1. National Centre for Immunisation Research and Surveillance, Sydney, Australia

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1 Electronic Supplementary Material (ESM) 1 Safety of human papillomavirus vaccines: An updated review Anastasia Phillips, 1,2 Cyra Patel, 1 Alexis Pillsbury, 1 Julia Brotherton, 3,4 Kristine Macartney 1,2 1. National Centre for Immunisation Research and Surveillance, Sydney, Australia 2. The University of Sydney, Australia 3. National HPV Vaccination Program Register, Victorian Cytology Service, Australia 4. The University of Melbourne, Australia Corresponding author: A/Prof Kristine Macartney National Centre for Immunisation Research and Surveillance Kids Research Institute The Sydney Children's Hospitals Network Cnr Hawkesbury Road and Hainsworth Street Westmead, NSW 2145 Australia Kristine.Macartney@health.nsw.gov.au Tel

2 ESM 1A and 1B: Summary of select data on adverse events reported in HPV vaccine clinical trials in generally healthy subjects (i.e. those without known immunocompromising or auto-immune medical conditions) published from 10 May August A: Studies comparing HPV vaccine with a placebo or control (non-hpv vaccine) group Reference Region Selected Adverse Events (AEs) a Studies with 2vHPV vaccine Angelo et 40 al 2014[1], 42 trials Skinner et al 2014 [2] Hildesheim et al 2014 [3] Sow et al 2013 [4] Zhu et al 2014a [5] (pooled) Multi: 12 Costa Rica Senegal & Tanzania China No. of vaccine & control (type) vHPV control (various) vHPV 2871 placebo vHPV 3739 control (Hepatitis A vaccine) 450 2vHPV 226 placebo 750 G 9-17 yrs; 1212 W yrs 980 2vHPV 982 placebo (G: AlOH; W: Unsolicited AE SAEs: full study, 30-day FU PIMD Solicited general symptoms Unsolicited symptoms Solicited local AE Solicited general AE Unsolicited AE Neurological condition Local AE General AE Unsolicited AE Grade 3 local symptoms Unsolicited symptoms NOAD Frequency of AEs in vaccine 30.8% [ ] 9.6% [ ] 7.9%, 0.5% 0.2% 85% 65% 40% 41% 10% (<1%, n=5) 5%, <1% 53.7% 90.5% 43.9% 24.5% (1.4%, n=53) 0.2% 10.3%, 0.6% 16.8% 59.7% [ ] 35.1% 25.3% [ ] 69.3 [ ] 3.8 [ ] (0) 2.4 [ ], 0.4% [ ] 0% [ ] G: 5.2%; W: 3.0% G: 37.2% [ ]; W: 5.3% [ ] G: 3.7% [ ]; W: 0.8% [ ] G:1.3%[ ](0); W: 0.5%[ ](0) G: 0% [ ]; W: not reported Frequency of AEs in control 29.7% [ ] 10.4% [ ] 9.3%, 0.6% 0.2% 67% 58% 41% 40% 9% (<1%, n=8) 6%, <1% 19.9% 89.1% 41.1% 23.8% (1.0%, n=39) 0.2% 11.2%, 0.6% 15.8% 43.1% [ ] 35.1% 30.2% [ ] 75.2 [ ] 6.2 [ ] (0) 4.9 [ ], 0.9% [ ] 0% [ ] G: 2.0%; W: 0.3% G: 33.2%[ ]; W: 5.9%[ ] G: 2.9% [ ]; W: 1.2% [ ] G: 0.5%[ ](0); W:0.5%[ ](0) G: 0.5% [ ]; W: not reported 2

