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
Full text
.(,# -1""8%%#"(#%")#8(" ***"8""#% %"4("9"8 ":4("1#;75 !"# $#%&&'''()*#(&#&+,- *.*/-)0,) ##, &1,)# %)2.)*).#* .)3)).(. 4564/678+69++6$#:6#,46 9#6;.4<69=>+.* 7# !"#$%&'()*+,%%"(-./. "&01+)23)455.56.)'7)8,.%. %5.9..2:8155#;"5<;, )(:)(4(3')2-88)8:'()*:)2*'88= 7#+# !"#$%& '()#*%#"#)+,+-."% (/001 2#*(# #"+ # '()#""#3#% () +(%#4(" &%#5#*6 2#*##%# 2#*1 7
RESEARCH PAPER 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 a , Dan Apter b , Tiina Eriksson c , Mari Hokkanen c , Julia Zima d , Silvia Damaso a , Maaria Soila e , Gary Dubin f , Matti Lehtinen c , and Frank Struyf a a GSK, Wavre, Belgium; b Sexual Health Clinic, Family Federation of Finland, Helsinki, Finland; c Faculty of Social Sciences, University of Tampere, Tampere, Finland; d EMD Serono, Billerica, MA, USA; e GSK, Espoo, Finland; f Takeda Pharmaceuticals, Zurich, Switzerland 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 populationbased 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. ARTICLE HISTORY Received 15 July 2019 Revised 28 October 2019 Accepted 9 November 2019 KEYWORDS Human papillomavirus (HPV); AS04-adjuvanted HPV-16/18 vaccine; adolescents; safety; autoimmune disease; insulin-dependent diabetes mellitus Introduction Since the first licensure in 2007, more than 71 million doses of the prophylactic AS04-adjuvanted human papillomavirus (HPV)-16 and −18 (AS04-HPV-16/18) vaccine have been distributed worldwide. 1 The vaccine was adjuvanted with an adjuvant system (AS04) containing 3-O-desacyl-4ʹmonophosphoryl lipid A (50 μg MPL; produced by GSK) adsorbed on aluminum salt (500 μgAl 3+ ) and has CONTACT Dan Bi [email protected] GSK, Avenue Fleming 20, Wavre 1300, Belgium This article has been republished with minor changes. These changes do not impact the academic content of the article. Supplemental data for this article can be accessed online at https://doi.org/10.1080/21645515.2019.1692557. HUMAN VACCINES & IMMUNOTHERAPEUTICS https://doi.org/10.1080/21645515.2019.1692557 © 2019 GlaxoSmithKline Biologicals SA. Published with license by Taylor & Francis Group, LLC This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
demonstrated a strong and long-term efficacy against HPV types 16 and 18, and a degree of cross-protection against the types HPV-31, −33 and −45 phylogenetically related to HPV16 and −18, and potentially other types. 2-5 The use of the AS04 adjuvant initially raised theoretical safety concerns that were not confirmed by the large quantity of data collected from clinical trials and post-marketing surveillance which have shown an acceptable safety profile of the AS04-HPV -16/18 vaccine. 6 The present phase III/IV controlled, randomized study (ClinicalTrials.gov NCT00534638) was designed to evaluate the effectiveness of two vaccination strategies (genderneutral versus females only) using the AS04-HPV-16/18 vaccine in reducing the prevalence of HPV-16/18 infection in young women when administered in adolescents in Finland. As an important secondary objective, new-onset autoimmune diseases (NOADs) and pregnancy outcomes were monitored in the study via nation-wide health registries which are part of the public health infrastructure in Nordic countries. Interim safety results of the trial reported in 2016 showed an acceptable safety profile of the AS04-HPV-16/18 vaccine in girls and boys. 7 This article reports the final safety outcomes from this population-based cluster-randomized trial. Materials and methods Methods of the study were previously detailed and published. 