Safety of the AS04-adjuvanted human papillomavirus (HPV)-16/18 vaccine in adolescents aged 12-15 years: end-of-study results from a community-randomized study up to 6.5 years

Dan Bi, Dan Apter, Tiina Eriksson, Mari Hokkanen, Julia Zima, Silvia Damaso, Maaria Soila, Gary Dubin, Matti Lehtinen, Frank Struyf, Dan Bi, Dan Apter, Tiina Eriksson, Mari Hokkanen, Julia Zima, Silvia Damaso, Maaria Soila, Gary Dubin, Matti Lehtinen, Frank Struyf

Abstract

This manuscript discloses end-of-study safety data of a community-randomized controlled trial in Finland (NCT00534638), assessing the effectiveness of two vaccination strategies (gender-neutral versus females only) using the AS04-adjuvanted human papillomavirus (HPV)-16/18 (AS04-HPV-16/18) vaccine. The total vaccination cohort included 32,175 adolescents aged 12-15 y at vaccination of whom 14,837 received the AS04-HPV-16/18 vaccine and 17,338 received the hepatitis-B virus vaccine (control). Spontaneous reporting of serious adverse events (SAEs) combined with surveillance using nation-wide health registries showed an acceptable safety profile of the AS04-HPV-16/18 vaccine. During the study period (up to 6.5 y), the incidences (per 100,000 person-years) of reported SAEs considered as possibly related to vaccination were 39.1 (95% confidence interval [CI]: 25.3-57.7) and 39.8 (95%CI: 26.8-56.8) in the HPV and control groups, respectively. The most frequently reported new-onset autoimmune diseases (NOADs) were ulcerative colitis (incidence rates of 28.2 and 33.1 per 100,000 person-years in the HPV and control groups, respectively), insulin-dependent diabetes mellitus (21.9 and 37.1), Crohn's disease (15.6 and 22.5), celiac disease (15.6 and 21.2), and juvenile idiopathic arthritis (14.1 and 15.9). Of 1,344 pregnancies reported (777 and 567 in the HPV and control groups, respectively), most resulted in elective termination (58.4% and 58.6%), birth of a live infant (32.7% and 32.3%), or in spontaneous abortion (8.0% and 7.9%). No major, registered congenital anomalies were identified. The incidence rates of NOADs and pregnancy outcomes were generally balanced between groups. No specific safety signals were identified in the population-based health registry surveillance. Plain Language Summary What is the context? ● Since first licensure in 2007 of the AS04-adjuvanted human papillomavirus (HPV)-16/18 vaccine (Cervarix, GSK), large quantity of safety data has been collected and confirmed its safety profile. This study provides further unique, population-based safety data from vaccinated Finnish adolescents monitored via health registries up to 6.5 y of follow-up. What is new? ● The vaccine has shown an acceptable safety profile in girls and boys. The risk of new-onset autoimmune diseases (NOADs) was similar between the HPV vaccine group and the control group and in line with the expectations for the studied population. ● The study supports that safety surveillance via national health registries is in general more sensitive than the conventional safety reporting, notably for monitoring specific chronic diseases, e.g. autoimmune disorders. What is the impact? ● This study highlights the importance of health registries in long-term vaccination safety surveillance. The population-based safety data reported in this study further support the routine administration of the HPV vaccine to girls and boys.

Keywords: AS04-adjuvanted HPV-16/18 vaccine; Human papillomavirus (HPV); adolescents; autoimmune disease; insulin-dependent diabetes mellitus; safety.

Figures

Figure 1.
Figure 1.
Subject disposition.
Figure 2.
Figure 2.
Estimated relative risk of the occurrence of NOADs in the AS04-HPV-16/18 vaccine group compared to the HBV vaccine group adjusted for gender with 95% confidence interval (Total Vaccinated Cohort).

