Safety of human papillomavirus vaccines: a review

Michela Stillo, Paloma Carrillo Santisteve, Pier Luigi Lopalco, Michela Stillo, Paloma Carrillo Santisteve, Pier Luigi Lopalco

Abstract

Introduction: Between 2006 and 2009, two different human papillomavirus virus (HPV) vaccines were licensed for use: a quadrivalent (qHPVv) and a bivalent (bHPVv) vaccine. Since 2008, HPV vaccination programmes have been implemented in the majority of the industrialized countries. Since 2013, HPV vaccination has been part of the national programs of 66 countries including almost all countries in North America and Western Europe. Despite all the efforts made by individual countries, coverage rates are lower than expected. Vaccine safety represents one of the main concerns associated with the lack of acceptance of HPV vaccination both in the European Union/European Economic Area and elsewhere.

Areas covered: Safety data published on bivalent and quadrivalent HPV vaccines, both in pre-licensure and post-licensure phase, are reviewed.

Expert opinion: Based on the latest scientific evidence, both HPV vaccines seem to be safe. Nevertheless, public concern and rumors about adverse events (AE) represent an important barrier to overcome in order to increase vaccine coverage. Passive surveillance of AEs is an important tool for detecting safety signals, but it should be complemented by activities aimed at assessing the real cause of all suspect AEs. Improved vaccine safety surveillance is the first step for effective communication based on scientific evidence.

Keywords: adverse events; human papillomavirus; safety; vaccine.

References

    1. WHO . 2012 Available from: [Cited 17 December 2014]
    1. European Centre for Disease Prevention and Control . Introduction of HPV vaccines in European Union countries - an update. 2012.
    1. CDC Centre for disease prevention and control . 2014 USA. Available from: Updated 2014]
    1. EMA . 2014 Update on. Available from: Updated 6 October 2014]
    1. Gamble HL, Klosky JL, Parra GR, Randolph ME. Factors influencing familial decision-making regarding human papillomavirus vaccination. J Pediatr Psychol. 2010;35(7):704–15.
    1. Sotiriadis A, Dagklis T, Siamanta V, et al. Increasing fear of adverse effects drops intention to vaccinate after the introduction of prophylactic HPV vaccine. Arch Gynecol Obstet. 2012;285(6):1719–24.
    1. Rambout L, Tashkandi M, Hopkins L, Tricco AC. Self-reported barriers and facilitators to preventive human papillomavirus vaccination among adolescent girls and young women: a systematic review. Prev Med. 2014;58:22–32.
    1. Angelo MG, Zima J, Tavares Da Silva F, et al. Post-licensure safety surveillance for human papillomavirus-16/18-AS04-adjuvanted vaccine: more than 4 years of experience. Pharmacoepidemiol Drug Saf. 2014;23(5):456–65.
    1. Gold MS, McIntyre P. Human papillomavirus vaccine safety in Australia: experience to date and issues for surveillance. Sex Health. 2010;7(3):320–4.
    1. Markowitz LE, Dunne EF, Saraiya M, et al. Human papillomavirus vaccination. MMWR Recomm Rep. 2014;63(RR-05):1–30.
    2. Large and comprehensive paper, focusing not only on the safety aspect, with a section for each vaccine. It is centred on the USA.

