Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Vesikari T, Knuf M, Wutzler P, et al. Oil-in-water emulsion adjuvant with influenza vaccine in young children. N Engl J Med 2011;365:1406-16.
SUPPLEMENTARY MATERIALS Contents: Supplementary Methods (Hemagglutination inhibition (HI) assays)... 1 GMT responses to Homologous and Heterologous antigens (Figure 1)... 2 Narratives of serious adverse events considered as possibly- or probably-related to vaccination: ATIV group... 3 TIV group... 4 Control group... 5 Solicited local reactions (Table 1)... 6 Solicited systemic reactions (Table 2)... 7 All treatment emergent adverse events by MedDRA term (Table 3)... 8 All possibly or probably related severe adverse events (Table 4)... 12 0
Supplementary Material and Methods Hemagglutination inhibition (HI) assays were undertaken in the usual manner with 8 hemagglutinating units of live viral antigens; the influenza B viral hemagglutinin was not ether extracted. We used vaccine strain antigens in assays reporting homologous responses. To measure cross-reactive responses to heterologous strains not contained in the vaccine, we used A/Solomon Islands/3/2006 (H1N1) as the heterovariant H1N1 antigen; an A/Wisconsin/15/2009 (H3N2) antigen that is antigenically equivalent to A/Perth/16/2009 (H3N2) as the heterovariant H3N2 antigen; and B/Brisbane/60/2008 a lineage-mismatched Victoria lineage strain. Although the A/Solomon Islands/3/2006 strain had circulated before the 2008-2009 season when the immunogenicity study was conducted, the children in the study were vaccine-naive and also of an age when they might not have been exposed naturally to those viruses. The A/Perth/16/2009(H3N2)-like and B/Brisbane/60/2008 viruses that were used as heterovariant antigens did not circulate extensively in the northern hemisphere until after the immunogenicity study had been conducted, providing an opportunity to measure responses to antigenically mismatched strains that emerged after the vaccine composition had been fixed. 1
Supplementary Figure 1: GMT Hemagglutination Inhibition responses to Homologous and Heterologous antigens in the three study groups 120 800 ATIV TIV IVControl 600 H1N1 H3N2 B 100 80 400 200 60 40 20 HI GMTs (95% CI) 0 800 0 Day 1 Day 22 Day 50 Day 181 Day 1 Day 22 Day 50 Day 181 Day 1 Day 22 Day 50 Day 181 Homologous strains 120 H1N1 H3N2 100 B 600 80 400 200 60 40 20 0 Day 1 Day 22 Day 50 Day 181 Day 1 Day 22 Day 50 Day 181 0 Day 1 Day 22 Day 50 Day 181 Heterolgous strains 2