7,8 Study design Between October 2007 and April 2010, 80,272 Finnish male and female adolescents, born between 1992 and 1995 from 33 communities were invited to participate in this study and randomized into three arms. 7 In Arm A communities, boys and girls were randomly assigned to receive either the AS04-HPV-16/18 vaccine (Cervarix, GSK; 90% of the vaccinated subjects) or the hepatitis B virus (HBV) vaccine (Engerix B, GSK; 10% of the vaccinated subjects). This vaccine was chosen as control vaccine given its well-known and acceptable safety profile and the benefit that it would confer to the subjects unvaccinated with it at the time of the enrollment. In Arm B communities, girls were randomly assigned to receive either the AS04-HPV-16/ 18 vaccine (90% of the vaccinated subjects) or the HBV vaccine (10% of the vaccinated subjects). All the remaining vaccinated subjects (i.e. 10% of boys and girls in Arm A, 10% of girls and all boys in Arm B, and all participants in Arm C communities) were assigned to receive the HBV vaccine. Vaccine doses were administered at Months 0, 1 and 6 at schools by the same study nurses. To limit bias for analysis, blinding was maintained for all subjects in Arm A and for girls in Arm B. The study was approved by the ethics committee of the Pirkanmaa hospital district and conducted in accordance with the Declaration of Helsinki, good clinical practice and all applicable regulatory requirements. Written informed assent was provided by subjects younger than 15 y while written informed consent was obtained from those aged ≥15 y and from participants’parents or legal representatives prior to the initiation of any study-specific procedures. Safety reporting Three methods were applied in the study for safety surveillance according to gender and intervention arm: active surveillance, registry-based surveillance and spontaneous reporting. Active safety surveillance was performed from Month 0 to Month 12 in all males from Arm A communities and in males from Arm C communities included in the Diary Card subset and who were actively questioned by the investigator at each visit about any serious adverse events (SAE) that occurred until Month 12 after the first vaccine dose. These subjects were asked to record solicited local and general symptoms within 7 days (D 0–6) and unsolicited AEs within 30 days (D 0–29) after each vaccine dose. These subjects were also actively questioned at Months 7 and 12 about any medically significant conditions including NOADs and SAEs that might have occurred after the first vaccination. Active safety surveillance for the occurrence of SAEs was also performed in boys from Arm A communities who were not included in the diary card subset at Months 7 and 12. 7 All SAEs reported to the investigator and considered possibly related to vaccination were reported using a remote data entry system at the study sites. Registry-based safety surveillance was performed for all study participants in all intervention arms during the entire study period up to visit 5 (within ± 1.5 months of reaching 18.5 y). For the Care Register for Social Welfare and Health Care (HILMO)-based analysis, consent was given by study participants for personal identity code (PIC)-based linkages of the Registry of Vaccinated Individuals (RVI) and the HILMO. The RVI and HILMO registry linkage for predefined NOADs was performed after the HILMO had been completed for the International Classification of Diseases-10 (ICD-10) diagnoses made by Finnish healthcare. 9 The cases identified in the register linkage were confirmed by medical history data obtained from the hospitals and hospital municipal health centers, which were reviewed by the principal investigator. Time of onset within 18 months from the first vaccine dose (i.e. approximately 12 months from the last vaccine dose) was the time window used for temporal association, and considered by the investigator to not exclude a possible causality. Indeed, Regulatory Authorities have previously recommended a safety follow-up period of 6–12 months post-vaccination for immune-mediated diseases for all vaccines formulated with novel adjuvants. It is considered that autoimmunity occurrence linked to a vaccine is less likely to occur after 6–12 months following vaccination. 10,11 For the NOAD causality assessment, the investigator was blinded to both vaccination and community status, that could have indirectly disclosed the vaccination status. Safety surveillance also included spontaneous reporting of pregnancies as well as pregnancies retrieved from the Medical Birth Registry and HILMO databases in all female study participants. The Medical Birth registry included subregisters such as the Medical Birth Register and Abortion Register, which were used in data retrieval. 2D. BI ET AL.