    1. Brotherton JM. Safety of the quadrivalent human papillomavirus vaccine. BMJ. 2013;347:f5631.
    1. Brotherton JM. Human papillomavirus vaccination: Where are we now? J Paediatr Child Health. 2014;50(12):959–65.
    1. Stokley S, Jeyarajah J, Yankey D, et al. Human papillomavirus vaccination coverage among adolescents, 2007-2013, and postlicensure vaccine safety monitoring, 2006-2014–United States. MMWR Morb Mortal Wkly Rep. 2014;63(29):620–4.
    1. Chen J, Ni G, Liu XS. Papillomavirus virus like particle-based therapeutic vaccine against human papillomavirus infection related diseases: immunological problems and future directions. Cell Immunol. 2011;269(1):5–9.
    1. EMA product information. Available from:
    1. EMA product information Cervarix. Available from:
    1. FDA Highlights of prescribing informationrevised 2014. 2014 Available from:
    1. FDA Highlights of prescribing information (Cervarix) 2014 Available from:
    1. Global Progress in HPV Vaccination. . updated September 2014. Available from: Cited 2014]
    1. EMA 2008 updated 14 August 201417 Dec 2014. Available from:
    1. Vaccine Schedule. . 2013 Internet. Available from: [Cited 17 December 2014]
    1. Einstein MH, Baron M, Levin MJ, et al. Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 vaccine and HPV-6/11/16/18 vaccine: follow-up from months 12-24 in a Phase III randomized study of healthy women aged 18-45 years. Hum Vaccin. 2011;7(12):1343–58.
    1. Petaja T, Pedersen C, Poder A, 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. Int J Cancer. 2011;129(9):2147–57.
    1. Basu P, Banerjee D, Singh P, et al. 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 J Cancer. 2013;2(4):187–92.
    1. Schiller JT, Castellsague X, Garland SM. A review of clinical trials of human papillomavirus prophylactic vaccines. Vaccine. 2012;30(Suppl 5):F123–38.
    1. Naud PS, Roteli-Martins CM, De Carvalho NS, 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. Hum Vaccin Immunother. 2014;10(8):2147–62.
    1. Harper DM, Franco EL, Wheeler CM, et al. 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.
    1. Dillner J, Kjaer SK, Wheeler CM, et al. 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.
    1. GlaxoSmithKline Cervarix: Summary of product Characteristics. . 2014 Available from: [Updated 8 Decemer 2014]
    1. Villa LL, Costa RL, Petta CA, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer. 2006;95(11):1459–66.
    1. David MP, Van Herck K, Hardt K, et al. Long-term persistence of anti-HPV-16 and -18 antibodies induced by vaccination with the AS04-adjuvanted cervical cancer vaccine: modeling of sustained antibody responses. Gynecol Oncol. 2009;115(3 Suppl):S1–6.
    1. Mariani L, Venuti A. HPV vaccine: an overview of immune response, clinical protection, and new approaches for the future. J Transl Med. 2010;8:105.
    1. Newman PA, Logie CH, Doukas N, Asakura K. HPV vaccine acceptability among men: a systematic review and meta-analysis. Sex Transm Infect. 2013;89(7):568–74.
    1. Hillman RJ, Giuliano AR, Palefsky JM, et al. Immunogenicity of the quadrivalent human papillomavirus (type 6/11/16/18) vaccine in males 16 to 26 years old. Clin Vaccine Immunol. 2012;19(2):261–7.
    1. Munoz N, Manalastas R, Jr, Pitisuttithum P, et al. 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.
    1. Castellsague X, Munoz N, Pitisuttithum P, et al. 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. Br J Cancer. 2011;105(1):28–37.
    1. Chen RT. Vaccine risks: real, perceived and unknown. Vaccine. 1999;17(Suppl 3):S41–S6.
    1. WHO safety training. 2014 Available from:
    1. 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 Infect Dis. 2011;11:13.
    2. This is still one of the most complete review and meta-analysis available in the literature.

    1. Agorastos T, Chatzigeorgiou K, Brotherton JM, Garland SM. Safety of human papillomavirus (HPV) vaccines: a review of the international experience so far. Vaccine. 2009;27(52):7270–81.
    2. This is a good and comprehensive review including evidence until 2009, we included also more recent review but this one is still useful.

    1. Macartney KK, Chiu C, Georgousakis M, Brotherton JM. Safety of human papillomavirus vaccines: a review. Drug Saf. 2013;36(6):393–412.
    2. One of the last and more update review on human papillomavirus virus (HPV) vaccines’ safety topic.

