biologicals’ hpv tm (hpv): gsk biologicals’...study number: 115887 (hpv -073) title: safety and...

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GSK Medicine: CervarixTM (GSK-580299), Priorix® (GSK-209762), Infanrix® (GSK-208355)

Study Number: 115887 (HPV-073)

Title: Safety and immunogenicity of GlaxoSmithKline (GSK) Biologicals’ HPV-16/18 L1 VLP AS04 vaccine (GSK-580299) in healthy female children 4-6 years old. CervarixTM (GSK-580299) (HPV): GSK Biologicals’ HPV-16/18 L1 Virus-like particle (VLP) vaccine, adjuvanted with AS04.

Rationale: The aim of this study was to evaluate the safety and immunogenicity of GSK Biologicals’ HPV vaccine administered according to a 2-dose schedule at 0, 6 months in healthy female children aged 4-6 years. Priorix® (GSK-209762) (MMR vaccine): GSK Biologicals’ combined measles-mumps rubella vaccine Infanrix® (GSK-208355) (DTPa vaccine): GSK Biologicals’ combined diphtheria-tetanus acellular pertussis vaccine

Phase: III

Study Period: From:

15-October-2012 to

30-July- 2014 (Month 7), to

28-November-2014 (Month 12)

Study Design: Randomized, single-blind*, multi-centre study with 2 parallel groups *Note: The study was single-blind until the Month 12 visit for the HPV-2D and MMR-DTPa groups, then the study was open for HPV_2D group (MMR_DTPa group concluded study at Month 12 visit).

Centres: 2 centres in Colombia, 1 in Mexico and 4 in Panama

Indication: Prevention of persistent infection, premalignant genital (cervical vulvar and vaginal) lesions and cervical, vulvar and vaginal cancer (squamous-cell carcinoma and adenocarcinoma) caused by oncogenic HPV types in girls from 9 years of age onwards.

Treatment: The study groups were as follows:

Group HPV-2D: subjects of 4-6 years old, who received two doses of HPV vaccine at Day 0 and Month 6.

Group MMR-DTPa: subjects of 4-6 years old, who received one dose of MMR vaccine at Day 0 and one dose of DTPa vaccine at Month 6.

Objectives: Safety:

To assess the safety, tolerability and occurrence of clinically relevant abnormalities in biochemistry and haematology parameters after administration of the HPV-16/18 L1 VLP AS04 vaccine according to a 2-dose schedule at 0, 6 months in 4-6 year old females, up to one month after the last dose (Month 7).

Immunogenicity:

To evaluate the immunogenicity (as determined by ELISA) of the HPV-16/18 L1 VLP AS04 vaccine administered according to a 2-dose schedule at 0, 6 months in 4-6 year old females , one month after the last dose (Month 7).

Primary Outcome/Efficacy Variable: Safety:

The occurrence and intensity of solicited local adverse events (AEs) during the 7-day period (Days 0-6) following each vaccination in the HPV-2D and MMR-DTPa groups.

The occurrence, intensity and relationship to vaccination of solicited general AEs during the 7-day period (Days 0-6) following each vaccination in the HPV-2D and MMR-DTPa groups.

The occurrence, intensity and relationship to vaccination of unsolicited AEs during the 43-day period (Days 0-42) following Day 0 vaccination (Dose 1, i.e. HPV vaccine 1st dose or MMR vaccine) in the HPV-2D and MMR-DTPa groups.

The occurrence, intensity and relationship to vaccination of unsolicited AEs during the 30-day period (Days 0-29) following Month 6 vaccination (Dose 2, i.e. HPV vaccine 2nd dose or DTPa vaccine) in the HPV-2D and MMR-DTPa groups.

The occurrence of clinically relevant abnormalities in biochemical and haematological parameters 43 days post Day 0 vaccination and 30 days post Month 6 vaccination in the HPV-2D and MMR-DTPa groups.

The occurrence of serious adverse events (SAEs) in the HPV-2D and MMR-DTPa groups up to Month 7.

The occurrence of AEs and SAEs leading to withdrawal in the HPV-2D and MMR-DTPa groups up to Month 7.

The occurrence of potential Immune mediated Diseases (pIMDs) and other Medically Significant Conditions

(MSCs), regardless of causal relationship to vaccination and intensity, in the HPV-2D and MMR-DTPa groups up to Month 7.

Immunogenicity:

Anti-HPV-16/18 seroconversion rates (SCRs) and antibody titres as determined by ELISA one month after the last dose (at Month 7)

Secondary Outcome/Efficacy Variable(s): Immunogenicity:

Anti-HPV-16/18 SCRs and antibody titres as determined by ELISA on Day 0 and at Months 7 and 12 in the MMR-DTPa group as well as on Day 0 and at Months 7 and 12 in the MMR_DTPa Group and on Day 0 and at Months 7, 12, 18*, 24* and 36* in the HPV-2D Group.

Anti-measles, mumps and rubella seropositivity rates and antibody titres on Days 0 and 42*

Seroprotection rates to D and T antigens at Month 7* Safety:

The occurrence of pIMDs up to Month 12

The occurrence of MSCs up to Month 12

The occurrence of SAEs up to Month 12

The occurrence of SAEs related to the investigational products or any fatal SAE throughout the study period in all groups (from Day 0 to Month 12 in the MMR-DTPa group and from Day 0 to Month 36* in the HPV-2D).

The occurrence of AEs/SAEs leading to withdrawal throughout the study period in all groups (from Day 0 to Month 12 in the MMR-DTPa group and from Day 0 to Month 36* in the HPV-2D).

Concomitant medication administered during the 43-day period (Days 0-42) following vaccination on Day 0.

Concomitant medication administered during the 30-day period (Days 0-29) following vaccination at Month 6.

The percentage of subjects completing the vaccination schedule.

The occurrence, intensity and relationship to vaccination solicited fever, measles/rubella-like rash, parotid gland swelling and signs of meningism including febrile convulsion during the 43-day period (Days 0-42) following vaccination on Day 0.

*At the time of writing this CTRS, only results pertaining to the HPV immune response (Anti HPV-16/18) and safety results up to Month 12 were available. The data pertaining to other outcomes will be added when available

Statistical Methods: The analyses were performed on the Total Vaccinated cohort and the According-to-Protocol (ATP) cohort for immunogenicity. - The Total Vaccinated cohort included all vaccinated subjects (i.e. subjects who received at least one dose of vaccine in this study) for whom data were available. - The ATP cohort for immunogenicity included all eligible subjects (i.e. meeting all eligibility criteria, complying with the procedures defined in the protocol) for whom data concerning immunogenicity outcome measures were available. This cohort included subjects for whom assay results were available for antibodies against at least one study vaccine antigen component after vaccination.