Serious Adverse Events (SAE) considered as possibly- or probably-related to vaccination. ATIV group: Subject 1: An 8-month-old Caucasian male randomized to ATIV group in influenza season 2007/08 met all protocol entry criteria. About 20 minutes after receiving second vaccine dose on 18 Dec 07, the subject experienced mild cyanosis in lips, wheezing and erythema. The subject was treated for mild allergic shock/ reaction with steroids (Prednisone) and salbutamol (by inhalation). All the three signs\symptoms were transient in nature and the subject recovered completely within 15 minutes; this SAE was assessed by the investigator to be probably related to the study vaccination. The subject had previously experienced cough and rhinitis on 26 Nov 07 after the first vaccination and had taken Cefixime (orally) and Euphorbium (nasal drops) for rhinitis. Subject 2: A 37-month-old Caucasian male randomized to ATIV group in influenza season 2008/09 met all protocol entry criteria. The subject experienced convulsions after about 23 days (on14 Jan 09) after receiving his second vaccination (on 23 Dec 08), while watching TV and was hospitalized. EEG and ECG were normal and MRI showed widening of the ventricular system without any signs of abnormal cerebrospinal fluid circulation. The subject received 10mg diazepam rectal by emergency physician, and phenobarbital and Sodium Oxybate for sedation. The subject was assessed to be completely recovered on 17 Jan 09. About 90 days after second vaccination (on 22 Mar 09), the subject experienced afebrile cerebral convulsion while jumping on a medicine ball for a duration of 15 minutes; parents administered diazepam after convulsion. The subject was hospitalized; MRI, sleep deprivation EEG were normal, simple widening of the inner cerebrospinal fluid space; the SAE was considered resolved on 25 Mar 09 and the subject was discharged on 26 Mar 09.The condition was severe in all the instances; the subject recovered completely after each seizure. The SAE was assessed to be possibly related to the study vaccination. The subject had earlier experienced infection of the upper airways and cough after first vaccination and after second vaccination the subject experienced upper respiratory infection, cough and pyrexia along with convulsions. The subject received Pentoxyverine citrate, Monapax, Cefpodoxime Proxetil, Ambroxol Hydrochloride and Acetylcysteine for these conditions. The subject had a medical history of Adipositas. 3
