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Table 1 Literature review of vaccine-related adverse events reported from HPV vaccination in randomized controlled trials

From: Literature review of vaccine-related adverse events reported from HPV vaccination in randomized controlled trials

Author, Year Study population Inclusion criteria Adverse events Vaccine group (%) Control group (%) P
Harper et al. 2004 [6] N = 1113 women from 32 study sites in North America and Brazil. 15–25 years
≤6 lifetime sexual partners
No abnormal Pap test
No external condylomata
HPV 16/18 seronegative
7-day period N = 531 Gardasil N = 538 Al(OH)3  
Injection-site symptoms
Pain
Swelling
Redness
General symptoms
Fatigue
Gastrointestinal
Headache
Itching
Rash
Fever
499 (93.97)
496 (93.41)
182 (34.27)
189 (35.59)
458 (56.25)
308 (58.00)
178 (33.52)
331 (62.34)
130 (24.48)
60 (11.30)
88 (16.57)
472 (87.73)
469 (87.17)
113 (21.00)
131 (24.35)
462 (85.87)
289 (53.72)
172 (31.97)
329 (61.15)
109 (20.26)
54 (10.04)
73 (13.57)
<0.001
<0.001
<0.001
<0.001
0.860
0.175
0.602
0.706
0.106
0.552
0.172
Entire study period (0–27 months)    
Vaccine-related serious adverse event
Discontinuation for non-serious adverse event
Discontinuation for serious adverse eventd
0
0
1 (0.19)
0
3 (0.56)
0
1.000
0.249
0.497
Villa et al. 2005 [7] N = 277 women from Brazil, Europe, and USA 16–23 years
Non-pregnant
No abnormal Pap smears
≤4 lifetime sex partners
  N = 272 Gardasil N = 274 AAHS  
Vaccine-associated adverse events
Injection-site
Systemic
Vaccine-related serious adverse events
Discontinued vaccination due to hypoaesthesia
243 (89.34)
234 (86.03)
104 (38.24)
0
0
225 (82.12)
212 (77.37)
90 (32.85)
0
1 (0.36)
0.016
0.009
0.188
1.000
0.319
Reisinger et al. 2007 [16] N = 1781 children from 47 sites in 10 countries in North America, Latin America, Europe, and Asia, enrolled from December 2002 to September 2004 9–15 years old
Sexually naïve
Intact uterus
No gross purulent cervicitis
No genital warts
No abnormal Pap smear
No cervical intraepithelial neoplasia
≤4 lifetime sex partners
Non-pregnant
15-day period N = 1165 Gardasil N = 584 Saline  
≥1 adverse events
Injection-site adverse events
Erythema
Pain
Swelling
Systemic adverse events
Serious vaccine-related adverse events
963 (82.66)
877 (75.28)
237 (20.34)
853 (73.22)
241 (20.68)
541 (46.44)
0
392 (97.12)
292 (50.00)
77 (13.18)
265 (45.38)
45 (7.71)
260 (44.52)
0
<0.001
<0.001
<0.001
<0.001
<0.001
0.448
1.000
  N = 1157 N = 579  
Fever 1074 (92.83) 541 (93.44) 0.638
Merck V501-013
FUTURE I Study
Garland et al. 2007 [2]
N = 5455 women at 62 study sites in 16 countries, enrolled from January 2002 to March 2003 16–24 year old
Non-pregnant
No history of genital warts
No abnormal cervical cytology testing
≤4 lifetime sex partners
Effective contraception
5-day period N = 2673 Gardasil N = 2672 AAHS  
Injection-site event
Erythema
Pain
Pruritus
Swelling
2320 (86.79)
659 (24.65)
2281 (85.33)
109 (4.70)
694 (25.96)
2068 (77.40)
450 (16.84)
2014 (75.37)
80 (2.99)
413 (15.46)
<0.001
<0.001
<0.001
<0.001
<0.001
15-day period    
Injection-related systemic event
Pyrexia
1161 (43.43)
361 (13.51)
1085 (40.61)
272 (10.18)
0.036
<0.001
Entire study period    
Vaccine-related serious eventa
Discontinuation for vaccine-related event
Death
1 (0.03)
0
2 (0.07)