Analysis of immunogenicity The primary analysis was performed on the ATP cohort for immunogenicity. For each time point, the SCR and the geometric mean antibody concentrations (GMCs) were tabulated with their 95% CIs by pre-vaccination status and at pre dose 1, for the HPV-2D and MMR-DTPa groups. Analysis of Safety The analysis was performed on the Total Vaccinated cohort. For each solicited symptom, the percentage of subjects during 7 days following each vaccination was summarized with its exact 95% CI by each dose and across doses. The same tabulation was performed for grade 3 symptoms and for general symptoms assessed by the investigators as causally related to vaccination. The percentages of subjects reporting unsolicited AEs during 30 days period following Month 6 vaccination and during 43 days period following Day 0 vaccination were summarized according to the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms. The same tabulation was performed for grade 3 unsolicited AEs and for unsolicited AEs assessed by the investigators as causally related to vaccination. The percentages of subjects with at least one report of a MSCs and pIMDs classified by MedDRA preferred terms and reported up to Month 7 and 12 were summarized. The percentage of subjects who started to receive at least one concomitant medication during the 43-day (Days 0-42) post-Dose 1 or within the 30-day (Days 0-29) post-Dose 2 with 95%

CI were calculated. The percentage of subjects completing the vaccination schedule was also summarized. The percentage of subjects outside the normal laboratory ranges 43 days post Day 0 vaccination and 30 days post Month 6 vaccination were also tabulated. The percentage of subjects (with exact 95% CIs) reporting fever ≥ 37.5°C and > 39.0°C (as measured axillary) during the 43-day (Days 0-42) post-Dose 1 was calculated. Similar tabulation was performed for any fever with a causal relationship to vaccination The percentage of subjects (with exact 95% CIs) reporting measles/rubella-like rash within 43-day (Days 0-42), solicited parotid gland swelling within 43-day (Days 0-42) and solicited signs of meningism within 43-day (Days 0-42) post-Dose 1 were tabulated. Similar tabulations were performed for grade 3 solicited AEs when collected and for solicited AEs assessed by the investigators as related to vaccination. The occurrence of SAEs and that of SAEs related to vaccination up to Month 7 and 12, classified by MedDRA preferred terms were summarized. The percentages of subjects completing the vaccination schedule and those with AEs or SAEs leading to withdrawal up to Month 7 were also tabulated.

Study Population: Healthy female subjects aged between, and including, 4 and 6 years at the time of the first vaccination. No previous vaccination with a HPV vaccine other than the study vaccine was allowed. Written informed consent from the subjects’ parents or legally acceptable representatives (LARs) and assent from each subject was obtained, before enrolling in the trial.

Number of Subjects: HPV-2D Group MMR-DTPa Group

Planned, N 75 75

Randomized, N (Total Vaccinated cohort) 74 74

Completed up to Month 12, n (%) 74 (100) 71 (96.0)

Total Number Subjects Withdrawn, n (%) 0 (0.0) 3 (4.0)

Withdrawn due to Adverse Events, n (%) 0 (0.0) 0 (0.0)

Withdrawn due to Lack of Efficacy, n (%) Not Applicable Not Applicable

Withdrawn for other reasons, n (%) 0 (0.0) 3 (4.0)

Demographics HPV-2D Group MMR-DTPa Group

N (Total Vaccinated cohort) 74 74

Sex, n (%) Females

74 (100) 74 (100)

Mean Age, years (SD) 4.3 (0.5) 4.4 (0.5)

Median Age, years 4.0 4.0

Minimum, Maximum 4, 6 4, 6

Mixed Origin*, n (%) 68 (91.9) 68 (91.9)

*Mixed Origin includes mixed race, Mestizo, Hispanic/Mexican and Indigenous

Primary Efficacy Results: Number (%) of subjects reporting solicited local symptoms during the 7-day (Days 0-6) post-vaccination period following each dose and across doses (Total Vaccinated cohort)

HPV-2D Group MMR-DTPa Group

95 % CI 95 % CI

Symptom Intensity N n % LL UL N n % LL UL Dose 1

Pain Any 74 45 60.8 48.8 72.0 74 15 20.3 11.8 31.2

Grade 3 74 2 2.7 0.3 9.4 74 0 0.0 0.0 4.9

Redness Any 74 10 13.5 6.7 23.5 74 7 9.5 3.9 18.5

>20.0 mm 74 1 1.4 0.0 7.3 74 0 0.0 0.0 4.9

Swelling Any 74 6 8.1 3.0 16.8 74 6 8.1 3.0 16.8

>20.0 mm 74 1 1.4 0.0 7.3 74 0 0.0 0.0 4.9

Dose 2

Pain Any 72 43 59.7 47.5 71.1 71 36 50.7 38.6 62.8

Grade 3 72 2 2.8 0.3 9.7 71 1 1.4 0.0 7.6

Redness Any 72 12 16.7 8.9 27.3 71 12 16.9 9.0 27.7

>20.0 mm 72 0 0.0 0.0 5.0 71 4 5.6 1.6 13.8

Any 72 16 22.2 13.3 33.6 71 15 21.1 12.3 32.4

>20.0 mm 72 3 4.2 0.9 11.7 71 7 9.9 4.1 19.3

Across Doses Pain Any 74 54 73.0 61.4 82.6 74 40 54.1 42.1 65.7

Grade 3 74 4 5.4 1.5 13.3 74 1 1.4 0.0 7.3

Redness Any 74 18 24.3 15.1 35.7 74 18 24.3 15.1 35.7

>20.0 mm 74 1 1.4 0.0 7.3 74 4 5.4 1.5 13.3

Swelling Any 74 19 25.7 16.2 37.2 74 18 24.3 15.1 35.7

>20.0 mm 74 4 5.4 1.5 13.3 74 7 9.5 3.9 18.5

N = number of subjects with at least one documented dose n/% = number/percentage of subjects reporting the symptom at least once 95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit Any = occurrence of any solicited local symptom regardless of their intensity grade Grade 3 pain = Cried when limb was moved/spontaneously painful

Primary Efficacy Results: Number (%) of subjects reporting solicited general symptoms during the 7-day (Days 0-6) post-vaccination period following each dose and across doses (Total Vaccinated cohort)


95 % CI 95 % CI

Symptom Intensity/relationship

N n % LL UL N n % LL UL

Dose 1 Arthralgia Any 74 5 6.8 2.2 15.1 74 8 10.8 4.8 20.2

Grade 3 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

Related 74 4 5.4 1.5 13.3 74 8 10.8 4.8 20.2

Drowsiness Any 74 14 18.9 10.7 29.7 74 7 9.5 3.9 18.5

Grade 3 74 3 4.1 0.8 11.4 74 0 0.0 0.0 4.9

Related 74 12 16.2 8.7 26.6 74 7 9.5 3.9 18.5

Fatigue Any 74 8 10.8 4.8 20.2 74 7 9.5 3.9 18.5

Grade 3 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

Related 74 7 9.5 3.9 18.5 74 7 9.5 3.9 18.5

Fever/(Axillary) 37.5°C 74 6 8.1 3.0 16.8 74 8 10.8 4.8 20.2

>39.0°C 74 1 1.4 0.0 7.3 74 0 0.0 0.0 4.9

Related 74 3 4.1 0.8 11.4 74 5 6.8 2.2 15.1

Gastrointestinal* Any 74 7 9.5 3.9 18.5 74 12 16.2 8.7 26.6

Grade 3 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

Related 74 5 6.8 2.2 15.1 74 10 13.5 6.7 23.5 Headache Any 74 11 14.9 7.7 25.0 74 19 25.7 16.2 37.2

Grade 3 74 0 0.0 0.0 4.9 74 1 1.4 0.0 7.3

Related 74 9 12.2 5.7 21.8 74 16 21.6 12.9 32.7

Irritability / fussiness

Any 74 13 17.6 9.7 28.2 74 7 9.5 3.9 18.5

Grade 3 74 1 1.4 0.0 7.3 74 0 0.0 0.0 4.9 Related 74 12 16.2 8.7 26.6 74 7 9.5 3.9 18.5