Statistical analyses Statistical analyses were performed on the Total Vaccinated Cohort, and were purely descriptive. The analysis of safety data was performed by treatment groups: study participants who received the AS04-HPV-16/18 vaccine and study participants who received the HBV vaccine. The number of withdrawn subjects was tabulated according to the reason for withdrawal. The mean, median, range and standard deviation of age in years at Dose 1 and at Visit 5 of the study participants were calculated by gender and vaccine group. Other demographic characteristics (i.e. birth cohort, area type, ethnicity, and geographic ancestry) were tabulated. The incidence rates (per 100,000 person-years) of subjects experiencing at least one SAE judged possibly related to vaccination according to the investigator and classified by the Medical Dictionary for Regulatory Activities (MedDRA) during the entire follow-up period were calculated by vaccine group for all participants and by gender (self-identified) with exact 95% confidence interval (CI), together with relative risk (RR) adjusted by gender (and 95% CI). The incidence rates (per 100,000 person-years) of subjects reporting at least one NOAD classified by MedDRA during the entire follow-up period were calculated with exact 95% CI, together with RR adjusted by gender (and 95% CI). NOADs reported as possibly related to vaccination and serious NOADs were tabulated similarly. Pregnancies and pregnancy outcomes over the total number of pregnancies reported during the entire study period were tabulated by vaccine group and overall. Results Study population Between October 2007 and December 2014, 32,175 Finnish adolescents (20,512 girls and 11,663 boys) from 33 communities were enrolled and received at least one dose of study vaccines (Figure 1). Overall, the AS04-HPV-16/18 vaccine was administered to 14,837 adolescents (12,401 girls and 2,436 boys) and the control HBV vaccine to 17,338 adolescents (8,111 girls and 9,227 boys). Almost all (99.4%) participants received all three doses and most were of Caucasian/European heritage (99.1%) (Table 1). SAEs considered as possibly related to vaccination During the follow-up period up to 6.5 y, the observed incidence rates (per 100,000 person-years) for SAEs considered as possibly related to vaccination according to investigators’ assessment were 39.1 (95% CI: 25.3–57.7) in the AS04-HPV -16/18 vaccine group and 39.8 (95% CI: 26.8–56.8) in the HBV vaccine group. Considering SAEs possibly related to vaccination (with incidence rates ≥5 per 100,000 personyears in at least one group), the most common were ulcerative colitis in the AS04-HPV-16/18 vaccine group (7.8 per 100,000 person-years in the AS04-HPV-16/18 vaccine group vs. 4.0 per 100,000 person-years in the HBV vaccine group) and insulin-dependent diabetes mellitus (IDDM) in the HBV vaccine group (4.7 per 100,000 person-years in AS04-HPV Figure 1. Subject disposition. a Subjects with registry-based follow-up during the entire study period regardless of their completion of the study. b Visit 5 (within ± 1.5 months of reaching 18.5 y). AS04-HPV-16/18: AS04-adjuvanted HPV-16/18 vaccine; HBV: hepatitis-B virus vaccine; N: number of subjects. HUMAN VACCINES & IMMUNOTHERAPEUTICS 3