3 Reference Zhu et al 2014b [6] Lim et al 2014 [7] Szarewski et al 2012 [8] Naud et al 2014 [11] Roteli- Martins 2012 [12] Konno et al 2014 [13] Region China Malaysia 14 Brazil Brazil Japan No. of vaccine & control (type) hepatitis B vaccine) vHPV 3025 placebo 135 2vHPV 136 placebo vHPV 9325 control (hepatitis A vaccine) 219 2vHPV 213 placebo 223 2vHPV 213 placebo 358 2vHPV 348 control (hepatitis A vaccine) Selected Adverse Events (AEs) a Frequency of AEs in vaccine Frequency of AEs in control PIMD G: Not reported; W: 0 G: Not reported; W: 0 IS pain, redness, swelling Unsolicited symptoms IS pain, redness, swelling Unsolicited AE HPV-DNA negative(sn/sp) overall IS pain, redness, swelling Systemic AE Fever HPV-DNA positive (SN/SP) IS pain, redness, swelling Systemic AE Fever SAE 62.6%, 14.5%, 14.4% 26.2% 1% (n=1) 5.2% 0.3%, 0.1% 76.4%, 22.1%, 17.3% 22.2% 7.4% n=5 (0) SN (Seronegative) /SP (seropositive) 82.0% [ ] / 78.0% [ ] 80.8%,29.2%,26.2%/76.8%,25.4%,23.5% 66.7% [ ] / 62.2% [ ] 4.9% [ ] / 6.4% [ ] SN (Seronegative) /SP (seropositive) 86.9% [ ] / 79.8% [ ] 86.6%,24.1%,19.2%/78.7%,25.6%,23.5% 69.3 [ ] / 63.7 [ ] 5.9 [ ] / 6.4 [ ] 8.9% [ ] 26.5% [ ] 2.7% [ ], 1.8% [ ] 4.5% [ ] (0) 17.9% [ ] 2.2% [ ], n=2 5.0% [ ] (n=1) 18.9% [ ] 1.2% [ ], 0.6% [ ] 0.2% [ ] 42.5%, 7.6%, 5.8% 25.6% 1.8% (n=1) 5.2% 0.4%, 0.1% 49.4%, 14.1%, 6.9% 26.5% 8.1% n=3 (0) NR (reported elsewhere)[9, 10] 5.2% [ ] 17.8% [ ] 1.4% [ ], 0.5% [ ] 3.3% [ ] (0) 11.3% [ ] 0.9% [ ], n=2 6.5% [ ] (n=0) 22.1% [ ] 1.5% [ ], 0.2% [ %] 0.0% [ ] 3

4 Reference Region Studies with 4vHPV Mugo et al Ghana, 2015 [14] Kenya & Senegal Li et al 2012 [15] Clark et al 2013 [16] China Europe, Americas Studies with 9vHPV Garland et 8 al 2015 [17] No. of vaccine & control (type) 227 4vHPV 19 placebo (Aluminium adjuvant); 9-12yrs 302 4vHPV 298 placebo (Aluminium adjuvant) 307 4vHPV 393 placebo (Aluminium adjuvant) 618 9vHPV 306 Placebo(saline) All received prior 4vHPV Selected Adverse Events (AEs) a : 9-12y, 13-16y, 16-26y Systemic AE:9-12y, 13-16y, 16-26y (vaccine related) SAE: 15-day follow-up Any AE, pain, IS swelling Systemic AE(vaccine-related) SAE Allergic reaction Frequency of AEs in vaccine 68.4%, 72.4%, 73.9% 48.1% (36.7%), 58.6% (51.7%), 61.3% (35.3%) 0% 50.7% 21.9%, 20.2%*, 3.0%* 42.7% (28.8%) 0% 2.6%* 49.0% 35.8% (23.8%) 1.7% 91.1% / 43.9% 59.7% (30.6%) 0.5% (n=1) Frequency of AEs in control 47.4% 57.9% (47.4%) 0% 44.0% 13.4%, 13.1%*, 0.7%* 39.9% (27.5%) 0.3% 0.7%* 41.0% 29.1% (18.2%) 1.6% 43.9% 55.7% (25.9%) 0.3% (n=1) 4