Loss of appetite Any 74 15 20.3 11.8 31.2 74 7 9.5 3.9 18.5

Grade 3 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

Related 74 13 17.6 9.7 28.2 74 7 9.5 3.9 18.5

Myalgia Any 74 13 17.6 9.7 28.2 74 9 12.2 5.7 21.8

Grade 3 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

Related 74 13 17.6 9.7 28.2 74 9 12.2 5.7 21.8

Rash Any 74 3 4.1 0.8 11.4 74 1 1.4 0.0 7.3

Grade 3 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

Related 74 2 2.7 0.3 9.4 74 1 1.4 0.0 7.3

Urticaria Any 74 5 6.8 2.2 15.1 74 3 4.1 0.8 11.4

Grade 3 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

Related 74 4 5.4 1.5 13.3 74 2 2.7 0.3 9.4

Dose 2

Arthralgia Any 72 10 13.9 6.9 24.1 71 8 11.3 5.0 21.0

Grade 3 72 0 0.0 0.0 5.0 71 0 0.0 0.0 5.1

Related 72 9 12.5 5.9 22.4 71 8 11.3 5.0 21.0

Drowsiness Any 72 9 12.5 5.9 22.4 71 9 12.7 6.0 22.7

Grade 3 72 0 0.0 0.0 5.0 71 0 0.0 0.0 5.1

Related 72 9 12.5 5.9 22.4 71 9 12.7 6.0 22.7

Fatigue Any 72 9 12.5 5.9 22.4 71 7 9.9 4.1 19.3

Grade 3 72 0 0.0 0.0 5.0 71 0 0.0 0.0 5.1

Related 72 8 11.1 4.9 20.7 71 7 9.9 4.1 19.3

Fever/(Axillary) 37.5°C 72 7 9.7 4.0 19.0 71 12 16.9 9.0 27.7

>39.0°C 72 0 0.0 0.0 5.0 71 0 0.0 0.0 5.1

Related 72 6 8.3 3.1 17.3 71 9 12.7 6.0 22.7


Grade 3 72 0 0.0 0.0 5.0 71 0 0.0 0.0 5.1

Related 72 2 2.8 0.3 9.7 71 8 11.3 5.0 21.0

Headache Any 72 12 16.7 8.9 27.3 71 13 18.3 10.1 29.3

Grade 3 72 0 0.0 0.0 5.0 71 0 0.0 0.0 5.1

Related 72 12 16.7 8.9 27.3 71 12 16.9 9.0 27.7


Any 72 18 25.0 15.5 36.6 71 17 23.9 14.6 35.5

Grade 3 72 0 0.0 0.0 5.0 71 0 0.0 0.0 5.1 Related 72 18 25.0 15.5 36.6 71 17 23.9 14.6 35.5


Grade 3 72 1 1.4 0.0 7.5 71 1 1.4 0.0 7.6

Related 72 8 11.1 4.9 20.7 71 8 11.3 5.0 21.0

Myalgia Any 72 13 18.1 10.0 28.9 71 11 15.5 8.0 26.0

Grade 3 72 0 0.0 0.0 5.0 71 0 0.0 0.0 5.1

Related 72 12 16.7 8.9 27.3 71 11 15.5 8.0 26.0

Rash Any 72 3 4.2 0.9 11.7 71 4 5.6 1.6 13.8

Grade 3 72 0 0.0 0.0 5.0 71 0 0.0 0.0 5.1

Related 72 3 4.2 0.9 11.7 71 3 4.2 0.9 11.9

Urticaria Any 72 5 6.9 2.3 15.5 71 4 5.6 1.6 13.8

Grade 3 72 0 0.0 0.0 5.0 71 0 0.0 0.0 5.1

Related 72 4 5.6 1.5 13.6 71 3 4.2 0.9 11.9

Across Doses

Arthralgia Any 74 13 17.6 9.7 28.2 74 11 14.9 7.7 25.0

Grade 3 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

Related 74 12 16.2 8.7 26.6 74 11 14.9 7.7 25.0 Drowsiness Any 74 16 21.6 12.9 32.7 74 15 20.3 11.8 31.2

Grade 3 74 3 4.1 0.8 11.4 74 0 0.0 0.0 4.9

Related 74 15 20.3 11.8 31.2 74 15 20.3 11.8 31.2

Fatigue Any 74 15 20.3 11.8 31.2 74 10 13.5 6.7 23.5

Grade 3 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

Related 74 13 17.6 9.7 28.2 74 10 13.5 6.7 23.5

Fever/(Axillary) 37.5°C 74 12 16.2 8.7 26.6 74 17 23.0 14.0 34.2

>39.0°C 74 1 1.4 0.0 7.3 74 0 0.0 0.0 4.9

Related 74 8 10.8 4.8 20.2 74 13 17.6 9.7 28.2


Grade 3 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

Related 74 7 9.5 3.9 18.5 74 15 20.3 11.8 31.2

Headache Any 74 18 24.3 15.1 35.7 74 25 33.8 23.2 45.7

Grade 3 74 0 0.0 0.0 4.9 74 1 1.4 0.0 7.3

Related 74 16 21.6 12.9 32.7 74 22 29.7 19.7 41.5


Any 74 22 29.7 19.7 41.5 74 19 25.7 16.2 37.2 Grade 3 74 1 1.4 0.0 7.3 74 0 0.0 0.0 4.9

Related 74 22 29.7 19.7 41.5 74 19 25.7 16.2 37.2


Grade 3 74 1 1.4 0.0 7.3 74 1 1.4 0.0 7.3

Related 74 18 24.3 15.1 35.7 74 13 17.6 9.7 28.2

Myalgia Any 74 21 28.4 18.5 40.1 74 14 18.9 10.7 29.7

Grade 3 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

Related 74 21 28.4 18.5 40.1 74 14 18.9 10.7 29.7

Rash Any 74 6 8.1 3.0 16.8 74 5 6.8 2.2 15.1

Grade 3 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

Related 74 5 6.8 2.2 15.1 74 4 5.4 1.5 13.3

Urticaria Any 74 10 13.5 6.7 23.5 74 7 9.5 3.9 18.5

Grade 3 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

Related 74 8 10.8 4.8 20.2 74 5 6.8 2.2 15.1

N = number of subjects with at least one documented dose n/% = number/percentage of subjects reporting the symptom at least once 95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit *Gastrointestinal symptoms: nausea, vomiting, diarrhoea and/or abdominal pain Any = occurrence of any general symptoms regardless of their intensity grade or relationship to vaccination Grade 3 = general symptom that prevented normal activities Related = general symptom assessed by the investigator as causally related to the study vaccination

Primary Efficacy Results: Number (%) of subjects with MSCs from Day 0 up to Month 7 (Total Vaccinated cohort) MSCs HPV-2D Group

N = 74 MMR-DTPa Group

N = 74 Subjects with any MSC(s), n (%) 38 (51.4) 28 (37.8)

Anaemia 1 (1.4) 3 (4.1)

Eosinophilia 2 (2.7) 2 (2.7)

Lymphadenopathy 1 (1.4) 1 (1.4) Ear pain 1 (1.4) 0 (0.0)

Conjunctivitis allergic 1 (1.4) 0 (0.0)

Eye allergy 1 (1.4) 0 (0.0) Anal fissure 1 (1.4) 0 (0.0)

Constipation 1 (1.4) 0 (0.0)

Diarrhoea 0 (0.0) 2 (2.7)

Dyspepsia 0 (0.0) 1 (1.4) Food poisoning 1 (1.4) 0 (0.0)

Chest pain 1 (1.4) 0 (0.0)

Influenza like illness 0 (0.0) 1 (1.4) Pyrexia 2 (2.7) 0 (0.0)

Abscess limb 0 (0.0) 1 (1.4)

Acarodermatitis 2 (2.7) 0 (0.0) Bronchitis 1 (1.4) 1 (1.4)

Bronchopneumonia 0 (0.0) 1 (1.4)

Conjunctivitis 1 (1.4) 0 (0.0)

Dengue fever 0 (0.0) 1 (1.4) Ear infection 0 (0.0) 1 (1.4)

Gingival abscess 0 (0.0) 1 (1.4)

Herpes simplex 0 (0.0) 1 (1.4) Hordeolum 1 (1.4) 1 (1.4)

Impetigo 3 (4.1) 0 (0.0)

Infection parasitic 1 (1.4) 2 (2.7) Infectious mononucleosis 0 (0.0) 1 (1.4)

Influenza 1 (1.4) 0 (0.0)

Lice infestation 1 (1.4) 1 (1.4)

Otitis externa 1 (1.4) 0 (0.0) Otitis media 0 (0.0) 1 (1.4)

Otitis media acute 3 (4.1) 1 (1.4)