TIV group: Subject 1: A 44-month-old Asian female randomized to TIV group in influenza season 2008/09 met all protocol entry criteria. Within a week after receiving the second vaccine dose (06 Mar 10) the subject was diagnosed with diabetes mellitus type 1 (glucose 330mg/dl) and hospitalized on 13 Mar 09. During hospitalization a raised TSH level was detected and incipient autoimmune thyroiditis as a secondary disorder of type 1 diabetes was assumed. The patient was treated with intensified conventional insulin therapy for diabetes and with levothyroxine for thyroiditis. These SAEs persisted beyond the study observation period and were assessed to be possibly related to the study vaccination. The subject had a family history of maternal grandfather suffering from type 2 diabetes mellitus and mother had suffered from gestational diabetes. Medical history shows that the subject was born prematurely and post partum experienced a respiratory adaption and disturbance following placenta praevia. The subject previously (pre-study) experienced cough and was given Ambroxol Hydrochloride. The subject had later (to SAEs) experienced vomiting, obstipation, infection of airways, bronchitis and conjunctivitis. Subject 2: A 15-month-old Caucasian male randomized to TIV group in influenza season 2008/09 met all protocol entry criteria. Within a week after first vaccination (on study day 4), the subject was diagnosed with SAE of severe gait disturbance, that continued for 11 days and the subject recovered within the study observation period. The condition was assessed to be possibly related to the study vaccination. Further vaccination was stopped and the subject withdrew from the study prematurely. On study day 3, the subject reported AE -rhinitis that lasted for 11 days and on study day 8 the subject reported cough that lasted for 4 days and the subject recovered. The subject received paracetamol for post injection fever. 4
Control group: Subject 1: A 20-month-old Caucasian male randomized to CTRL group in influenza season 2008/09 met all protocol entry criteria. In the post-study period (99 days after second vaccination) the subject was diagnosed with mild behavior disorder and was hospitalized for 3 days; the subject was discharged with sequelae and the condition was assessed to be possibly related to the study vaccination. The outcome of the condition is unknown as the subject was lost to follow-up. The subject was earlier treated for obstipation, local and systemic reactions, infection of airways and eczema; he also received vaccinations for Influenza (Begrivac 2009/10), measles, mumps, rubella and varicella (Priorix-Tetra), and meningitis (menjugate). Subject 2: A 17-month-old Caucasian female randomized to CTRL group in influenza season 2008/09 met all protocol entry criteria. Within a week after receiving first vaccination (on study day 5, 09 Nov 08), the subject was diagnosed with infectious asthma of moderate intensity that occurred intermittently. The subject was treated with Salbutamol, Budesonide and corticosteroids; she was hospitalized for 2 days and discharged without sequelae. The condition was assessed to be possibly related to the study vaccination. The subject withdrew from the study prematurely due to the AE. The subject had a medical history of recurrent upper respiratory infections since Aug 08 and had a birth history of being a premature baby. 5
Table 1. Solicited local reactions within 7 days of receiving trivalent influenza vaccine (TIV), adjuvanted TIV (ATIV), and non-influenza vaccine control vaccine (CTRL), by age and dose. Solicited Local Reactions (95%CI) Age Dose N All Ecchymosis Erythema Induration Swelling Tenderness Pain ATIV TIV CTRL 6-<36 36-<72 6-<36 36-<72 6-<36 36-<72 1 1100 66.7 (63.9-69.5) 7.6 (6.1-9.4) 24.7 (22.2-27.4) 9.5 (7.9-11.4) 5.5 (4.2-7) 19.1 (16.8-21.5) - 2 1075 62.3 (59.4-65.2) 6.8 (5.4-8.5) 27.6 (25-30.4) 13.1 (11.2-15.3) 7.3 (5.9-9.1) 18.2 (16-20.7) - 1 833 69.6 (66.4-72.7) 8.4 (6.6-10.5) 23.2 (20.3-26.2) 10 (8-12.2) 8.8 (6.9-10.9) - 45.2 (41.8-48.6) a 2 813 68.5 (65.2-71.7) 9.1 (7.2-11.3) 31 (27.8-34.3) 15 (12.6-17.6) 14.1 (11.8-16.7) - 43.3 (39.9-46.8) 1 992 64.7 (61.7-67.7) 5.9 (4.6-7.6) 21.1 (18.6-23.7) 6.6 (5.1-8.3) 4.9 (3.7-6.5) 17 (14.7-19.5) - 2 966 59 (55.8-62.1) 5.2 (3.9-6.8) 22.8 (20.2-25.6) 8.2 (6.5-10.1) 6 (4.6-7.7) 15.8 (13.5-18.2) b - 1 777 59.6 (56-63.1) 6.7 (5-8.7) 22.3 (19.4-25.4) 11.1 (8.9-13.5) 9.3 (7.3-11.5) - 35.3 (31.9-38.7) 2 757 54 (50.4-57.6) 6.3 (4.7-8.3) 25.5 (22.4-28.8) 14.4 (12-17.1) 12.8 (10.5-15.4) - 32.5 (29.2-36) 1 566 65 (60.9-68.9) 7.8 (5.7-10.3) 32.5 (28.7-36.5) 17.3 (14.3-20.7) 9.2 (6.9-11.9) 20 (16.7-23.5) - 2 545 60.2 (55.9-64.3) 5.7 (3.9-8) 27.7 (24-31.7) 18.2 (15-21.7) 9.4 (7-12.1) 19.1 (15.9-22.6) - 1 422 57.8 (52.9-62.6) 7.3 (5-10.3) 23 (19.1-27.3) 12.8 (9.8-16.4) 8.3 (5.8-11.3) - 34.1 (29.6-38.9) 2 410 53.2 (48.2-58.1) 6.3 (4.2-9.2) 21.2 (17.4-25.5) 12.7 (9.6-16.3) 9 (6.4-12.2) - 30.7 (26.3-35.4) 6
Table 2. Solicited systemic reactions within 7 days of receiving trivalent influenza vaccine (TIV), adjuvanted TIV (ATIV), and noninfluenza vaccine control vaccine (CTRL), by age and dose. Solicited Systemic Reactions (95%CI) Change in eating habits Sleepiness Unusual crying Irritability Vomiting Diarrhea Shivering Fever ATIV TIV CTRL 6-<36 1 1100 18.5 (16.2-20.9) 22.7 (20.3-25.3) 22.6 (20.2-25.2) 24.1 (21.6-26.7) 6.7 (5.3-8.4) 14.4 (12.3-16.6) 4.1 (3-5.4) 15.3 (13.2-17.5) 2 1075 15.7 (13.6-18) 20.8 (18.4-23.4) 