0
0
2 (0.07)
0.317
1.000
0.999
Merck V501-015
FUTURE II Study, 2007 [3]
N = 12,167 women in 13 countries, enrolled from June 2002 to March 2003 15–26 year old
Non-pregnant
No abnormal Papanicolaou smear
≤4 lifetime sex partners
Effective contraception
15-day period N = 448 Gardasil N = 447 AAHS  
≥1 adverse event    
Injection-site event
Pain
Systemic event
378 (84.38)
372 (83.04)
275 (61.38)
348 (77.85)
339 (75.84)
268 (59.96)
0.012
0.008
0.662
Entire study period N = 6019 N = 6031  
Serious injection-related eventb
Discontinuation for serious injection-related event
Death
3 (0.05)
0
7 (0.12)
2 (0.03)
0
5 (0.08)
0.202
1.000
0.338
Muñoz et al. 2009 [8] N = 3819 women from 38 international sites in Colombia, France, Germany, Philippines, Spain, Thailand, and USA 24–45 year old
Non-pregnant
Intact uterus
No genital warts or cervical disease
HIV seronegative
15-day period N = 1889 Gardasil N = 1886 AAHS  
Vaccine-related adverse events
Injection-site adverse events
Systemic adverse events
Serious vaccine-related adverse events
1565 (82.84)
1449 (76.71)
745 (39.44)
0
1389 (73.65)
1212 (64.26)
695 (36.85)
0
<0.001
<0.001
0.102
1.000
Bhatla et al. 2010 [9] N = 330 women at four teaching/ tertiary care hospitals across India, enrolled from July 2006 to March 2007 Non-pregnant
No investigational products/ steroids
Contraception or sexual abstinence
7-day period N = 171 Cervarix N = 174 Al(OH)3  
Pain, all-type
Grade 3 Pain
Redness, any size
>50 mm
Swelling, any size
>50 mm
Grade 3 solicited general symptoms
Medically significant adverse event
Serious adverse events
Acute pancreatitis
Lymph node tuberculosis
Bronchogenic cyst
Cataract
Miscarriage
Pneumothorax
Death
137 (80.12)
35 (20.47)
56 (32.75)
1 (0.58)
69 (40.35)
5 (2.92)
11 (6.43)
13 (7.60)
2 (1.717)
1 (0.58)
1 (0.58)
0
0
0
0
0
105 (60.34)
7 (4.02)
24 (13.79)
1 (0.57)
35 (20.11)
3 (1.72)
10 (5.75)
24 (13.79)
4 (2.30)
0
0
1 (0.57)
1 (0.57)
1 (0.57)
1 (0.57)
0
<0.001
<0.001
<0.001
0.990
<0.001
0.459
0.790
0.063
0.422
0.312
0312
0.321
0.321
0.321
0.321
1.00
Ngan et al. 2010 [10] N = 300 women at a single center in Hong Kong 18–35 year old
No chronic disease
Non-pregnant/ breastfeeding
Entire study period N = 145 Cervarix N = 145 Al(OH)3  
Abdominal pain, IBS, dizziness, headache
Pelvic inflammatory disease
Medically significant conditions
New onset chronic disease
3 (2.07)
0
42 (2.90)
7 (4.83)
0
1 (0.69)
24 (16.55)
5 (3.44)
0.082
0.316
0.012
0.555
Levin et al. 2010 [11] N = 126 children HIV-seropositive children 7–12 years old
HIV with CD4 ≥ 15 %
≥3 months HAART if CD4 < 25 %
14-day period N = 96 Gardasil N = 30 Saline Placebo  
Adverse events
Ear, eye, respiratory symptom
Injection-site reactions
Laboratory abnormality
Systemic reactions
Other
35 (36.46)
1 (1.04)
21 (21.89)
3 (3.13)
2 (2.08)
1 (1.04)
15 (50.00)
1 (3.33)
3 (10.00)
1 (3.33)
1 (3.33)
1 (3.33)
0.186
0.381
0.148
0.955
0.695
0.381
V501-20
Giuliano et al. 2011 [12, 39]
N = 4065 males from 71 sites in 18 countries 16–26 years old
1–5 male or female sexual partners
No anogenital lesions
15-day period N = 1945 Gardasil N = 1950 AAHS  
Vaccine-related events
Injection-site
Systemic
Vaccine-related serious events
Death
Discontinuation for vaccine-related adverse evente
1242 (63.86)
1169 (60.10)
274 (14.09)
0
0
2 (0.10)
1134 (58.15)
1046 (53.64)