Table 1. Summary of demographic characteristics, by gender and vaccine group, at subject level (Total Vaccinated Cohort). Female Male AS04-HPV-16/18 N= 12,401 HBV N= 8,111 Total N= 20,512 AS04-HPV-16/18 N= 2,436 HBV N= 9,227 Total N= 11,663 Characteristics Value or n% Value or n% Value or n% Value or n% Value or n% Value or n% Birth cohort 1992 3,120 25.2 2,117 26.1 5,237 25.5 594 24.4 2,225 24.1 2,819 24.2 1993 3,109 25.1 1,909 23.5 5,018 24.5 546 22.4 2,256 24.4 2,802 24.0 1994 3,252 26.2 2,104 25.9 5,356 26.1 648 26.6 2,350 25.5 2,998 25.7 1995 2,920 23.5 1,981 24.4 4,901 23.9 648 26.6 2,396 26.0 3,044 26.1 Area type Urban 10,665 86.0 7,139 88.0 17,804 86.8 2,252 92.4 7,511 81.4 9,763 83.7 Semi-urban 1,736 14.0 972 12.0 2,708 13.2 184 7.6 1,716 18.6 1,900 16.3 HPV-16/18 seroprevalence strata <20.5% 3,590 28.9 3,247 40.0 6,837 33.3 690 28.3 3,161 34.3 3,851 33.0 20.5–24% 2,763 22.3 1,679 20.7 4,442 21.7 621 25.5 2,093 22.7 2,714 23.3 >24% 6,048 48.8 3,185 39.3 9,233 45.0 1125 46.2 3,973 43.1 5,098 43.7 Age [y] at vaccination dose 1 Mean 14.1 - 14.1 - 14.1 - 14.1 - 14.1 - 14.1 - SD 0.75 - 0.75 - 0.75 - 0.78 - 0.76 - 0.76 - Median 14.0 - 14.0 - 14.0 - 14.0 - 14.0 - 14.0 - Minimum 12 - 12 - 12 - 12 - 12 - 12 - Maximum 16 - 16 - 16 - 16 - 16 - 16 - Age [y] at visit 5 Mean 18.0 - 18.0 - 18.0 - 18.0 - 18.0 - 18.0 - SD 0.04 - 0.03 - 0.04 - 0.06 - 0.00 - 0.05 - Median 18.0 - 18.0 - 18.0 - 18.0 - 18.0 - 18.0 - Minimum 18 - 18 - 18 - 18 - 18 - 18 - Maximum 19 - 19 - 19 - 19 - 18 - 19 - Missing or NA 5,148 - 3,980 - 9128 - 2,117 - 9,205 - 11,322 - Ethnicity American hispanic or latino 20 0.2 9 0.1 29 0.1 2 0.1 11 0.1 13 0.1 Not american hispanic or latino 12,381 99.8 8,102 99.9 20,483 99.9 2,434 99.9 9,216 99.9 11,650 99.9 Geographic Ancestry African Heritage/African American 9 0.1 4 0.0 13 0.1 0 0.0 4 0.0 4 0.0 Asian –Central/South Asian Heritage 2 0.0 1 0.0 3 0.0 1 0.0 3 0.0 4 0.0 Asian –East Asian Heritage 8 0.1 0 0.0 8 0.0 0 0.0 0 0.0 0 0.0 Asian –Japanese Heritage 1 0.0 1 0.0 2 0.0 0 0.0 0 0.0 0 0.0 Asian –South East Asian Heritage 12 0.1 2 0.0 14 0.1 1 0.0 2 0.0 3 0.0 White –Arabic/North African Heritage 25 0.2 22 0.3 47 0.2 6 0.2 17 0.2 23 0.2 White –Caucasian/European Heritage 12,260 98.9 8,040 99.1 20,300 99.0 2,409 98.9 9,150 99.2 11,559 99.1 Other 84 0.7 41 0.5 125 0.6 19 0.8 51 0.6 70 0.6 AS04-HPV-16/18: AS04-adjuvanted HPV-16/18 vaccine; HBV: hepatitis-B virus vaccine; N: number of subjects; n: number of subjects in a given category; NA: not applicable; SD: Standard deviation. 4D. BI ET AL.