5 1B: Studies where all participants received HPV vaccine Reference Region No. of vaccine type (group) Selected Adverse Events (AEs) a Studies with 9vHPV vaccine used in all subjects (no placebo arms) Castellsague et al 2015 [18] vHPV 1101 women (A) 1419 men (B) Van Damme et al 2015 [19] Kosalaraksa et al 2015 [20] Schilling et al 2015 [21] Moreira et al 2016 [22] , Post-hoc pooled analysis (7 trials) vHPV 1800 girls 9-15y (A1) 600 boys 9-15y (A2) 400 women 16-26y (B) vHPV 525 concomitant(a) & 528 nonconcomitant Tdap- IPV (B) vHPV 621 concomitant(a) & 620 nonconcomitant MCV4 & Tdap (B) 15,776 all 9vHPV (A) 12,583 female 9vHPV (B1) 3,193 male 9vHPV (B2) Severe pain, Severe IS pain Fatigue Headache Fever PD-1, 2, 3 PD-1 IS pain, erythema, swelling PD-any IS pain erythema, swelling Systemic AE PD-1, 2, 3 PD-1, 2, 3 PD-1 pain, erythema, swelling Systemic AE PD-1, 2, 3 IS pain, swelling, erythema Fever Syncope NOCD (n=15,875) Frequency of AEs in Group A 84.1% 1.9% 48.8% (23.4%) 2.4% (0) A1: 81.9%, 4.1% A2: 72.8%, 0.5% A1:45.0%(20.8%)A2:41.8%(21.8%) A1: 1.0% A2: 0.5% A1: 9.5% A2: 9.1% A1: 6.7% A2: 8.6% A1: 0.9% (n=0) A2: 1.7% (n=1) A1: 0.1% A2: 0% 93.9%, 60.7%, 68.3% 59.2%, 8.2%, 13.0% # 84.8%, 30.5%, 40.6% 48.6%, 19.2%, 21.5% 1.7% (0) 80.9%, 46.7%, 52.1% 58.3%, 10.0%, 14.4% # 43.1%, 16.1%, 14.8% 0.8% (0) 84.8% 83.2%, 36.1%, 30.8% 51.9% (26.7%) 6.1% (n=955) 0.2% (n=36) 2.3% (n=7) 2.4% <0.1% (n=7) Frequency of AEs in Group B recipients % or number [95% confidence interval shown where 67.2% 0.6% 37.1% (16.0%) 1.6% (0) 85.4%, 2.6% 57.1% (26.0%) 2.6% 9.9% 6.9% 3.2% (n=1) 0.2% 90.1%, 60.2%, 66.1% 60.5%, 5.7%, 8.2% # 83.7%, 24.1%, 31.1% 48.6%, 18.0%, 19.8% 1.3% (0) 80.4%, 46.5%, 48.4% 55.0%, 8.9%, 9.4% # 42.4%, 15.0%, 16.2% 0.8% (0) B1: 88.1%; B2: 71.6% B1: 86.9%, 39.1%, 32.9% B2: 68.3%, 24.4%, 22.4% B1:53.8%(27.8%); B2:44.2%(22.5%) B1:5.8%(n=734); B2:6.9%(n=221) B1: 0.3% (n=34); B2: <0.1% (n=2) B1: 2.5% (n=6); B2: 1.4% (n=1) NR B1: 0.1 (n=7); B2: 0 5

6 Reference Region No. of vaccine type (group) Studies comparing 9vHPV and 4vHPV Joura et al [23] Vesikari et al 2015 [24] (Sanofi Pasteur/ Merck) vHPV (A) vHPV (B) 299 9vHPV (A) 300 4vHPV (B) Studies comparing 2vHPV and 4vHPV Einstein et al USA 2014a [25] Einstein et al 2014b [26] Gilca et al 2015 [27] (Investigator) Leung et al 2015 [28] USA Quebec, Canada vHPV(A) 216 4vHPV (B) 159 2vHPV (A) 156 4vHPV (B) 366 randomised 1:1 2vHPV (A) or 4vHPV (B). All 2 prior doses 4vHPV 359 2vHPV 2 dose (A) 358 4vHPV 2 dose (B1) 358 4vHPV 3 dose (B2) Selected Adverse Events (AEs) a Severe IS Pain IS swelling, Fever Spontaneous abortion Spontaneous abortion (no anomaly) IS Pain (grade 3), swelling, redness Systemic AE SAE IS pain, redness, swelling IS pain grade 3 Solicited Systemic AE, Fever Unsolicited AE (grade 3) PIMD Frequency of AEs in Group A 90.7% 4.3% 55.8% (29.5%) 3.3% (n=2, <1%) 0.1% 91.6% 47.8% # 47.5% (20.7%), 5.0% 0.3% (0) 6.7% ( ) (n=1) 6.0% [ ], 1.3% [ ] 45.4% [ ] 13% 8.0% [ ] (n=1) 7.1% [ ], 1.3% [ ] 46.8% [ ] 15.6% 89.1%* (9%*), 26.2%*, 28.4% 58% 0 93% 91.6%, 53.2%, 45.4% 11.7% [ ] 74%, 14.8% 25% (5%) 3.6% (0) 14% 0.8% (n=3) Frequency of AEs in Group B recipients % or number [95% confidence interval shown where 84.9% 2.6% 54.9% (27.3%) 2.6% (n=2, <1%) 0.1% 88.3% 36.0% # 52.0% (24.3%), 2.7% 0.7% (0) 6.1% [ ] (n=1) 6.0% [ ], 2.2% [ ] 39.1% [ ] 15% 6.7% [ ] (n=1) 7.8% [ ], 2.4% [ ] 40.9% [ ] 14.5% 72.1%* (2%*), 17.5%*, 21.9% 59% 0 B1: 81%; B2: 86% B1: 77.3%, 37.5%, 27.5%; B2: 82.9%, 44.1%, 33.1% B1:4.8%[ ];B2: 5%[ ] B1: 75%, 16.5%; B2:74%, 13.2% B1: 27% (2%); B2: 28% (6%) B1: 0.6% (0); B2: 0.3% (0) B1: 16%; B2: 13% B1: 0.8% (n=3); B2: 0 6