Parotitis 1 (1.4) 0 (0.0) Pyoderma 0 (0.0) 2 (2.7)

Tinea pedis 1 (1.4) 0 (0.0)

Tooth abscess 2 (2.7) 1 (1.4)

Varicella 1 (1.4) 1 (1.4) Viral infection 3 (4.1) 2 (2.7)

Burns second degree 1 (1.4) 0 (0.0)

Clavicle fracture 1 (1.4) 0 (0.0) Contusion 0 (0.0) 1 (1.4)

Foreign body 1 (1.4) 0 (0.0)

Fracture 0 (0.0) 1 (1.4)

Head injury 0 (0.0) 1 (1.4)

Joint injury 1 (1.4) 0 (0.0) Limb injury 0 (0.0) 1 (1.4)

Mouth injury 1 (1.4) 0 (0.0)

Multiple injuries 0 (0.0) 1 (1.4)

Stab wound 0 (0.0) 1 (1.4) Wound 2 (2.7) 0 (0.0)

Dehydration 0 (0.0) 1 (1.4)

Pain in extremity 1 (1.4) 0 (0.0) Skin papilloma 0 (0.0) 1 (1.4)

Headache 0 (0.0) 1 (1.4)

Meningism 1 (1.4) 0 (0.0) Adenoidal hypertrophy 3 (4.1) 0 (0.0)

Asthma 1 (1.4) 5 (6.8)

Asthmatic crisis 1 (1.4) 0 (0.0)

Bronchial hyperreactivity 1 (1.4) 0 (0.0) Cough 2 (2.7) 0 (0.0)

Epistaxis 1 (1.4) 2 (2.7)

Oropharyngeal pain 0 (0.0) 1 (1.4) Rhinitis allergic 2 (2.7) 3 (4.1)

Vasomotor rhinitis 1 (1.4) 1 (1.4)

Dermatitis 3 (4.1) 1 (1.4)

Dermatitis atopic 1 (1.4) 0 (0.0) Dermatitis contact 0 (0.0) 1 (1.4)

Dry skin 1 (1.4) 0 (0.0)

Eczema 0 (0.0) 1 (1.4) Keratosis pilaris 1 (1.4) 0 (0.0)

Prurigo 1 (1.4) 0 (0.0)

Rash 0 (0.0) 1 (1.4)

Primary Efficacy Results: Number (%) of subjects with pIMDs from Day 0 up to Month 7 (Total Vaccinated cohort) pIMDs HPV-2D Group


N = 74

Subjects with any pIMD(s), n (%) 0 (0.0) 0 (0.0)

Primary Efficacy Results: Seroconversion rates and GMCs by pre-vaccination status (ATP cohort for immunogenicity) ≥ 19 EU/mL* GMC (EU/mL)

95% CI 95% CI

Antibody Group Pre-vacc status

Timing N n % LL UL value LL UL

anti-HPV-16 HPV-2D S- PRE 65 0 0.0 0.0 5.5 9.5 9.5 9.5

PII(M7)* 65 65 100 94.5 100 19677.4 16463.7 23518.4

Total PRE 65 0 0.0 0.0 5.5 9.5 9.5 9.5

PII(M7)* 65 65 100 94.5 100 19677.4 16463.7 23518.4

MMR-DTPa S- PRE 44 0 0.0 0.0 8.0 9.5 9.5 9.5

PII(M7)* 44 1 2.3 0.1 12.0 10.4 8.7 12.4

S+ PRE 1 1 100 2.5 100 345.0 - -

PII(M7) 1 1 100 2.5 100 97.0 - -

Total PRE 45 1 2.2 0.1 11.8 10.3 8.8 12.1

PII(M7)* 45 2 4.4 0.5 15.1 10.9 8.9 13.4

S- = seronegative subjects (antibody concentration < 19 EU/mL) prior to vaccination S+ = seropositive subjects (antibody concentration ≥ 19 EU/mL) prior to vaccination GMC = geometric mean antibody concentration calculated on all subjects N = number of subjects with pre-vaccination results available n/% = number/percentage of subjects with concentration equal to or above specified value 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre Dose 1 PII(M7) = 30 Days Post Dose 2

*Primary Outcome Result

Primary Efficacy Results: Seroconversion rates and GMCs by pre-vaccination status (ATP cohort for immunogenicity) ≥ 18 EU/mL* GMC (EU/mL)

95% CI 95% CI

Antibody Group Pre-vacc status

Timing N n % LL UL value LL UL

anti-HPV-18

HPV-2D S- PRE 63 0 0.0 0.0 5.7 9.0 9.0 9.0

PII(M7)* 63 63 100 94.3 100 10458.9 8731.8 12527.5

S+ PRE 2 2 100 15.8 100 20.9 6.2 70.4

PII(M7)* 2 2 100 15.8 100 12220.6 327.8 455632.9

Total PRE 65 2 3.1 0.4 10.7 9.2 8.9 9.6

PII(M7) 65 65 100 94.5 100 10509.1 8818.9 12523.2

MMR-DTPa S- PRE 45 0 0.0 0.0 7.9 9.0 9.0 9.0

PII(M7)* 45 1 2.2 0.1 11.8 9.6 8.4 11.0

Total PRE 45 0 0.0 0.0 7.9 9.0 9.0 9.0

PII(M7)* 45 1 2.2 0.1 11.8 9.6 8.4 11.0

S- = seronegative subjects (antibody concentration < 18 EU/mL) prior to vaccination S+ = seropositive subjects (antibody concentration ≥ 18 EU/mL) prior to vaccination GMC = geometric mean antibody concentration calculated on all subjects N = number of subjects with pre-vaccination results available n/% = number/percentage of subjects with concentration equal to or above specified value 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre Dose 1 PII(M7) = 30 Days Post Dose 2 *Primary Outcome Result

Primary Efficacy Results: Distribution of change from baseline in haematology and biochemistry with respect to normal laboratory ranges (Total Vaccinated cohort)


Unknown Below Within Above Unknown

Below Within Above

Laboratory parameter

Timing

Baseline (PRE D0)