    1. Weber SK, Schlagenhauf P. Childhood vaccination associated adverse events by sex: A literature review. Travel Med Infect Dis. 2014;12(5):459–80.
    1. Block SL, Brown DR, Chatterjee A, et al. Clinical trial and post-licensure safety profile of a prophylactic human papillomavirus (types 6, 11, 16, and 18) l1 virus-like particle vaccine. Pediatr Infect Dis J. 2010;29(2):95–101.
    1. Gasparini R, Bonanni P, Levi M, et al. Safety and tolerability of bivalent HPV vaccine: an Italian post-licensure study. Hum Vaccin. 2011;7(Suppl):136–46.
    1. 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. CMAJ. 2007;177(5):469–79.
    1. Paavonen J, Jenkins D, Bosch FX, et al. 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.
    1. Medina DM, Valencia A, de Velasquez A, et al. Safety and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine: a randomized, controlled trial in adolescent girls. J Adolescent Health. 2010;46(5):414–21.
    1. VAERS website Vaccine Adverse Events Reporting system: centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), agencies of the U.S. Department of Health and Human Service. Available from:
    1. Public Health Agency of Canada Adverse events following immunization reporting form: public Health Agency of Canada. Available from: [Cited October 2014]
    1. Medicines and Health products Regulatory Agency (MHRA). Yellowcard: medicines and Health products Regulatory Agency (MHRA) Available from: [Cited 17 December 2014]
    1. Medicines and Healthcare products Regulatory Agency (MHRA) Public assessment report. Cervarix (HPV vaccine): update on UK safety experience at the end of 4 years use in the HPV routine immunisation programme: Medicines and Healthcare products Regulatory Agency (MHRA) Available from: [Cited 17 December 2014]
    1. Australian Goverment Australian TGA system for adverse events surveillance: australian Government. . Available from: [Cited October 2014]
    1. Lindquist M. Use of triage strategies in the WHO signal-detection process. Drug Saf. 2007;30(7):635–7.
    1. Baggs J, Gee J, Lewis E, et al. The vaccine safety datalink: a model for monitoring immunization safety. Pediatrics. 2011;127(Suppl 1):S45–53.
    1. Angelo MG, David MP, Zima J, et al. Pooled analysis of large and long-term safety data from the human papillomavirus-16/18-AS04-adjuvanted vaccine clinical trial programme. Pharmacoepidemiol Drug Saf. 2014;23(5):466–79.
    1. Khatun S, Akram Hussain SM, Chowdhury S, et al. Safety and immunogenicity profile of human papillomavirus-16/18 AS04 adjuvant cervical cancer vaccine: a randomized controlled trial in healthy adolescent girls of Bangladesh. Jpn J Clin Oncol. 2012;42(1):36–41.
    1. Skinner SR, Szarewski A, Romanowski B, et al. 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. The Lancet. 2014;384(9961):2213–27.
    1. Reisinger KS, Block SL, Lazcano-Ponce E, et al. Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial. Pediatr Infect Dis J. 2007;26(3):201–9.
    1. van 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.
    1. Levi M, Bonanni P, Burroni E, et al. Evaluation of bivalent human papillomavirus (HPV) vaccine safety and tolerability in a sample of 25 year old Tuscan women. Hum Vaccin Immunother. 2013;9(7):1407–12.
    1. Klein NP, Hansen J, Chao C, et al. Safety of quadrivalent human papillomavirus vaccine administered routinely to females. Arch Pediatr Adolesc Med. 2012;166(12):1140–8.
    1. Slade BA, Leidel L, Vellozzi C, et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. Jama. 2009;302(7):750–7.
    2. This study include quadrivalent (qHPVv) reports received by VAERS from June 2006 through December 2008, it explains well the results for each outcome including Guillain–Barre’s syndrome, venous thromboembolism and death.

    1. Labadie J. Postlicensure safety evaluation of human papilloma virus vaccines. Int J Risk Saf Med. 2011;23(2):103–12.
    2. This study collects safety data about HPV vaccines from three different passive surveillance sources, providing quite robust and consistent evidence.