7 Reference Nelson et al 2013 [29] (Investigator) Sangar et al 2015 [30] (Investigator) Region Hong Kong India No. of vaccine type (group) Pilot: 10 males, 5 2vHPV (A), 5 4vHPV (B) Main study: 40 females, 19 2vHPV (A), 21 4vHPV (B) 31 2vHPV (A) 31 4vHPV (B) Selected Adverse Events (AEs) a Pilot (intradermal administration): Main study (various doses/ methods): ISPain,Redness,Swelling,Tenderness Headache Tiredness Muscle ache Dizziness Any AE post-dose 1, 2, 3, any IS pain Solicited symptom SAE Frequency of AEs in Group A n=5 n=18*, 12, 11, 17* n=4 n=4 n=3 n=2 51.6%*, 17.9%, 38.1%, 36.25%* 80.6% 28 of 80* 0 Frequency of AEs in Group B recipients % or number [95% confidence interval shown where n=5 n=11*, 11, 8, 10* n=2 n=10 n=5 n=3 19.4%*, 7.1%, 13.0%, 13.4%* 29.0% 11 of 82* 0 Studies with 2vHPV or 4vHPV and no control group Luna et al 2013 Columbia vHPV New onset medical condition 13% No control group [31] Watson-Jones et al 2012 [32] (Investigator) Tanzania vHPV AE SAE N=11 N=3 Giuliano et al 2015 [33] US, Mexico 145 males 4vHPV Total AEs (vaccine-related) Vaccine-related Vaccine-related systemic Vaccine-related grade 3 AE N=144 (107 in 63 men (42%)) N=50 N= 57 N=1 Walter et al 2015 USA 72 4vHPV (concomitantly IS Pain Higher pain score in HPV vaccine [34] (Investigator) with other vaccines) site Levi et al 2013 Italy 271 2vHPV IS pain, IS swelling 83.4%, 20.8% [35] (Investigator) Medical attention post-dose 1 0.9% Footnotes for ESM 1A and 1B: Abbreviations: AE adverse event; AlOH aluminum hydroxide; d day; G girls; GSK GlaxoSmithKline; IS injection site; injection site reaction; IPV inactivated polio vaccine; MCV4 quadrivalent meningococcal conjugate vaccine; : medically significant conditions; NOAD new onset autoimmune disease; NOCD new onset chronic disease; PD post-dose; PIMD potential immune-mediated disease; SAE serious adverse event; Tdap tetanus, diphtheria, acellular pertussis vaccine; VLP virus like particles; yo year olds; SN seronegative; SP seropositive; NR not reported; yrs years; FU follow-up; PD post dose; W women. *Significant at p<0.05 a The terms used regarding adverse events reflect those presented and defined within each individual study, thus are not necessarily consistent across this summary of data. In general, a solicited AE includes those for which information was specifically sought from the study participants. Unsolicited AEs were those that were spontaneously reported by the subject. Solicited local AEs typically included injection-site pain, erythema, swelling and/or redness. AE given as vaccine-related are those determined by the study investigators. s were conditions prompting emergency room or physician visits that were not related to common diseases or routine visits for physical examination or vaccination, or SAEs not related to common disease (which included upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervicovaginal yeast infections, menstrual cycle abnormalities and injury). SAEs were typically predefined as any AE that resulted in death, were deemed by the investigator to be lifethreatening, resulted in a persistent or significant disability or incapacity, resulted in or prolonged an existing in-patient hospitalisation or was a congenital anomaly, a cancer or an other important medical event. SAEs were typically followed for the entire duration of patient follow-up, unless otherwise specified in the table. 7

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