N n % n % n % n % N n % n % n % n %

Alanine Aminotransferase

PI(D42) Unknown 2 0 0.0 0 0.0 2 100 0 0.0 2 0 0.0 0 0.0 2 100 0 0.0

Below 2 0 0.0 1 50.0 1 50.0 0 0.0 1 0 0.0 0 0.0 1 100 0 0.0

Within 67 0 0.0 0 0.0 64 95.5 3 4.5 64 0 0.0 0 0.0 62 96.9 2 3.1

Above 3 0 0.0 0 0.0 1 33.3 2 66.7 5 0 0.0 0 0.0 3 60.0 2 40.0

PII(M7) Unknown 2 0 0.0 0 0.0 2 100 0 0.0 2 0 0.0 0 0.0 2 100 0 0.0

Below 2 0 0.0 1 50.0 1 50.0 0 0.0 1 0 0.0 0 0.0 1 100 0 0.0

Within 66 0 0.0 2 3.0 64 97.0 0 0.0 64 0 0.0 2 3.1 61 95.3 1 1.6

Above 3 0 0.0 0 0.0 2 66.7 1 33.3 5 0 0.0 0 0.0 5 100 0 0.0

Basophils PI(D42) Unknown 2 0 0.0 0 0.0 2 100 0 0.0 0 - - - - - - - -

Below 0 - - - - - - - - 0 - - - - - - - -

Within 70 0 0.0 0 0.0 70 100 0 0.0 69 0 0.0 0 0.0 69 100 0 0.0

Above 0 - - - - - - - - 4 0 0.0 0 0.0 4 100 0 0.0

PII(M7) Unknown 2 0 0.0 0 0.0 2 100 0 0.0 0 - - - - - - - -

Below 0 - - - - - - - - 0 - - - - - - - -

Within 72 0 0.0 0 0.0 71 98.6 1 1.4 68 0 0.0 0 0.0 67 98.5 1 1.5

Above 0 - - - - - - - - 4 0 0.0 0 0.0 2 50.0 2 50.0

Creatinine PI(D42) Unknown 2 0 0.0 0 0.0 2 100 0 0.0 1 0 0.0 0 0.0 1 100 0 0.0

Below 27 0 0.0 20 74.1 7 25.9 0 0.0 22 0 0.0 15 68.2 7 31.8 0 0.0

Within 45 0 0.0 7 15.6 38 84.4 0 0.0 49 1 2.0 12 24.5 36 73.5 0 0.0

Above 0 - - - - - - - - 1 0 0.0 0 0.0 1 100 0 0.0

PII(M7) Unknown 2 0 0.0 1 50.0 1 50.0 0 0.0 1 0 0.0 0 0.0 1 100 0 0.0

Below 26 0 0.0 20 76.9 6 23.1 0 0.0 22 0 0.0 18 81.8 4 18.2 0 0.0

Within 45 0 0.0 11 24.4 34 75.6 0 0.0 48 1 2.1 11 22.9 36 75.0 0 0.0

Above 0 - - - - - - - - 1 0 0.0 1 100 0 0.0 0 0.0

Eosinophils PI(D42) Unknown 2 0 0.0 0 0.0 2 100 0 0.0 0 - - - - - - - -

Below 1 0 0.0 0 0.0 1 100 0 0.0 0 - - - - - - - -

Within 49 0 0.0 1 2.0 41 83.7 7 14.3 50 0 0.0 1 2.0 38 76.0 11 22.0

Above 20 0 0.0 0 0.0 3 15.0 17 85.0 23 0 0.0 1 4.3 10 43.5 12 52.2

PII(M7) Unknown 2 0 0.0 0 0.0 2 100 0 0.0 0 - - - - - - - -

Below 1 0 0.0 0 0.0 1 100 0 0.0 0 - - - - - - - -

Within 51 0 0.0 0 0.0 42 82.4 9 17.6 49 0 0.0 1 2.0 35 71.4 13 26.5

Above 20 0 0.0 0 0.0 2 10.0 18 90.0 23 0 0.0 0 0.0 10 43.5 13 56.5

Erythrocytes (Red Blood Cells)

PI(D42) Unknown 2 0 0.0 0 0.0 2 100 0 0.0 0 - - - - - - - -

Below 4 0 0.0 0 0.0 4 100 0 0.0 4 0 0.0 0 0.0 4 100 0 0.0

Within 66 0 0.0 3 4.5 61 92.4 2 3.0 66 0 0.0 2 3.0 63 95.5 1 1.5

Above 0 - - - - - - - - 3 0 0.0 0 0.0 2 66.7 1 33.3

PII(M7) Unknown 2 0 0.0 0 0.0 2 100 0 0.0 0 - - - - - - - -

Below 4 0 0.0 0 0.0 4 100 0 0.0 4 0 0.0 2 50.0 2 50.0 0 0.0

Within 68 0 0.0 2 2.9 65 95.6 1 1.5 65 0 0.0 2 3.1 63 96.9 0 0.0

Above 0 - - - - - - - - 3 0 0.0 0 0.0 2 66.7 1 33.3 Hematocrit PI(D42) Unknown 2 0 0.0 0 0.0 2 100 0 0.0 0 - - - - - - - -

Below 19 0 0.0 8 42.1 11 57.9 0 0.0 21 0 0.0 12 57.1 8 38.1 1 4.8

Within 48 0 0.0 5 10.4 41 85.4 2 4.2 48 0 0.0 1 2.1 42 87.5 5 10.4

Above 3 0 0.0 0 0.0 2 66.7 1 33.3 4 0 0.0 0 0.0 4 100 0 0.0

PII(M7) Unknown 2 0 0.0 0 0.0 1 50.0 1 50.0 0 - - - - - - - -

Below 20 0 0.0 5 25.0 15 75.0 0 0.0 21 0 0.0 10 47.6 11 52.4 0 0.0

Within 49 0 0.0 3 6.1 45 91.8 1 2.0 47 0 0.0 3 6.4 44 93.6 0 0.0

Above 3 0 0.0 0 0.0 3 100 0 0.0 4 0 0.0 0 0.0 4 100 0 0.0

Hemoglobin PI(D42) Unknown 2 0 0.0 0 0.0 1 50.0 1 50.0 0 - - - - - - - -

Below 15 0 0.0 7 46.7 8 53.3 0 0.0 11 0 0.0 2 18.2 9 81.8 0 0.0

Within 50 0 0.0 3 6.0 43 86.0 4 8.0 56 0 0.0 6 10.7 46 82.1 4 7.1

Above 5 0 0.0 0 0.0 3 60.0 2 40.0 6 0 0.0 0 0.0 5 83.3 1 16.7

PII(M7) Unknown 2 0 0.0 0 0.0 1 50.0 1 50.0 0 - - - - - - - -

Below 16 0 0.0 1 6.3 15 93.8 0 0.0 11 0 0.0 2 18.2 9 81.8 0 0.0

Within 51 0 0.0 1 2.0 44 86.3 6 11.8 55 0 0.0 4 7.3 50 90.9 1 1.8

Above 5 0 0.0 0 0.0 3 60.0 2 40.0 6 0 0.0 0 0.0 5 83.3 1 16.7

Leukocytes (White Blood Cells)

PI(D42) Unknown 2 0 0.0 0 0.0 1 50.0 1 50.0 0 - - - - - - - -

Below 5 0 0.0 1 20.0 3 60.0 1 20.0 7 0 0.0 5 71.4 1 14.3 1 14.3

Within 62 0 0.0 3 4.8 56 90.3 3 4.8 61 0 0.0 1 1.6 57 93.4 3 4.9

Above 3 0 0.0 0 0.0 1 33.3 2 66.7 5 0 0.0 0 0.0 3 60.0 2 40.0

PII(M7) Unknown 2 0 0.0 0 0.0 2 100 0 0.0 0 - - - - - - - -

Below 5 0 0.0 3 60.0 2 40.0 0 0.0 7 0 0.0 4 57.1 3 42.9 0 0.0

Within 63 0 0.0 1 1.6 60 95.2 2 3.2 60 0 0.0 7 11.7 50 83.3 3 5.0

Above 4 0 0.0 0 0.0 2 50.0 2 50.0 5 0 0.0 0 0.0 4 80.0 1 20.0 Lymphocytes PI(D42) Unknown 2 0 0.0 0 0.0 1 50.0 1 50.0 0 - - - - - - - -