    1. Gee J, Naleway A, Shui I, et al. Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink. Vaccine. 2011;29(46):8279–84.
    2. This study reports the results from a passive surveillance on more than 600 000 qHPVv administered doses.

    1. FDA safety. . Available from: [cited 17 December 2014]
    1. European parliament and the council 2001 Dir 2001/83/EC art.1(12) Available from:
    1. Schwarz TF, Huang LM, Lin TY, et al. Long-term immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in 10-14 year old girls: Open six-year follow-up of an initial observer-blinded, randomized trial. Pediatr Infect Dis J. 2014;33(12):1255–61.
    1. Harris T, Williams DM, Fediurek J, et al. Adverse events following immunization in Ontario’s female school-based HPV program. Vaccine. 2014;32(9):1061–6.
    1. Arnheim-Dahlstrom L, Pasternak B, Svanstrom H, et al. 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.
    2. This study is a passive surveillance including a population of more than 1 million girls; it’s particularly useful for reviewing autoimmune, neurological, and venous thromboembolic adverse events.

    1. Scheller NM, Pasternak B, Svanstrom H, Hviid A. Quadrivalent human papillomavirus vaccine and the risk of venous thromboembolism. Jama. 2014;312(2):187–8.
    1. Pellegrino P, Carnovale C, Pozzi M, et al. On the relationship between human papilloma virus vaccine and autoimmune diseases. Autoimmun Rev. 2014;13(7):736–41.
    1. Souayah N, Michas-Martin PA, Nasar A, et al. Guillain-barre syndrome after gardasil vaccination: data from vaccine adverse event reporting system. 2006-2009. Vaccine. 2011;29(5):886–9.
    1. Ojha RP, Jackson BE, Tota JE, et al. Guillain-Barre syndrome following quadrivalent human papillomavirus vaccination among vaccine-eligible individuals in the United States. Hum Vaccin Immunother. 2014;10(1):232–7.
    1. Chao C, Klein NP, Velicer CM, et al. Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine. J Intern Med. 2012;271(2):193–203.
    2. The study is about 200,000 women who received qHPVv between 2006 and 2008 and reports comprehensive data on autoimmune diseases.