-16/18 vaccine group vs. 11.9 per 100,000 person-years in the HBV vaccine group) (Table 2). No fatal SAEs considered possibly related to vaccination were reported. Incidence rates by gender are presented in supplementary Tables 1 and 2. New-onset auto-immune diseases in all study participants The overall incidence rates of NOADs were similar in both vaccine groups: 233.1 per 100,000 person-years in the AS04HPV-16/18 vaccine group and 238.5 per 100,000 person-years in the HBV vaccine group. During the entire study period, in all study participants, the most common NOADs (with incidence rates ≥15 per 100,000 person-years in any group) were ulcerative colitis (incidence rates of 28.2 and 33.1 per 100,000 person-years in the AS04-HPV-16/18 vaccine and HBV vaccine groups, respectively), IDDM (incidence rates of 21.9 and 37.1 per 100,000 person-years, respectively), Crohn’s disease (incidence rates of 15.6 and 22.5 per 100,000 person-years, respectively), celiac disease (incidence rates of 15.6 and 21.2 per 100,000 person-years, respectively), and juvenile idiopathic arthritis (incidence rates of 14.1 and 15.9 per 100,000 personyears, respectively) (Table 2). Incidence rates by gender are presented in supplementary Tables 1 and 2. The 95% CIs of RR estimates for the incidence of NOADs in the AS04-HPV-16/18 vaccine group as compared to the HBV vaccine group are presented in Figure 2. The observed RR (adjusted for gender) for IDDM was 0.72 (95% CI: 0.33–1.52) in the overall population, 0.65 in females (95% CI: 0.24–1.75), and 0.85 in males (95% CI: 0.21–2.58). All 95% CIs of RR estimates included 1. Overall, incidence rates for serious NOADs were also similar between groups; 76.6 (95% CI 56.7–101.3) and 94.1 (95% CI 73.5–118.7) per 100,000 person-years for the AS04-HPV -16/18 and HBV vaccine groups, respectively. The most common serious NOADs in all study participants (≥10 per 100,000 person-years) were ulcerative colitis (incidence rates of 18.8 and 18.6 per 100,000 person-years in the AS04-HPV -16/18 and HBV vaccine groups, respectively), Crohn’s disease (incidence rates of 10.9 and 19.9 per 100,000 personyears, respectively), and IDDM (incidence rates of 20.3 and 33.1 per 100,000 person-years, respectively). For NOADs that were possibly causally related to vaccination according to investigator assessment, no new cases were reported since the previous results disclosed in the interim analysis. 3 The most common NOADs possibly related to vaccination (≥10 per 100,000 person-years) in all study participants were celiac disease (incidence rates of 7.8 and 10.6 per 100,000 person-years in the AS04-HPV-16/18 and HBV vaccine groups, respectively), IDDM (incidence rates of 6.3 and 13.3 per 100,000 person-years, respectively), and juvenile idiopathic arthritis (incidence rates of 10.9 and 9.3 per 100,000 person-years, respectively). Pregnancies in all female study participants During the entire study, a total of 1,344 pregnancies were reported (777 in girls receiving the AS04-HPV-16/18 vaccine and 567 in girls receiving the HBV vaccine) at the time of the final analysis. Most of the pregnancies resulted in elective termination with no major, registered congenital anomaly (58.4% in the AS04-HPV-16/18 vaccine group and 58.6% in the HBV vaccine group) or birth of a live infant with no major, registered congenital anomaly (32.7% and 32.3%, respectively). The other pregnancy outcomes were spontaneous abortion with no major, registered congenital anomaly (8.0% in the AS04-HPV-16/18 vaccine group and 7.9% in the HBV vaccine group), ectopic pregnancy (0.6% and 0.9%, respectively), molar pregnancy (0.3% and 0.2%) and stillbirth with no major, registered congenital anomaly (one case in HBV vaccine group [0.2%]). Discussion This large cluster-randomized post-marketing cohort study provides a significant amount of unique health registrybased safety data of the AS04-HPV-16/18 vaccine comparing with a routinely used HBV vaccine up to 6.5 y of follow-up in young adolescents recruited in a population-based fashion. Population-based health registries using online linkage systems are important sources for quantitative real-world data analysis in safety surveillance of population-based vaccination trials and programs and are of more and more interest to health authorities. As one of the most important health registers in Finland, HILMO gathers electronic medical records from discharge information of all hospitals and care periods in social care institutions and is widely used for scientific research. 9 Several studies that assessed the reports of HILMO in different therapeutic areas concluded to its reliability and the validity of the data collected. 12-14 Given longstanding theoretical concerns of an association between vaccines and autoimmune disorders, the follow-up of NOADs is important to ensure confidence in immunization programs. This is more relevant to HPV vaccines which are mostly used in young women who may be more prone to develop autoimmune diseases due to hormonal and genetic factors. 15 At its launch, the AS04-HPV-16/18 vaccine raised a similar theoretical concern of inducing or exacerbating potential immune-mediated diseases due to the use of a novel adjuvant. The safety of the vaccine has been monitored through the standardized methodology for the collection of AEs of special interest (AESI) in the 13 y post-marketing surveillance. Data collected and analyzed do not support a link between the vaccine and autoimmune disorders 10,16-18 and the benefit–risk balance of the AS04-HPV-16/18 vaccine remains favorable. Long-term prospective registry-based safety follow-up in this cluster-randomized trial showed that the incidence rates of NOADs were generally balanced (all 95% CI of the RR estimates included 1) between subjects who received the AS04-HPV-16/18 vaccine and those who received an HBV vaccine. For many of the potential autoimmune disorders searched in HILMO with pre-defined ICD-10 codes, only few medical record-confirmed NOADs were found in either vaccine group. During the entire follow-up period of the study (from 3.5 to 6.5 y for individual subjects who joined the study at the ages of 12–15 y), the most commonly reported NOADs were inflammatory bowel diseases (IBD) (ulcerative colitis and Crohn’s disease) and IDDM. More HUMAN VACCINES & IMMUNOTHERAPEUTICS 5