Below 7 0 0.0 4 57.1 2 28.6 1 14.3 10 0 0.0 6 60.0 2 20.0 2 20.0

Within 48 0 0.0 7 14.6 38 79.2 3 6.3 42 0 0.0 2 4.8 34 81.0 6 14.3

Above 15 0 0.0 0 0.0 6 40.0 9 60.0 21 0 0.0 2 9.5 5 23.8 14 66.7

PII(M7) Unknown 2 0 0.0 0 0.0 2 100 0 0.0 0 - - - - - - - -

Below 7 0 0.0 6 85.7 1 14.3 0 0.0 10 0 0.0 6 60.0 4 40.0 0 0.0

Within 49 0 0.0 6 12.2 38 77.6 5 10.2 42 0 0.0 5 11.9 37 88.1 0 0.0

Above 16 0 0.0 0 0.0 16 100 0 0.0 20 0 0.0 1 5.0 15 75.0 4 20.0

Monocytes PI(D42) Unknown 2 0 0.0 1 50.0 1 50.0 0 0.0 0 - - - - - - - -

Below 7 0 0.0 4 57.1 3 42.9 0 0.0 9 0 0.0 5 55.6 4 44.4 0 0.0

Within 51 0 0.0 3 5.9 42 82.4 6 11.8 55 0 0.0 2 3.6 48 87.3 5 9.1

Above 12 0 0.0 0 0.0 6 50.0 6 50.0 9 0 0.0 0 0.0 3 33.3 6 66.7

PII(M7) Unknown 2 0 0.0 1 50.0 1 50.0 0 0.0 0 - - - - - - - -

Below 7 0 0.0 2 28.6 5 71.4 0 0.0 9 0 0.0 4 44.4 4 44.4 1 11.1

Within 53 0 0.0 4 7.5 49 92.5 0 0.0 54 0 0.0 3 5.6 51 94.4 0 0.0

Above 12 0 0.0 0 0.0 12 100 0 0.0 9 0 0.0 0 0.0 7 77.8 2 22.2

Neutrophils PI(D42) Unknown 2 0 0.0 1 50.0 1 50.0 0 0.0 0 - - - - - - - -

Below 14 0 0.0 8 57.1 6 42.9 0 0.0 21 0 0.0 14 66.7 6 28.6 1 4.8

Within 52 0 0.0 4 7.7 41 78.8 7 13.5 46 0 0.0 6 13.0 39 84.8 1 2.2

Above 4 0 0.0 0 0.0 3 75.0 1 25.0 6 0 0.0 0 0.0 3 50.0 3 50.0

PII(M7) Unknown 2 0 0.0 0 0.0 2 100 0 0.0 0 - - - - - - - -

Below 15 0 0.0 1 6.7 13 86.7 1 6.7 21 0 0.0 4 19.0 16 76.2 1 4.8

Within 53 0 0.0 4 7.5 43 81.1 6 11.3 45 0 0.0 4 8.9 35 77.8 6 13.3

Above 4 0 0.0 0 0.0 2 50.0 2 50.0 6 0 0.0 0 0.0 3 50.0 3 50.0

Platelets PI(D42) Unknown 3 0 0.0 0 0.0 2 66.7 1 33.3 0 - - - - - - - -

Below 0 - - - - - - - - 2 0 0.0 0 0.0 2 100 0 0.0

Within 60 0 0.0 0 0.0 53 88.3 7 11.7 58 0 0.0 0 0.0 54 93.1 4 6.9

Above 9 0 0.0 0 0.0 3 33.3 6 66.7 13 0 0.0 0 0.0 8 61.5 5 38.5

PII(M7) Unknown 3 0 0.0 0 0.0 2 66.7 1 33.3 0 - - - - - - - -

Below 0 - - - - - - - - 2 0 0.0 0 0.0 2 100 0 0.0

Within 61 0 0.0 0 0.0 58 95.1 3 4.9 57 0 0.0 0 0.0 56 98.2 1 1.8

Above 10 0 0.0 0 0.0 6 60.0 4 40.0 13 0 0.0 0 0.0 7 53.8 6 46.2

Urea Nitrogen PI(D42) Unknown 2 0 0.0 0 0.0 2 100 0 0.0 1 0 0.0 0 0.0 1 100 0 0.0

Below 12 0 0.0 4 33.3 8 66.7 0 0.0 4 0 0.0 1 25.0 3 75.0 0 0.0

Within 57 0 0.0 2 3.5 54 94.7 1 1.8 64 0 0.0 7 10.9 57 89.1 0 0.0

Above 3 0 0.0 0 0.0 3 100 0 0.0 4 0 0.0 0 0.0 4 100 0 0.0

PII(M7) Unknown 2 0 0.0 0 0.0 2 100 0 0.0 1 0 0.0 0 0.0 1 100 0 0.0

Below 12 0 0.0 5 41.7 7 58.3 0 0.0 4 0 0.0 0 0.0 4 100 0 0.0

Within 55 0 0.0 3 5.5 52 94.5 0 0.0 63 0 0.0 10 15.9 53 84.1 0 0.0

Above 3 0 0.0 0 0.0 3 100 0 0.0 4 0 0.0 0 0.0 4 100 0 0.0

N = number of subjects with available results for the specified laboratory parameter and timing in a given baseline category n/% = number/percentage of subjects in the specified category Unknown = missing result or normal laboratory range for the specified laboratory parameter Below = below the normal laboratory range defined for the specified laboratory parameter Within = within the normal laboratory range defined for the specified laboratory parameter Above = above the normal laboratory range defined for the specified laboratory parameter PI(D42) = 42 days post Dose 1 PII(M7) = 30 days post Dose 2

Primary Efficacy Results: Number (%) of subjects with AEs or SAEs leading to withdrawal up to Month 7 (Total Vaccinated cohort)

HPV-2D Group N = 74

MMR-DTPa Group N = 74

Number of subjects withdrawn, n (%) 0 (0.0) 2 (2.7)

Reasons for withdrawal

Serious Adverse Event, n (%) 0 (0.0) 0 (0.0)

Non-Serious Adverse Event, n (%) 0 (0.0) 0 (0.0)

Primary Efficacy Results: For results on unsolicited AE and SAE, please refer to the safety section of this CTRS

Secondary Outcome Variable(s): Number (%) of subjects who received study vaccine doses (Total Vaccinated cohort)

HPV-2D Group N = 74


Total number of doses received n % n %

1 0 0.0 3 4.1

2 74 100 71 95.9

Any 74 100 74 100

N = number of subjects in each group included in the considered cohort n/% = number/percentage of subjects receiving the specified total number of doses Any = number and percentage of subjects receiving at least one dose

Secondary Outcome Variable(s): Number (%) of subjects with MSCs from Day 0 up to Month 12 (Total Vaccinated cohort) MSCs HPV-2D Group


N = 74

Subjects with any MSCs, n (%) 38 (51.4) 30 (40.5)

Anaemia 1 (1.4) 3 (4.1) Eosinophilia 2 (2.7) 2 (2.7)

Lymphadenopathy 1 (1.4) 1 (1.4)

Ear pain 1 (1.4) 0 (0.0) Chalazion 0 (0.0) 1 (1.4)

Conjunctivitis allergic 1 (1.4) 0 (0.0)

Eye allergy 1 (1.4) 0 (0.0) Anal fissure 1 (1.4) 0 (0.0)

Constipation 1 (1.4) 0 (0.0)

Diarrhoea 1 (1.4) 4 (5.4)

Dyspepsia 0 (0.0) 1 (1.4) Food poisoning 1 (1.4) 0 (0.0)

Gastritis 0 (0.0) 1 (1.4)

Chest pain 1 (1.4) 0 (0.0) Influenza like illness 0 (0.0) 1 (1.4)

Pyrexia 3 (4.1) 0 (0.0)

Hypersensitivity 1 (1.4) 1 (1.4)

Abscess limb 0 (0.0) 1 (1.4) Acarodermatitis 2 (2.7) 0 (0.0)

Bronchitis 2 (2.7) 1 (1.4)

Bronchopneumonia 0 (0.0) 1 (1.4) Conjunctivitis 1 (1.4) 0 (0.0)

Dengue fever 0 (0.0) 1 (1.4)

Ear infection 0 (0.0) 1 (1.4) Eye infection 1 (1.4) 0 (0.0)

Gingival abscess 0 (0.0) 1 (1.4)

Herpes simplex 0 (0.0) 1 (1.4)

Hordeolum 1 (1.4) 1 (1.4) Impetigo 4 (5.4) 1 (1.4)

Infection parasitic 2 (2.7) 3 (4.1)

Infectious mononucleosis 0 (0.0) 1 (1.4) Influenza 1 (1.4) 1 (1.4)

Lice infestation 1 (1.4) 1 (1.4)

Molluscum contagiosum 1 (1.4) 0 (0.0)

Otitis externa 1 (1.4) 0 (0.0) Otitis media 0 (0.0) 1 (1.4)


Parotitis 1 (1.4) 0 (0.0) Pyoderma 1 (1.4) 2 (2.7)