284 (14.56)
0
0
3 (0.15)
<0.001
<0.001
0.67
1.000
1.000
0.657
Entire study period    
Vaccine-related events
Injection-site
Systematic
Vaccine-related serious events
Death
Discontinuation for vaccine-related adverse evente
1242 (63.86)
1169 (60.10)
274 (14.09)
0
3
2 (0.10)
1134 (58.15)
1046 (53.64)
284 (14.56)
0
10
3 (0.15)
<0.001
<0.001
0.67
1.00
0.052
0.657
Sow et al. 2013 [13] N = 676 women in 2 centers in sub-Saharan Africa (Senegal and Tanzania) from October 2007 to July 2010 10–25 years old
HIV seronegative
Not pregnant
≤6 lifetime sexual partners
0–12 months* N = 450 Cervarix N = 226 Al(OH)3  
Grade 3 injection-site pain
Serious adverse eventc
Medically significant condition
New onset chronic disease
New onset autoimmune disease
Deaths
Premature births- infant death
2 (0.44)
17 (3.78)
312 (69.33)
11 (2.44)
2 (0.44)
0
1 (0.22)
0
14 (6.19)
170 (75.22)
11 (4.87)
2 (0.88)
0
1 (0.44)
0.316
0.156
0.110
0.094
0.481
1.000
0.619
Yoshikawa et al. 2013 [14] N = 1030 Japanese women, multicenter 18–26 years old
Not pregnant
No previous abnormal Pap smears
≤4 males sex partners
Effective contraception
Days 1–15 N = 480 Gardasil N = 468 AAHS  
All-type adverse event
Injection-site adverse event
Systemic adverse event
Serious adverse event
Discontinuation for vaccine-related adverse eventf
Death
417 (86.88)
408 (85.00)
66 (13.75)
0
1 (0.21)
0
347 (74.15)
338 (72.22)
53 (11.32)
0
0
0
<0.001
<0.001
0.260
1.000
1.000
Denny et al. 2013 [15] N = 150 women at a single center in Khayelitsha, Cape Town, Republic of South Africa. 18–25 years old
≤6 lifetime sexual partners
Non-pregnant
Intact cervix
30-day period N = HIV 61 (+)/30 (-) Cervarix N = 59 HIV(+) Al(OH)3  
Unsolicited adverse event
Headache
Upper respiratory tract infection
Lobar Pneumonia (Grade 3)
Bacterial Pneumonia (Grade 3)
53 (86.89)/ 26 (86.67)
12 (19.67)/ 4 (13.33)
10 (16.39)/ 7 (23.33)
1 (1.64)/ 0 (0.00)
0/ 0
46 (77.97)
14 (23.73)
10 (16.95)
0
1 (1.69)
0.199
0.590
0.935/0.390
0.323/1.000
0.311/0.473
Up to 7 months    
Medically significant adverse event 18 (29.51)/5 (16.67) 21 (35.59) 0.477/0.063
7–12 months N = HIV54 (+)/ 24 (-) N = 52 HIV(+)  
Medically significant adverse event
Discontinuation for vaccine-related adverse event
6 (11.11)/ 2 (8.33)
0/ 0
5 (9.62)
0
0.801/0.857
1.000
  1. Statistically significant values are in bold
  2. *Number of adverse events expressed as a function of the number of doses, rather than the number of patients, were excluded. These adverse events included malaria, headache, dysmenorrhea, abdominal pain, vertigo, cough, nasopharyngitis
  3. Amorphous aluminum hydroxyphosphate sulfate (AAHS) adjuvant; aluminum hydroxide [Al(OH)3]
  4. aBronchospasm 1 day after the third dose
  5. bSerious adverse events in the vaccine group were gastroenteritis, headache, hypertension, injection-site pain, and decrease in joint movement at the injection site
  6. cSerious adverse events in both the vaccinated and control groups were likely due to malaria infection, unrelated to the vaccine
  7. dElective discontinuation in the vaccine group was due to spontaneous abortion, unrelated to the vaccine
  8. eElective discontinuation in the vaccine group was due to vaccine-related malaise and headache
  9. fElective discontinuation in the vaccine group was due to vaccine-related pyrexia