References

    1. Comité sur l’immunisation du Québec (CIQ). Avis sur le calendrier de vaccination contre les virus du papillome humain (VPH) . 2018. [accessed 2019 September11]. .
    1. Wheeler CM, Castellsague X, Garland SM, Szarewski A, Paavonen J, Naud P, Salmeron J, Chow SN, Apter D, Kitchener H, et al. Cross-protective efficacy of HPV-16/18 AS04-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 Oncol. 2012;13(1):100–10. doi:10.1016/S1470-2045(11)70287-X.
    1. Lehtinen M, Paavonen J, Wheeler CM, Jaisamrarn U, Garland SM, Castellsague X, Skinner SR, Apter D, Naud P, Salmeron J, et al. Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol. 2012;13(1):89–99. doi:10.1016/S1470-2045(11)70286-8.
    1. Arbyn M, Xu L, Simoens C, Martin-Hirsch PP.. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database Syst Rev. 2018;5:CD009069.
    1. Lehtinen M, Lagheden C, Luostarinen T, Eriksson T, Apter D, Harjula K, Kuortti M, Natunen K, Palmroth J, Petaja T, et al. Ten-year follow-up of human papillomavirus vaccine efficacy against the most stringent cervical neoplasia end-point-registry-based follow-up of three cohorts from randomized trials. BMJ Open. 2017;7(8):e015867. doi:10.1136/bmjopen-2017-015867.
    1. Wacholder S, Chen BE, Wilcox A, Macones G, Gonzalez P, Befano B, Hildesheim A, Rodriguez AC, Solomon D, Herrero R, et al. 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. doi:10.1136/bmj.c712.
    1. Lehtinen M, Eriksson T, Apter D, Hokkanen M, Natunen K, Paavonen J, Pukkala E, Angelo MG, Zima J, David MP, 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. Hum Vaccin Immunother. 2016;12(12):3177–3185. doi:10.1080/21645515.2016.1183847.
    1. Lehtinen M, Apter D, Baussano I, Eriksson T, Natunen K, Paavonen J, Vanska S, Bi D, David MP, Datta S, et al. Characteristics of a cluster-randomized phase IV human papillomavirus vaccination effectiveness trial. Vaccine. 2015;33(10):1284–1290. doi:10.1016/j.vaccine.2014.12.019.
    1. Kajantie M, Manderbacka K, McCallum A, Notkola I-L, Arffman M, Forssas E, Karvonen S, Kortteinen M, Leyland A, Keskimäki I. How to carry out register-based health services research in Finland? 2006. [accessed 2019 September11]. .
    1. Laupeze B, Herve C, Di Pasquale A, Tavares Da Silva F. Adjuvant systems for vaccines: 13 years of post-licensure experience in diverse populations have progressed the way adjuvanted vaccine safety is investigated and understood. Vaccine. 2019;37(38):5670–5680. doi:10.1016/j.vaccine.2019.07.098.
    1. Tavares Da Silva F, De Keyser F, Lambert P-H, Robinson WH, Westhovens R, Sindic C. Optimal approaches to data collection and analysis of potential immune mediated disorders in clinical trials of new vaccines. Vaccine. 2013;31(14):1870–1876. doi:10.1016/j.vaccine.2013.01.042.
    1. Pajunen P, Koukkunen H, Ketonen M, Jerkkola T, Immonen-Raiha P, Karja-Koskenkari P, Mahonen M, Niemela M, Kuulasmaa K, Palomaki P, et al. The validity of the Finnish hospital discharge register and causes of death register data on coronary heart disease. Eur J Cardiovasc Prev Rehabil. 2005;12(2):132–137. doi:10.1097/00149831-200504000-00007.
    1. Sund R. Quality of the Finnish hospital discharge register: a systematic review. Scand J Public Health. 2012;40(6):505–515. doi:10.1177/1403494812456637.
    1. Taha AG, Vikatmaa P, Albäck A, Aho PS, Railo M, Lepäntalo M. Are adverse events after carotid endarterectomy reported comparable in different registries? Eur J Vasc Endovasc Surg. 2008;35(3):280–285. doi:10.1016/j.ejvs.2007.10.023.
    1. Quintero OL, Amador-Patarroyo MJ, Montoya-Ortiz G, Rojas-Villarraga A, Anaya JM. Autoimmune disease and gender: plausible mechanisms for the female predominance of autoimmunity. J Autoimmun. 2012;38(2–3):J109–J119. doi:10.1016/j.jaut.2011.10.003.
    1. Genovese C, LAF V, Squeri A, Trimarchi G, Squeri R. HPV vaccine and autoimmune diseases: systematic review and meta-analysis of the literature. J Prev Med Hyg. 2018;59(3):E194–E199. doi:10.15167/2421-4248/jpmh2018.59.3.998.
    1. van der Laan JW, Gould S, Tanir JY, ILSI HESI Vaccines and Adjuvants Safety Project Committee. Adjuvants safety project C. Safety of vaccine adjuvants: focus on autoimmunity. Vaccine. 2015;33(13):1507–1514. doi:10.1016/j.vaccine.2015.01.073.
    1. Verstraeten T, Descamps D, David MP, Zahaf T, Hardt K, Izurieta P, Dubin G, Breuer T. Analysis of adverse events of potential autoimmune aetiology in a large integrated safety database of AS04 adjuvanted vaccines. Vaccine. 2008;26(51):6630–6638. doi:10.1016/j.vaccine.2008.09.049.
    1. Langholz E. Current trends in inflammatory bowel disease: the natural history. Therap Adv Gastroenterol. 2010;3(2):77–86. doi:10.1177/1756283X10361304.
    1. Harjutsalo V, Sjoberg L, Tuomilehto J. Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study. Lancet. 2008;371(9626):1777–1782. doi:10.1016/S0140-6736(08)60765-5.
    1. Cooper GS, Stroehla BC. The epidemiology of autoimmune diseases. Autoimmun Rev. 2003;2(3):119–125. doi:10.1016/S1568-9972(03)00006-5.
    1. Skufca J, Ollgren J, Artama M, Ruokokoski E, Nohynek H, Palmu AA. The association of adverse events with bivalent human papilloma virus vaccination: A nationwide register-based cohort study in Finland. Vaccine. 2018;36(39):5926–5933. doi:10.1016/j.vaccine.2018.06.074.
    1. Willame C, Rosillon D, Zima J, Angelo MG, Stuurman AL, Vroling H, Boggon R, Bunge EM, Pladevall-Vila M, Baril L. Risk of new onset autoimmune disease in 9- to 25-year-old women exposed to human papillomavirus-16/18 AS04-adjuvanted vaccine in the United Kingdom. Hum Vaccin Immunother. 2016;12(11):2862–2871. doi:10.1080/21645515.2016.1199308.

Source: PubMed

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