Tinea pedis 1 (1.4) 0 (0.0)

Tooth abscess 2 (2.7) 1 (1.4) Varicella 2 (2.7) 1 (1.4)

Viral infection 4 (5.4) 2 (2.7)

Burns second degree 1 (1.4) 0 (0.0)

Clavicle fracture 1 (1.4) 0 (0.0) Contusion 0 (0.0) 1 (1.4)

Foreign body 1 (1.4) 0 (0.0)

Fracture 0 (0.0) 1 (1.4)

Head injury 0 (0.0) 1 (1.4)

Joint injury 1 (1.4) 0 (0.0) Limb injury 0 (0.0) 1 (1.4)

Mouth injury 1 (1.4) 0 (0.0)

Multiple injuries 0 (0.0) 1 (1.4)

Stab wound 0 (0.0) 1 (1.4) Wound 2 (2.7) 0 (0.0)

Dehydration 0 (0.0) 1 (1.4)

Pain in extremity 1 (1.4) 0 (0.0) Skin papilloma 0 (0.0) 1 (1.4)

Headache 0 (0.0) 1 (1.4)

Adenoidal hypertrophy 3 (4.1) 0 (0.0) Asthma 1 (1.4) 5 (6.8)

Asthmatic crisis 1 (1.4) 0 (0.0)

Bronchial hyperreactivity 1 (1.4) 0 (0.0)

Cough 2 (2.7) 0 (0.0) Epistaxis 1 (1.4) 2 (2.7)

Oropharyngeal pain 0 (0.0) 1 (1.4)

Rhinitis allergic 4 (5.4) 3 (4.1) Vasomotor rhinitis 1 (1.4) 1 (1.4)

Dermatitis 3 (4.1) 1 (1.4)

Dermatitis atopic 1 (1.4) 0 (0.0)

Dermatitis contact 0 (0.0) 1 (1.4) Dry skin 1 (1.4) 0 (0.0)

Eczema 0 (0.0) 1 (1.4)

Keratosis pilaris 1 (1.4) 0 (0.0) Onychomadesis 1 (1.4) 0 (0.0)

Prurigo 1 (1.4) 1 (1.4)

Rash 0 (0.0) 1 (1.4)

Secondary Outcome Variable(s): Number (%) of subjects with pIMDs from Day 0 up to Month 12 (Total Vaccinated cohort) pIMDs HPV-2D Group


N = 74

Subjects with any pIMD(s), n (%) 0 (0.0) 0 (0.0)

Secondary Outcome Variable(s): Incidence of fever during the 43-day (Days 0-42) post-Dose 1 (Total Vaccinated cohort)


95 % CI 95 % CI

Symptom Intensity/ Relationship N n % LL UL N n % LL UL

Fever/(Axillary) 37.5°C 74 30 40.5 29.3 52.6 74 26 35.1 24.4 47.1

>39.0°C 74 7 9.5 3.9 18.5 74 2 2.7 0.3 9.4

Related 74 6 8.1 3.0 16.8 74 7 9.5 3.9 18.5

N = number of subjects with the documented dose n/% = number/percentage of subjects reporting the symptom at least once 95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit Related= fever assessed by the investigator as causally related to study vaccination

Secondary Outcome Variable(s): Incidence of solicited Measles/Rubella-like rash within the 43-day (Days 0-42) post-Dose 1 (Total Vaccinated cohort)

HPV-2D Group N = 74


95% CI 95% CI

Rash type n % LL UL n % LL UL Any 1 1.4 0.0 7.3 1 1.4 0.0 7.3

With fever* 0 0.0 0.0 4.9 0 0.0 0.0 4.9

Grade 3 0 0.0 0.0 4.9 0 0.0 0.0 4.9

Related 1 1.4 0.0 7.3 1 1.4 0.0 7.3 N = number of subjects having received the administered dose n = number of subjects reporting a specified symptom

% = percentage of subjects reporting a specified symptom Exact 95% Lower and Upper confidence limits = LL, UL for percentage Grade 3= > 150 lesions *This included any rash episode with at least one day of fever (axillary temperature ≥ 37.5°C) during a period from 3 days (included) before the starting date of the rash to the end date of the rash episode (included)

Secondary Outcome Variable(s): Incidence of solicited parotid gland swelling reported during the 43-day (Days 0-42) post-Dose 1 (Total Vaccinated cohort)


95 % CI 95 % CI

Symptom Intensity/ Relationship N n % LL UL N n % LL UL Parotid gland swelling Any 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

Grade 3 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

Related 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

N = number of subjects with the documented dose n/% = number/percentage of subjects reporting the symptom at least once Grade 3 = Swelling with accompanying general symptoms 95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit

Secondary Outcome Variable(s): Incidence of solicited signs of meningism reported during the 43-day (Days 0-42) post-Dose 1 (Total Vaccinated cohort)


95 % CI 95 % CI

Symptom Intensity/ Relationship N n % LL UL N n % LL UL

Signs of Meningism including febrile convulsion

Any 74 0 0.0 0.0 4.9 74 1 1.4 0.0 7.3

Grade 3 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9 Related 74 0 0.0 0.0 4.9 74 1 1.4 0.0 7.3

N = number of subjects with the documented dose n/% = number/percentage of subjects reporting the symptom at least once Grade 3 = An event that prevented normal, everyday activities 95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit

Secondary Outcome Variable(s): Number (%) of subjects starting a concomitant medication during the 43-day (Days 0-42) post-Dose 1 or within the 30-day (Days 0-29) post-Dose 2 by dose and across doses (Total Vaccinated cohort)


95% CI 95% CI

N n % LL UL N n % LL UL

Dose 1

Any 74 43 58.1 46.1 69.5 74 36 48.6 36.9 60.6 Any antipyretic 74 27 36.5 25.6 48.5 74 22 29.7 19.7 41.5

Prophylactic antipyretic 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

Any antibiotic 74 17 23.0 14.0 34.2 74 10 13.5 6.7 23.5

Dose 2 Any 74 19 25.7 16.2 37.2 71 23 32.4 21.8 44.5

Any antipyretic 74 10 13.5 6.7 23.5 71 8 11.3 5.0 21.0

Prophylactic antipyretic 74 0 0.0 0.0 4.9 71 0 0.0 0.0 5.1 Any antibiotic 74 6 8.1 3.0 16.8 71 6 8.5 3.2 17.5

Across doses

Any 74 49 66.2 54.3 76.8 74 43 58.1 46.1 69.5

Any antipyretic 74 30 40.5 29.3 52.6 74 25 33.8 23.2 45.7 Prophylactic antipyretic 74 0 0.0 0.0 4.9 74 0 0.0 0.0 4.9

Any antibiotic 74 20 27.0 17.4 38.6 74 15 20.3 11.8 31.2

N = number of subjects with at least one administered dose n/% = number/percentage of subjects who started to take the specified concomitant medication at least once during the mentioned period 95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Safety Results: Number (%) of subjects with unsolicited AEs within the 43-day (Days 0-42) post-Dose 1 (Total Vaccinated cohort)

Most frequent adverse events –On-Therapy (occurring within Days HPV-2D Group MMR-DTPa Group

0-42 following vaccination) N = 74 N = 74

Subjects with any unsolicited AE(s), n (%) 40 (54.1) 40 (54.1)

Subjects with grade 3 unsolicited AE(s), n (%) 3 (4.1) 2 (2.7)

Subjects with related unsolicited AE(s), n (%) 1 (1.4) 5 (6.8)

Nasopharyngitis 21 (28.4) 23 (31.1)

Pharyngitis 4 (5.4) 3 (4.1)

Gastroenteritis 3 (4.1) 5 (6.8)

Impetigo 3 (4.1) -


Sinusitis 2 (2.7) -

Viral infection 2 (2.7) 2 (2.7)

Headache 2 (2.7) 3 (4.1)