    1. Slade BA, Gee J, Broder KR, Vellozzi C. Comment on the contribution by Souayah et al., Guillain-Barre syndrome after Gardasil vaccination: data from Vaccine Adverse Event Reporting System 2006-2009. Vaccine. 2011;29(5):865–6.
    1. Centers for Disease Control and Prevention Vaccine safety: centers for Disease Control and Prevention. . Available from: [Cited 17 December 2014]
    1. Grimaldi-Bensouda L, Guillemot D, Godeau B, et al. Autoimmune disorders and quadrivalent human papillomavirus vaccination of young female subjects. J Intern Med. 2014;275(4):398–408.
    1. Tam LS, Chan AY, Chan PK, et al. Increased prevalence of squamous intraepithelial lesions in systemic lupus erythematosus: association with human papillomavirus infection. Arthritis Rheum. 2004;50(11):3619–25.
    1. Soldevilla HF, Briones SF, Navarra SV. Systemic lupus erythematosus following HPV immunization or infection? Lupus. 2012;21(2):158–61.
    1. Gatto M, Agmon-Levin N, Soriano A, et al. Human papillomavirus vaccine and systemic lupus erythematosus. Clin Rheumatol. 2013;32(9):1301–7.
    1. Soybilgic A, Onel KB, Utset T, et al. Safety and immunogenicity of the quadrivalent HPV vaccine in female systemic lupus erythematosus patients aged 12 to 26 years. Pediatr Rheumatol Online J. 2013;11:29.
    1. Zhu FC, Chen W, Hu YM, 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. Int J Cancer. 2014;135(11):2612–22.
    1. Garnock-Jones KP, Giuliano AR. Quadrivalent human papillomavirus (HPV) types 6, 11, 16, 18 vaccine: for the prevention of genital warts in males. Drugs. 2011;71(5):591–602.
    1. Fairweather D, Rose NR. Women and autoimmune diseases. Emerg Infect Dis. 2004;10(11):2005–11.
    1. Luna J, Plata M, Gonzalez M, et al. Long-term follow-up observation of the safety, immunogenicity, and effectiveness of Gardasil in adult women. PLoS One. 2013;8(12):e83431.
    1. Moscicki AB, Ellenberg JH, Farhat S, Xu J. Persistence of human papillomavirus infection in HIV-infected and -uninfected adolescent girls: risk factors and differences, by phylogenetic type. J Infect Dis. 2004;190(1):37–45.
    1. Palefsky J. Human papillomavirus infection in HIV-infected persons. Top HIV Med. 2007;15(4):130–3.
    1. Palefsky JM. HPV infection in men. Dis Markers. 2007;23(4):261–72.
    1. Levin MJ, Moscicki AB, Song LY, et al. Safety and immunogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine in HIV-infected children 7 to 12 years old. J Acquir Immune Defic Syndr. 2010;55(2):197–204.
    1. Denny L, Hendricks B, Gordon C, et al. 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.
    1. Kahn JA, Xu J, Kapogiannis BG, et al. Immunogenicity and safety of the human papillomavirus 6, 11, 16, 18 vaccine in HIV-infected young women. Clin Infect Dis. 2013;57(5):735–44.
    1. Wilkin T, Lee JY, Lensing SY, et al. Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in HIV-1-infected men. J Infect Dis. 2010;202(8):1246–53.
    1. Toft L, Storgaard M, Muller 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. J Infect Dis. 2014;209(8):1165–73.
    1. Kojic EM, Kang M, Cespedes MS, et al. Immunogenicity and safety of the quadrivalent human papillomavirus vaccine in HIV-1-infected women. Clin Infect Dis. 2014;59(1):127–35.
    1. Giacomet V, Penagini F, Trabattoni D, et al. Safety and immunogenicity of a quadrivalent human papillomavirus vaccine in HIV-infected and HIV-negative adolescents and young adults. Vaccine. 2014;32(43):5657–61.
    1. Presidencia de la repbúlica de Colombia. Presidente Santos pide a Ministro de Salud ir a El Carmen de Bolívar para explicar alcances de vacuna contra el VPH 2014. p. Communication from the President of the Republic of Colombia regarding the events taking place in Carmen Bolivar related to HPV vaccination
    1. Fox News Latino 2014 President: There Is Not Link Between Mystery Illness And HPV Vaccine. Fox news latino. on-line edition ed.
    1. Adetunji J. Schoolgirl dies after cervical cancer vaccination. Guardian News and Media Limited; UK: 2009.
    1. Bowcott O. Girl who died after cervical cancer injection had tumour in her chest. The Guardian; 2009.
    1. Sheridan A, White J. Department of Health; London, UK: 2011. Annual HPV vaccine coverage in England in 2009/2010.
    1. Reuters web page UPDATE 1-Spain halts batch of Merck’s Gardasil. 2009 Available from:
    1. Morimoto A, Ueda Y, Egawa-Takata T, et al. Effect on HPV vaccination in Japan resulting from news report of adverse events and suspension of governmental recommendation for HPV vaccination. Int J Clin Oncol. 2014 Epub ahead of print]
    1. Peres J. For cancers caused by HPV, two vaccines were just the beginning. J Natl Cancer Inst. 2011;103(5):360–2.
    1. Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007;356(19):1928–43.
    1. Paavonen J, Naud P, Salmeron J, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-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(9686):301–14.
    1. Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002;347(21):1645–51.
    1. Mao C, Koutsky LA, Ault KA, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol. 2006;107(1):18–27.

Source: PubMed

3
Iratkozz fel