Table 2. Incidence (per 100,000 person-years) and relative risk of major new onset autoimmune diseases (NOADs) and SAE possibly causally related to vaccination in all study participants (Total Vaccinated Cohort). AS04-HPV-16/18 T(y) = 63932.7 HBV T(years) = 75460.8 Relative Risk adjusted for gender (AS04-HPV-16/18/HBV) 95% CI 95% CI 95% CI Primary System Organ Class Preferred Term Case Identification n n/T (per 10 5 )LL UL n n/T (per 10 5 )LL UL RR LL UL Blood and lymphatic system disorders Immune thrombocytopenic purpura Registry 3 4.7 1.0 13.7 4 5.3 1.4 13.6 0.75 0.10 5.10 SAEs possibly related 1 1.6 0.0 8.7 1 1.3 0.0 7.4 0.65 0.01 51.36 Endocrine disorders Auto-immune thyroiditis Registry 5 7.8 2.5 18.3 1 1.3 0.0 7.4 3.27 0.37 154.58 SAEs possibly related - - - - - - - - - - - Basedow’s disease Registry 8 12.5 5.4 24.7 3 4.0 0.8 11.6 2.12 0.48 13.22 SAEs possibly related - - - - - - - - - - - Thyroiditis Registry 1 1.6 0.0 8.7 0 0.0 0.0 4.9 INF 0.02 INF SAEs possibly related 1 1.6 0.0 8.7 0 0.0 0.0 4.9 INF 0.02 INF Eye disorders Iridocyclitis Registry 1 1.6 0.0 8.7 0 0.0 0.0 4.9 INF 0.02 INF SAEs possibly related - - - - - - - - - - - Iritis Registry 1 1.6 0.0 8.7 5 6.6 2.2 15.5 0.19 0.00 1.93 SAEs possibly related - - - - - - - - - - - Uveitis Registry 7 10.9 4.4 22.6 4 5.3 1.4 13.6 1.35 0.33 6.64 SAEs possibly related - - - - - - - - - - - Gastrointestinal disorders Abdominal pain Registry - - - - - - - - - - - SAEs possibly related 1 1.6 0.0 8.7 0 0.0 0.0 4.9 INF 0.10 INF Celiac disease Registry 10 15.6 7.5 28.8 16 21.2 12.1 34.4 0.53 0.21 1.29 SAEs possibly related - - - - - - - - - - - Ulcerative Colitis Registry 18 28.2 16.7 44.5 25 33.1 21.4 48.9 0.99 0.48 2.02 SAEs possibly related 5 7.8 2.5 18.3 3 4.0 0.8 11.6 1.75 0.30 12.99 Crohn’s disease Registry 10 15.6 7.5 28.8 17 22.5 13.1 36.1 0.75 0.29 1.89 SAEs possibly related 2 3.1 0.4 11.3 5 6.6 2.2 15.5 0.82 0.07 5.92 Proctitis ulcerative Registry 3 4.7 1.0 13.7 2 2.7 0.3 9.6 1.41 0.14 19.63 SAEs possibly related - - - - - - - - - - - Hepatobiliary disorders Cholangitis sclerosing Registry 1 1.6 0.0 8.7 0 0.0 0.0 4.9 INF 0.02 INF SAEs possibly related - - - - - - - - - - - Immune system disorders Sarcoidosis Registry 1 1.6 0.0 8.7 0 0.0 0.0 4.9 INF 0.02 INF SAEs possibly related - - - - - - - - - - - Anaphylactic reaction Registry - - - - - - - - - - - SAEs possibly related 2 3.1 0.4 11.3 0 0.0 0.0 4.9 INF 0.12 INF Infections and infestations Encephalitis Registry 0 0.0 0.0 5.8 1 1.3 0.0 7.4 0.00 0.00 149.07 SAEs possibly related - - - - - - - - - - - Reiter’s syndrome Registry 1 1.6 0.0 8.7 2 2.7 0.3 9.6 0.51 0.01 12.38 SAEs possibly related - - - - - - - - - - - Metabolism and nutrition disorders Type 1 diabetes mellitus (IDDM) Registry 14 21.9 12.0 36.7 28 37.1 24.7 53.6 0.72 0.33 1.52 SAEs possibly related 3 4.7 1.0 13.7 9 11.9 5.5 22.6 0.43 0.07 1.97 (Continued) 6D. BI ET AL.
Table 2. (Continued). AS04-HPV-16/18 T(y) = 63932.7 HBV T(years) = 75460.8 Relative Risk adjusted for gender (AS04-HPV-16/18/HBV) 95% CI 95% CI 95% CI Primary System Organ Class Preferred Term Case Identification n n/T (per 10 5 )LL UL n n/T (per 10 5 )LL UL RR LL UL Musculoskeletal and connective tissue disorders Ankylosing spondylitis Registry 2 3.1 0.4 11.3 2 2.7 0.3 9.6 0.98 0.06 16.17 SAEs possibly related - - - - - - - - - - - Arthritis Registry - - - - - - - - - - - SAEs possibly related 0 0.0 0.0 5.8 1 1.3 0.0 7.4 0.00 0.00 25.52 Arthritis reactive Registry 3 4.7 1.0 13.7 3 4.0 0.8 11.6 1.58 0.18 14.26 SAEs possibly related 0 0.0 0.0 5.8 1 1.3 0.0 7.4 0.00 0.00 148.83 Juvenile idiopathic arthritis Registry 9 14.1 6.4 26.7 12 15.9 8.2 27.8 0.75 0.26 2.08 SAEs possibly related 3 4.7 1.0 13.7 0 0.0 0.0 4.9 INF 0.54 