Adenoidal hypertrophy 2 (2.7) -

Asthma 2 (2.7) 3 (4.1)

Cough 2 (2.7) 1 (1.4)

Dermatitis 2 (2.7) 1 (1.4)

Diarrhoea - 2 (2.7)

Rhinitis - 2 (2.7)

Viral infection - 2 (2.7)

Anaemia - 1 (1.4)

Abdominal pain upper - 1 (1.4)

Dyspepsia - 1 (1.4)

Nausea - 1 (1.4)

Vomiting - 1 (1.4)

Influenza like illness - 1 (1.4)

Bronchopneumonia - 1 (1.4)

Ear infection - 1 (1.4)

Infection parasitic - 1 (1.4)

Otitis media - 1 (1.4)

Tooth abscess - 1 (1.4)

Vulvovaginitis - 1 (1.4)

Contusion - 1 (1.4)

Pain in extremity - 1 (1.4)

Epistaxis - 1 (1.4)

Oropharyngeal pain - 1 (1.4)

Rhinitis allergic - 1 (1.4)

Rhinorrhoea - 1 (1.4)

Vasomotor rhinitis - 1 (1.4)

Skin lesion - 1 (1.4)

Counting rule applied: As there were more than 30 subjects per treatment group and ≤ 3 groups,only the 10 most frequent events in each treatment group are to be listed. -: Implies that adverse event was not reported in the particular group or that the adverse event was reported in the particular group but did not fall within the pre-defined counting rule of 10 most frequent events for that group. Grade 3 = unsolicited AE that prevented normal activity Related = unsolicited AE assessed by the investigator as causally related to the study vaccination

Safety Results: Number (%) of subjects with unsolicited AEs within the 30-day (Days 0-29) post-Dose 2 (Total Vaccinated cohort)

Most frequent adverse events –On-Therapy (occurring within Days 0-29 following vaccination)

HPV-2D Group N = 74

MMR-DTPa Group N = 71*

Subjects with any unsolicited AE(s), n (%) 18 (24.3) 13 (18.3)

Subjects with grade 3 unsolicited AE(s), n (%) 0 (0.0) 0 (0.0)

Subjects with related unsolicited AE(s), n (%) 0 (0.0) 1 (1.4)

Lymphadenopathy - 1 (1.4)

Conjunctivitis allergic 1 (1.4) -

Pyrexia 2 (2.7) -

Acarodermatitis 1 (1.4) -

Conjunctivitis 1 (1.4) -

Gastroenteritis 2 (2.7) 3 (4.2)

Gingival abscess - 1 (1.4)

Hordeolum - 1 (1.4)

Influenza 1 (1.4) -

Lice infestation - 1 (1.4)

Nasopharyngitis 4 (5.4) 5 (7.0)

Pharyngitis 2 (2.7) 1 (1.4)

Pyoderma - 1 (1.4)

Rhinitis 1 (1.4) -

Sinusitis 1 (1.4) -

Tooth abscess 1 (1.4) -

Urinary tract infection - 1 (1.4)

Vulvovaginitis 1 (1.4) -

Burns second degree 1 (1.4) -

Head injury - 1 (1.4)

Multiple injuries 1 (1.4) -

Stab wound - 1 (1.4)

Dehydration - 1 (1.4)

Pain in extremity 1 (1.4) -

Meningism 1 (1.4) -

Adenoidal hypertrophy 1 (1.4) -

Asthma - 1 (1.4)

Alopecia - 1 (1.4)

Dermatitis 1 (1.4) -

-: Adverse event absent Grade 3 = unsolicited AE that prevented normal activity Related = unsolicited AE assessed by the investigator as causally related to the study vaccination *Note: out of the 74 subjects present in the initial group, 3 did not receive the second vaccination and were hence excluded from the Total Vaccinated cohort.

Safety Results: Number (%) of subjects with SAEs from Day 0 up to Month 7 (Total Vaccinated cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication]

All SAEs HPV-2D Group N = 74


Subjects with any SAE(s), n (%) [n assessed by the investigator as related] 0 (0.0) [0] 2 (2.7) [0] Abscess limb 0 (0.0) [0] 1 (1.4) [0]

Dehydration 0 (0.0) [0] 1 (1.4) [0]

Gastroenteritis 0 (0.0) [0] 1 (1.4) [0]

Fatal SAEs HPV-2D Group N = 74


Subjects with fatal SAE(s), n (%) [n assessed by the investigator as related] 0 (0.0) [0] 0 (0.0) [0]

Safety Results: Number (%) of subjects with SAEs from Day 0 up to Month 12 (Total Vaccinated cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication]

All SAEs HPV-2D Group N = 74


Subjects with any SAE(s), n (%) [n assessed by the investigator as related] 1 (1.4) [0] 2 (2.7) [0] Abscess limb 0 (0.0) [0] 1 (1.4) [0]

Dehydration 0 (0.0) [0] 1 (1.4) [0]

Gastroenteritis 1 (1.4) [0] 1 (1.4) [0] Fatal SAEs HPV-2D Group


N = 74

Subjects with fatal SAE(s), n (%) [n assessed by the investigator as related] 0 (0.0) [0] 0 (0.0) [0]

Safety Results: Number (%) of subjects with SAEs related to investigational products or any fatal from Day 0 up to Month 12 (Total Vaccinated cohort)


N = 74 N = 74

Subjects with any SAEs/fatal SAEs, n (%) 0 (0.0) 0 (0.0) Safety Results: Number (%) of subjects with AEs/SAEs leading to withdrawal from Day 0 up to Month 12 (Total Vaccinated cohort)

HPV-2D Group N = 74


Number of subjects withdrawn, n (%) 0 (0.0) 0 (0.0)

Reasons for withdrawal

AE(s), n (%) 0 (0.0) 0 (0.0) SAE(s), n (%) 0 (0.0) 0 (0.0)

Conclusion: One month after the 2-dose [M0, 6] of HPV vaccination, all subjects who were baseline seronegative for the type analysed experienced HPV-16 and HPV-18 seroconversion (100%). The geometric mean concentration (GMC) of the antibody was 19677.4 EU/mL (95% CI: 16463.7, 23518.4) for HPV-16 antibody and 10509.1 EU/mL (95% CI: 8818.9, 12523.2) for HPV-18 antibody. During the 7-day (Days 0-6) post-vaccination period, Injection site pain was the most frequently reported solicited local event in both vaccine groups. . During the same time period, Irritability and headache were the most frequently reported solicited general event during the 7-day (Days 0-6) post-vaccination period in groups HPV-2D and MMR-DTPa, respectively. During the 43-day (Days 0-42) post-vaccination at Day 0 and during the 30-day (Days 0-29) post-vaccination at Month 6, the most frequently reported unsolicited AE was nasopharyngitis in both vaccine groups. Up to Month 7, 38 subjects (51.4%) in the HPV_2D Group and 28 subjects (37.8%) in the MMR/DTPa Group reported at least one MSC. Clinically relevant eosinophil count abnormality (reported as EOSINOPHILIA) was observed in 4 subjects (2 HPV vaccine recipients and 2 MMR/DTPa vaccine recipients); clinically relevant Hb/Hct/RBC abnormality (reported as ANEMIA) was observed in 3 subjects (1 HPV vaccine recipients and 2 MMR/DTPa vaccine recipients). None of them were considered by the study investigator as related to a study vaccine. Two subjects (2.7%) in the Group MMR-DTPa and one subject (1.4%) in the Group HPV-2D reported at least one SAE up to Month 12, none of them assessed by the investigator as being related to the study vaccinations. No fatality was reported up to Month 12. No pIMDs were reported for any of the groups up to Month 12. No subjects from either vaccine group reported an AE or SAE leading to study withdrawal.

Date updated: 23-Sep-2016

biologicals’ hpv tm (hpv): gsk biologicals’...study number: 115887 (hpv -073) title: safety and...

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