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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