05, 0.08]

4.2 Age group 24‐45 years

2

6728

Risk Ratio (IV, Random, 95% CI)

0.11 [0.06, 0.20]

5 Persistent HPV16/18 infection (6M), at least 1 dose Show forest plot

6

30323

Risk Ratio (IV, Random, 95% CI)

0.12 [0.08, 0.17]

5.1 Age group 15‐26 years

4

22803

Risk Ratio (IV, Random, 95% CI)

0.10 [0.08, 0.12]

5.2 Age group 24‐45 years

2

7520

Risk Ratio (IV, Random, 95% CI)

0.17 [0.10, 0.29]

6 Persistent HPV16/18 infection (6M), 1 or 2 doses (post hoc analysis) Show forest plot

4

1229

Risk Ratio (IV, Random, 95% CI)

0.26 [0.16, 0.44]

6.1 Age group 15‐26 years

2

437

Risk Ratio (IV, Random, 95% CI)

0.12 [0.03, 0.42]

6.2 Age group 24‐45 years

2

792

Risk Ratio (IV, Random, 95% CI)

0.31 [0.18, 0.54]

7 Persistent HPV6/11/16/18 infection (6M), 3 doses Show forest plot

2

4008

Risk Ratio (IV, Random, 95% CI)

0.12 [0.06, 0.21]

8 Persistent HPV6/11/16/18 infection (6M), at least 1 dose Show forest plot

2

4129

Risk Ratio (IV, Random, 95% CI)

0.13 [0.05, 0.37]

9 Persistent HPV16/18 infection (12M), 3 doses Show forest plot

4

22267

Risk Ratio (IV, Random, 95% CI)

0.09 [0.06, 0.13]

10 Persistent HPV16/18 infection (12M), at least 1 dose Show forest plot

5

29464

Risk Ratio (IV, Random, 95% CI)

0.16 [0.12, 0.20]

11 Persistent HPV16/18 infection (12M), 1 or 2 doses (post hoc analysis) Show forest plot

3

3912

Risk Ratio (IV, Random, 95% CI)

0.13 [0.06, 0.33]

Figuras y tablas -
Comparison 5. HPV16/18 infection in HPV16/18 DNA negative women at baseline
Comparison 6. Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Incident HPV16/18 infection, at least 1 dose Show forest plot

1

4210

Risk Ratio (IV, Random, 95% CI)

0.24 [0.17, 0.33]

2 Persistent HPV16/18 infection (6M), at least 1 dose Show forest plot

4

33847

Risk Ratio (IV, Random, 95% CI)

0.48 [0.41, 0.57]

2.1 Age group 15‐26 years

2

25199

Risk Ratio (IV, Random, 95% CI)

0.44 [0.38, 0.51]

2.2 Age group 24‐45 years

2

8648

Risk Ratio (IV, Random, 95% CI)

0.57 [0.47, 0.69]

3 Persistent HPV6/11/16/18 infection (6M), at least 1 dose Show forest plot

1

3713

Risk Ratio (IV, Random, 95% CI)

0.52 [0.42, 0.65]

4 Persistent HPV16/18 infection (12M), at least 1 dose Show forest plot

2

24785

Risk Ratio (IV, Random, 95% CI)

0.46 [0.40, 0.54]

5 Persistent HPV16/18 infection (12M) by dose (post hoc analysis) Show forest plot

1

7153

Risk Ratio (IV, Random, 95% CI)

0.18 [0.12, 0.27]

Figuras y tablas -
Comparison 6. Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline
Comparison 7. Adverse events

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall local/injection site adverse events Show forest plot

8

18113

Risk Ratio (IV, Fixed, 95% CI)

1.18 [1.16, 1.20]

1.1 Bivalent vaccine

2

6503

Risk Ratio (IV, Fixed, 95% CI)

1.29 [1.26, 1.33]

1.2 Quadrivalent vaccine

6

11610

Risk Ratio (IV, Fixed, 95% CI)

