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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