21.2 (18.8-23.8) 21 (18.6-23.6) 6 (4.7-7.6) 12.4 (10.5-14.5) 2.9 (2-4.1) 15.9 (13.8-18.2) 1 992 15.9 (13.7-18.4) 21.4 (18.9-24.1) 21.9 (19.3-24.6) 24.5 (21.8-27.3) 7 (5.5-8.7) 14.7 (12.6-17.1) 4.1 (3-5.6) 13.3 (11.3-15.6) c 2 965 13.2 (11.1-15.5) 16.3 (14-18.8) 20.1 (17.6-22.8) 20.4 (17.9-23.1) 5.7 (4.3-7.4) 10.2 (8.3-12.2) 3 (2-4.3) 13.4 (11.3-15.7) 1 566 17.8 (14.8-21.3) 22.3 (18.9-25.9) 21 (17.7-24.6) 22.1 (18.7-25.7) 7.1 (5.1-9.5) 12.7 (10.1-15.7) 4.9 (3.3-7.1) 13.6 (10.9-16.7) 2 545 15.6 (12.7-18.9) 19.6 (16.4-23.2) 17.2 (14.2-20.7) 20.6 (17.2-24.2) 5.1 (3.4-7.3) 10.3 (7.9-13.1) 4 (2.5-6) 10.8 (8.3-13.7) Chills Malaise Myalgia Arthralgia Headache Sweating Fatigue Fever ATIV TIV CTRL 36-<72 1 832 10.5 (8.5-12.7) 16 (13.6-18.7) 14.8 (12.4-17.4) 6.7 (5.1-8.7) 16.8 (14.3-19.5) 5.6 (4.2-7.4) 29.8 (26.7-33) 17.5 (15-20.3) 2 813 8 (6.2-10.1) 12.8 (10.6-15.3) 14 (11.7-16.6) 4.2 (2.9-5.8) 12.3 (10.1-14.8) 3.8 (2.6-5.4) 23.9 (21-26.9) 16.9 (14.3-19.6) 1 777 3.5 (2.3-5) 10.6 (8.5-12.9) 7.6 (5.8-9.7) 3.1 (2-4.6) 7.7 (5.9-9.8) 4 (2.7-5.6) 19.7 (16.9-22.7) 6.7 (5.1-8.7) d 2 757 3.7 (2.5-5.3) 7.7 (5.9-9.8) 8.5 (6.6-10.7) 2.2 (1.3-3.6) 6.6 (4.9-8.6) 1.5 (0.7-2.6) 17.3 (14.7-20.2) 6.9 (5.2-8.9) 1 422 4.5 (2.7-6.9) 9.5 (6.9-12.7) 9.2 (6.7-12.4) 2.6 (1.3-4.6) 7.1 (4.8-10) 4 (2.4-6.4) 19.4 (15.8-23.5) 7.6 (5.3-10.6) e 2 410 5.1 (3.2-7.7) 7.6 (5.2-10.6) 9.8 (7.1-13) 4.9 (3-7.4) 8 (5.6-11.1) 3.9 (2.2-6.3) 17.6 (14-21.6) 11.7 (8.8-15.2) a N=832; b N=965; c N=991; d N=775; e N=419 7
Table 3. All treatment emergent adverse events occurring in at least 1% of subjects sorted by overall frequency, by MedDRA preferred term, by vaccine group ATIV ATIV TIV TIV CONTROL CONTROL 6-36 m 36-72 m 6-36 m 36-72 m 6-36 m 36-72 m MedDRA Preferred Term (N=1099) (N=835) (N=993) (N=777) (N=566) (N=422) UPPER RESPIRATORY TRACT INFECTION 347 ( 32%) 170 ( 20%) 297 ( 30%) 156 ( 20%) 170 ( 30%) 85 ( 20%) RHINITIS 253 ( 23%) 122 ( 15%) 207 ( 21%) 96 ( 12%) 120 ( 21%) 58 ( 14%) COUGH 237 ( 22%) 176 ( 21%) 200 ( 20%) 166 ( 21%) 112 ( 20%) 97 ( 23%) OTITIS MEDIA 244 ( 22%) 109 ( 13%) 224 ( 23%) 110 ( 14%) 128 ( 23%) 62 ( 15%) PYREXIA 246 ( 22%) 102 ( 12%) 219 ( 22%) 105 ( 14%) 119 ( 21%) 65 ( 15%) GASTROENTERITIS 188 ( 17%) 76 ( 9%) 161 ( 16%) 87 ( 11%) 98 ( 17%) 37 ( 9%) BRONCHITIS 171 ( 16%) 69 ( 8%) 151 ( 15%) 66 ( 8%) 95 ( 17%) 51 ( 12%) NASOPHARYNGITIS 154 ( 14%) 77 ( 9%) 159 ( 16%) 76 ( 10%) 91 ( 16%) 37 ( 9%) CONJUNCTIVITIS 151 ( 14%) 81 ( 10%) 150 ( 15%) 62 ( 8%) 87 ( 15%) 45 ( 11%) EAR INFECTION 129 ( 12%) 57 ( 7%) 128 ( 13%) 49 ( 6%) 72 ( 13%) 22 ( 5%) DIARRHOEA 85 ( 8%) 44 ( 5%) 72 ( 7%) 35 ( 5%) 54 ( 10%) 10 ( 2%) VOMITING 69 ( 6%) 64 ( 8%) 65 ( 7%) 70 ( 9%) 43 ( 8%) 22 ( 5%) INFLUENZA 27 ( 2%) 16 ( 2%) 46 ( 5%) 50 ( 6%) 43 ( 8%) 36 ( 9%) RESPIRATORY TRACT INFECTION 76 ( 7%) 30 ( 4%) 62 ( 6%) 37 ( 5%) 43 ( 8%) 17 ( 4%) 8