INF Psoriatic arthropathy Registry 1 1.6 0.0 8.7 1 1.3 0.0 7.4 0.65 0.01 51.31 SAEs possibly related - - - - - - - - - - - Rheumatoid arthritis Registry 2 3.1 0.4 11.3 4 5.3 1.4 13.6 0.33 0.03 2.28 SAEs possibly related 1 1.6 0.0 8.7 0 0.0 0.0 4.9 INF 0.02 INF Scleroderma Registry 1 1.6 0.0 8.7 0 0.0 0.0 4.9 INF 0.02 INF SAEs possibly related - - - - - - - - - - - Sjogren’s syndrome Registry 0 0.0 0.0 5.8 2 2.7 0.3 9.6 0.00 0.00 3.48 SAEs possibly related 0 0.0 0.0 5.8 1 1.3 0.0 7.4 0.00 0.00 25.52 Spondylitis Registry 0 0.0 0.0 5.8 1 1.3 0.0 7.4 0.00 0.00 149.07 SAEs possibly related - - - - - - - - - - - Spondyloarthropathy Registry 1 1.6 0.0 8.7 2 2.7 0.3 9.6 0.51 0.01 12.38 SAEs possibly related - - - - - - - - - - - Systemic lupus erythematosus Registry 1 1.6 0.0 8.7 1 1.3 0.0 7.4 0.65 0.01 51.31 SAEs possibly related - - - - - - - - - - - Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenoma benign Registry - - - - - - - - - - - SAEs possibly related 0 0.0 0.0 5.8 1 1.3 0.0 7.4 0.00 0.00 25.52 (Continued) HUMAN VACCINES & IMMUNOTHERAPEUTICS 7
Table 2. (Continued). AS04-HPV-16/18 T(y) = 63932.7 HBV T(years) = 75460.8 Relative Risk adjusted for gender (AS04-HPV-16/18/HBV) 95% CI 95% CI 95% CI Primary System Organ Class Preferred Term Case Identification n n/T (per 10 5 )LL UL n n/T (per 10 5 )LL UL RR LL UL Nervous system disorder Facial paralysis Registry 3 4.7 1.0 13.7 10 13.3 6.4 24.4 0.36 0.06 1.56 SAEs possibly related - - - - - - - - - - - Guillain-barre syndrome Registry 0 0.0 0.0 5.8 1 1.3 0.0 7.4 0.00 0.00 149.07 SAEs possibly related - - - - - - - - - - - Mononeuritis Registry 1 1.6 0.0 8.7 0 0.0 0.0 4.9 INF 0.02 INF SAEs possibly related - - - - - - - - - - - Multiple sclerosis Registry 3 4.7 1.0 13.7 1 1.3 0.0 7.4 3.47 0.23 227.04 SAEs possibly related - - - - - - - - - - - Multiple sclerosis relapse Registry 1 1.6 0.0 8.7 0 0.0 0.0 4.9 INF 0.02 INF SAEs possibly related - - - - - - - - - - - Narcolepsy Registry 3 4.7 1.0 13.7 2 2.7 0.3 9.6 2.11 0.20 30.93 SAEs possibly related 1 1.6 0.0 8.7 0 0.0 0.0 4.9 INF 0.02 INF Optic neuritis Registry 2 3.1 0.4 11.3 2 2.7 0.3 9.6 0.98 0.06 16.17 SAEs possibly related 1 1.6 0.0 8.7 0 0.0 0.0 4.9 INF 0.02 INF Radiculopathy Registry 1 1.6 0.0 8.7 1 1.3 0.0 7.4 1.58 0.01 175.12 SAEs possibly related - - - - - - - - - - - Cataplexy Registry - - - - - - - - - - - SAEs possibly related 1 1.6 0.0 8.7 0 0.0 0.0 4.9 INF 0.02 INF Epilepsy Registry - - - - - - - - - - - SAEs possibly related 1 1.6 0.0 8.7 2 2.7 0.3 9.6 0.33 0.01 6.28 Headache Registry - - - - - - - - - - - SAEs possibly related 0 0.0 0.0 5.8 1 1.3 0.0 7.4 0.00 0.00 148.83 Syncope Registry - - - - - - - - - - - SAEs possibly related 0 0.0 0.0 5.8 1 1.3 0.0 7.4 0.00 0.00 25.52 Psychiatric disorders Sleep attacks Registry - - - - - - - - - - - SAEs possibly related 1 1.6 0.0 8.7 0 0.0 0.0 4.9 INF 0.02 INF Renal and urinary disorders Iga nephropathy Registry 0 0.0 0.0 5.8 1 1.3 0.0 7.4 0.00 0.00 149.07 SAEs possibly related - - - - - - - - - - - Tubulointerstitial nephritis and uveitis syndrome Registry 1 1.6 0.0 8.7 0 0.0 0.0 4.9 INF 0.02 INF SAEs possibly related 1 1.6 0.0 8.7 0 0.0 0.0 4.9 INF 0.02 INF Respiratory, thoracic and mediastinal disorders Hyperventilation Registry - - - - - - - - - - - SAEs possibly related 0 0.0 0.0 5.8 1 1.3 0.0 7.4 0.00 0.00 25.52 (Continued) 8D. BI ET AL.