1.14 [1.12, 1.16]

2 Pain at injection site Show forest plot

13

25691

Risk Ratio (IV, Random, 95% CI)

1.35 [1.23, 1.49]

2.1 Monovalent vaccine

1

2280

Risk Ratio (IV, Random, 95% CI)

1.05 [1.01, 1.09]

2.2 Bivalent vaccine

8

16897

Risk Ratio (IV, Random, 95% CI)

1.49 [1.26, 1.75]

2.3 Quadrivalent vaccine

4

6514

Risk Ratio (IV, Random, 95% CI)

1.13 [1.07, 1.19]

3 Swelling at injection site Show forest plot

9

22106

Risk Ratio (IV, Random, 95% CI)

1.73 [1.32, 2.27]

3.1 Bivalent vaccine

7

16603

Risk Ratio (IV, Random, 95% CI)

1.62 [1.15, 2.29]

3.2 Quadrivalent vaccine

2

5503

Risk Ratio (IV, Random, 95% CI)

2.79 [0.85, 9.15]

4 Redness at injection site Show forest plot

6

19996

Risk Ratio (IV, Random, 95% CI)

1.72 [1.50, 1.97]

4.1 Quadrivalent vaccine

1

5345

Risk Ratio (IV, Random, 95% CI)

1.46 [1.32, 1.63]

4.2 Bivalent vaccine

5

14651

Risk Ratio (IV, Random, 95% CI)

1.80 [1.53, 2.11]

5 Overall systemic event and general symptoms Show forest plot

8

18191

Risk Ratio (IV, Random, 95% CI)

1.02 [0.98, 1.07]

5.1 Bivalent vaccine

2

6503

Risk Ratio (IV, Random, 95% CI)

1.07 [0.97, 1.19]

5.2 Quadrivalent vaccine

6

11688

Risk Ratio (IV, Random, 95% CI)

1.01 [0.98, 1.04]

6 Serious adverse events Show forest plot

23

71597

Risk Ratio (IV, Random, 95% CI)

0.98 [0.92, 1.05]

6.1 Monovalent vaccine

1

2387

Risk Ratio (IV, Random, 95% CI)

0.95 [0.51, 1.78]

6.2 Bivalent vaccine

15

46231

Risk Ratio (IV, Random, 95% CI)

1.01 [0.96, 1.07]

6.3 Quadrivalent vaccine

7

22979

Risk Ratio (IV, Random, 95% CI)

0.81 [0.65, 1.02]

7 Deaths Show forest plot

23

71176

Risk Ratio (IV, Random, 95% CI)

1.29 [0.85, 1.98]

7.1 Monovalent vaccine

1

2280

Risk Ratio (IV, Random, 95% CI)

0.0 [0.0, 0.0]

7.2 Bivalent vaccine

15

46231

Risk Ratio (IV, Random, 95% CI)

1.21 [0.66, 2.22]

7.3 Quadrivalent vaccine

7

22665

Risk Ratio (IV, Random, 95% CI)

1.54 [0.73, 3.23]

Figuras y tablas -
Comparison 7. Adverse events
Comparison 8. Pregnancy outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Normal infant Show forest plot

8

8782

Risk Ratio (IV, Random, 95% CI)

1.00 [0.97, 1.02]

2 Spontaneous abortion/miscarriage Show forest plot

9

8618

Risk Ratio (IV, Random, 95% CI)

0.88 [0.68, 1.14]

3 Elective termination/induced abortion Show forest plot

9

10909

Risk Ratio (IV, Random, 95% CI)

0.90 [0.80, 1.02]

4 Stillbirth Show forest plot

6

8754

Risk Ratio (IV, Random, 95% CI)

1.12 [0.68, 1.83]

5 Abnormal infant Show forest plot

5

9252

Risk Ratio (IV, Random, 95% CI)

1.22 [0.88, 1.69]

Figuras y tablas -
Comparison 8. Pregnancy outcomes