DERMATITIS DIAPER 76 ( 7%) 4 ( <1%) 61 ( 6%) 5 ( 1%) 40 ( 7%) 2 ( <1%) VIRAL INFECTION 63 ( 6%) 35 ( 4%) 61 ( 6%) 28 ( 4%) 20 ( 4%) 19 ( 5%) ENTERITIS 54 ( 5%) 23 ( 3%) 60 ( 6%) 18 ( 2%) 32 ( 6%) 11 ( 3%) TONSILLITIS 63 ( 6%) 39 ( 5%) 44 ( 4%) 38 ( 5%) 25 ( 4%) 25 ( 6%) ECZEMA 58 ( 5%) 25 ( 3%) 38 ( 4%) 16 ( 2%) 28 ( 5%) 9 ( 2%) OROPHARYNGEAL PAIN 13 ( 1%) 40 ( 5%) 20 ( 2%) 30 ( 4%) 7 ( 1%) 12 ( 3%) PHARYNGITIS 51 ( 5%) 30 ( 4%) 39 ( 4%) 24 ( 3%) 23 ( 4%) 17 ( 4%) TEETHING 50 ( 5%) 0 44 ( 4%) 1 ( <1%) 19 ( 3%) 0 CONSTIPATION 41 ( 4%) 17 ( 2%) 42 ( 4%) 12 ( 2%) 23 ( 4%) 10 ( 2%) ABDOMINAL PAIN 9 ( 1%) 24 ( 3%) 13 ( 1%) 30 ( 4%) 5 ( 1%) 11 ( 3%) RASH 41 ( 4%) 18 ( 2%) 37 ( 4%) 18 ( 2%) 20 ( 4%) 3 ( 1%) LARYNGITIS 38 ( 3%) 19 ( 2%) 36 ( 4%) 13 ( 2%) 12 ( 2%) 5 ( 1%) HEADACHE 6 ( 1%) 29 ( 3%) 6 ( 1%) 28 ( 4%) 5 ( 1%) 15 ( 4%) ACUTE TONSILLITIS 32 ( 3%) 30 ( 4%) 24 ( 2%) 20 ( 3%) 14 ( 2%) 11 ( 3%) EAR PAIN 9 ( 1%) 23 ( 3%) 13 ( 1%) 15 ( 2%) 8 ( 1%) 15 ( 4%) INJECTION SITE INDURATION 4 ( <1%) 0 2 ( <1%) 2 ( <1%) 17 ( 3%) 7 ( 2%) CRYING 32 ( 3%) 5 ( 1%) 29 ( 3%) 3 ( <1%) 8 ( 1%) 0 IRRITABILITY 32 ( 3%) 8 ( 1%) 26 ( 3%) 6 ( 1%) 16 ( 3%) 4 ( 1%) CONTUSION 27 ( 2%) 11 ( 1%) 19 ( 2%) 21 ( 3%) 9 ( 2%) 7 ( 2%) EXANTHEMA SUBITUM 24 ( 2%) 1 ( <1%) 23 ( 2%) 1 ( <1%) 15 ( 3%) 1 ( <1%) DERMATITIS 28 ( 3%) 9 ( 1%) 25 ( 3%) 6 ( 1%) 14 ( 2%) 2 ( <1%) DERMATITIS ATOPIC 7 ( 1%) 6 ( 1%) 17 ( 2%) 4 ( 1%) 14 ( 2%) 5 ( 1%) ABDOMINAL PAIN UPPER 8 ( 1%) 18 ( 2%) 8 ( 1%) 19 ( 2%) 5 ( 1%) 8 ( 2%) LICE INFESTATION 6 ( 1%) 19 ( 2%) 9 ( 1%) 13 ( 2%) 1 ( <1%) 7 ( 2%) 9
SCARLET FEVER 5 ( <1%) 18 ( 2%) 10 ( 1%) 11 ( 1%) 4 ( 1%) 9 ( 2%) VARICELLA 16 ( 1%) 18 ( 2%) 17 ( 2%) 12 ( 2%) 10 ( 2%) 6 ( 1%) ARTHROPOD BITE 16 ( 1%) 12 ( 1%) 20 ( 2%) 9 ( 1%) 10 ( 2%) 9 ( 2%) EATING DISORDER 16 ( 1%) 3 ( <1%) 15 ( 2%) 1 ( <1%) 12 ( 2%) 1 ( <1%) STOMATITIS 23 ( 2%) 4 ( <1%) 18 ( 2%) 5 ( 1%) 8 ( 1%) 4 ( 1%) CANDIDIASIS 19 ( 2%) 3 ( <1%) 16 ( 2%) 1 ( <1%) 11 ( 2%) 1 ( <1%) PSEUDOCROUP 13 ( 1%) 1 ( <1%) 19 ( 2%) 8 ( 1%) 6 ( 1%) 2 ( <1%) OTITIS MEDIA ACUTE 21 ( 2%) 6 ( 1%) 18 ( 2%) 10 ( 1%) 10 ( 2%) 6 ( 1%) ASTHMA 20 ( 2%) 7 ( 1%) 16 ( 2%) 5 ( 1%) 9 ( 2%) 7 ( 2%) FEBRILE INFECTION 17 ( 2%) 3 ( <1%) 17 ( 2%) 1 ( <1%) 7 ( 1%) 3 ( 1%) URTICARIA 13 ( 1%) 5 ( 1%) 17 ( 2%) 6 ( 1%) 9 ( 2%) 4 ( 1%) PAIN IN EXTREMITY 2 ( <1%) 10 ( 1%) 4 ( <1%) 13 ( 2%) 2 ( <1%) 5 ( 1%) TRACHEITIS 18 ( 2%) 2 ( <1%) 14 ( 1%) 1 ( <1%) 8 ( 1%) 4 ( 1%) SKIN LACERATION 10 ( 1%) 11 ( 1%) 10 ( 1%) 4 ( 1%) 9 ( 2%) 3 ( 1%) ENURESIS 3 ( <1%) 9 ( 1%) 2 ( <1%) 12 ( 2%) 1 ( <1%) 3 ( 1%) SEASONAL ALLERGY 5 ( <1%) 11 ( 1%) 7 ( 1%) 12 ( 2%) 3 ( 1%) 2 ( <1%) URINARY TRACT INFECTION 10 ( 1%) 6 ( 1%) 13 ( 1%) 12 ( 2%) 2 ( <1%) 5 ( 1%) FUNGAL INFECTION 16 ( 1%) 1 ( <1%) 5 ( 1%) 3 ( <1%) 3 ( 1%) 0 ECCHYMOSIS 4 ( <1%) 3 ( <1%) 3 ( <1%) 4 ( 1%) 3 ( 1%) 6 ( 1%) INJECTION SITE ERYTHEMA 0 2 ( <1%) 1 ( <1%) 3 ( <1%) 5 ( 1%) 6 ( 1%) SKIN PAPILLOMA 0 10 ( 1%) 3 ( <1%) 7 ( 1%) 3 ( 1%) 6 ( 1%) HAND-FOOT-AND-MOUTH DISEASE 10 ( 1%) 3 ( <1%) 10 ( 1%) 4 ( 1%) 8 ( 1%) 5 ( 1%) MYRINGOTOMY 9 ( 1%) 2 ( <1%) 9 ( 1%) 0 8 ( 1%) 3 ( 1%) ERYTHEMA 15 ( 1%) 8 ( 1%) 5 ( 1%) 2 ( <1%) 1 ( <1%) 2 ( <1%) 10
RHINORRHOEA 15 ( 1%) 7 ( 1%) 6 ( 1%) 3 ( <1%) 7 ( 1%) 2 ( <1%) FATIGUE 1 ( <1%) 11 ( 1%) 2 ( <1%) 7 ( 1%) 1 ( <1%) 4 ( 1%) PNEUMONIA 12 ( 1%) 5 ( 1%) 13 ( 1%) 7 ( 1%) 4 ( 1%) 4 ( 1%) ERYTHEMA INFECTIOSUM 8 ( 1%) 5 ( 1%) 7 ( 1%) 8 ( 1%) 7 ( 1%) 3 ( 1%) OTITIS EXTERNA 7 ( 1%) 2 ( <1%) 8 ( 1%) 8 ( 1%) 7 ( 1%) 2 ( <1%) SINUSITIS 6 ( 1%) 10 ( 1%) 7 ( 1%) 9 ( 1%) 7 ( 1%) 2 ( <1%) CANDIDA NAPPY RASH 4 ( <1%) 0 12 ( 1%) 1 ( <1%) 2 ( <1%) 0 IMPETIGO 8 ( 1%) 9 ( 1%) 12 ( 1%) 8 ( 1%) 3 ( 1%) 4 ( 1%) SPEECH DISORDER DEVELOPMENTAL 7 ( 1%) 4 ( <1%) 7 ( 1%) 6 ( 1%) 0 5 ( 1%) BALANITIS 9 ( 1%) 7 ( 1%) 11 ( 1%) 6 ( 1%) 2 ( <1%) 1 ( <1%) FLATULENCE 12 ( 1%) 3 ( <1%) 4 ( <1%) 2 ( <1%) 1 ( <1%) 0 INFECTION 4 ( <1%) 3 ( <1%) 7 ( 1%) 4 ( 1%) 6 ( 1%) 3 ( 1%) ORAL CANDIDIASIS 7 ( 1%) 1 ( <1%) 10 ( 1%) 0 6 ( 1%) 0 EPISTAXIS 2 ( <1%) 6 ( 1%) 2 ( <1%) 8 ( 1%) 3 ( 1%) 2 ( <1%) CONJUNCTIVITIS INFECTIVE 11 ( 1%) 3 ( <1%) 7 ( 1%) 2 ( <1%) 3 ( 1%) 0 DYSPNOEA 11 ( 1%) 1 ( <1%) 4 ( <1%) 1 ( <1%) 1 ( <1%) 1 ( <1%) SLEEP DISORDER 11 ( 1%) 1 ( <1%) 9 ( 1%) 2 ( <1%) 2 ( <1%) 0 11
Table 4. All possibly or probably related severe adverse events by MedDRA preferred term, by vaccine group SOC ATIV TIV Control PREFERRED TERM 6-< 36 36-< 72 6-< 36 36-< 72 6-< 36 36-< 72 GASTROINTESTINAL DISORDERS ABDOMINAL PAIN UPPER 1 (<1%) DIARRHOEA 1 (<1%) 1 (<1%) VOMITING 1 (<1%) GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS INJECTION SITE ERYTHEMA 1 (<1%) INJECTION SITE INDURATION 1 (<1%) IRRITABILITY 1 (<1%) PYREXIA 1 (<1%) 1 (<1%) INFECTIONS AND INFESTATIONS BRONCHITIS 1 (<1%) NASOPHARYNGITIS 1 (<1%) UPPER RESPIRATORY TRACT INFECTION 2 (<1%) 1 (<1%) NERVOUS SYSTEM DISORDERS HEADACHE 1 (<1%) PSYCHIATRIC DISORDERS EATING DISORDER 1 (<1%) RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS ASTHMA 1 (<1%) COUGH 1 (<1%) 1 (<1%) RHINORRHOEA 1 (<1%) SKIN AND SUBCUTANEOUS TISSUE DISORDERS ERYTHEMA 1 (<1%) 12