Safety of human papillomavirus 6, 11, 16 and 18 (recombinant): systematic review and meta-analysis

Coelho, Pedro Luiz Spinelli; Calestini, Gustavo Lacerda da Silva; Alvo, Fernando Salgueiro; Freitas, Jefferson Michel de Moura; Castro, Paula Marcela Vilela; Konstantyner, Tulio

doi:10.1016/j.rpped.2015.02.006

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Revista Paulista de Pediatria

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Review Articles • Rev. paul. pediatr. 33 (4) • Oct-Dec 2015 • https://doi.org/10.1016/j.rpped.2015.02.006 copy

Safety of human papillomavirus 6, 11, 16 and 18 (recombinant): systematic review and meta-analysis

Authorship SCIMAGO INSTITUTIONS RANKINGS

Objective:

To identify and quantify the adverse effects associated with the recombinant human papillomavirus (types 6, 11, 16 and 18) vaccine in adolescents.

Data source:

Systematic review of randomized clinical trials from PubMed, SciELO and Lilacs databases. Articles investigating the safety of the vaccine in subjects under 18 years and comparing the recombinant human papillomavirus types 6, 11, 16 and 18 vaccine with a control group were included. Meta-analyses were performed for the outcomes of pain, erythema, swelling and fever, using clinical trials with maximum Jadad score.

Data synthesis:

Fourteen studies were included. The most common adverse effects related to the human papillomavirus vaccine were effects with no severity (pain, erythema, edema, and fever). Five studies were used for the meta-analyses: pain-risk difference (RD)=11% (p<0.001); edema-RD=8% (p<0.001); erythema-RD=5% (p<0.001); fever-RD=2% (p<0.003).

Conclusions:

The recombinant human papillomavirus types 6, 11, 16 and 18 vaccine was safe and well tolerated. The main adverse effects related to vaccination were pain, erythema, edema and fever. The low frequency of severe adverse effects encourages the administration of the vaccine in the population at risk.

Papillomavirus vaccines; Adverse effects; Adolescent; Meta-analysis; Safety

Adverse effects	FI	PI (%)
Local
Local pain	13	20.2–88.4
Edema	12	3.0–31.0
Erythema	11	1.0–41.0
Pruritus	3	1.1–4.1

Systemic
Fever	12	2.7–23.5
Fatigue	9	0.3–38.8
Headache	12	5.3–35.2
Cough	2	3.6
Arthralgia	7	5.5–13.4
Myalgia	8	3.6–33.9
Sore throat	3	0.4–4.0
Nausea	2	0.8–2.6
Chills	1	–
Abdominal pain	2	0.3
Diarrhea and/or vomiting	12	0.5–19.3
Acne	1	0.8
Dizziness and vertigo	3	1.0

Diseases
Psychiatric	2	1.7–2.2
Blood and lymphatic system	1	0.4
Cardiovascular	3	0.1–0.6
Ear and labyrinth	1	1.2
Nervous system	4	1.3–33.7
Ocular	1	1.0
Immunological/allergies	3	0.6–2.6
Metabolic and nutritional	1	0.8
Infectious	1	20.7
Renal and urinary	3	0.4–1.4
Reproductive and breasts	1	8.4
Respiratory, thoracic or mediastinal	1	0.9–7.7
Skin and subcutaneous tissue	3	4.2
Musculoskeletal and of connective tissue	5	1.1–9.1
Mastoiditis	1	–
Upper airways infections	11	0.1–6.0
Diabetes mellitus	2	–
Renal failure	1	–
Poisoning, trauma	2	–
Intoxication	1	1.7
Appendicitis	1	–
Rash/hives	7	0.8–6.6
Hypothyroidism	1	0.4
Malaria	1	–

Perinatal
Dysfunctional uterine bleeding	1	–
Prematurity	2	–
Congenital anomaly	1	2.3
Late fetal death	1	–
Miscarriage	1	22.2

Author (year/JADAD)	Method			Effects associated with the vaccine
	Design	Intervention	Gender (age range)
Moreira et al. ^[³⁴34 Moreira ED Jr, Palefsky JM, Giuliano AR, et al. Safety and reactogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 viral-like-particle vaccine in older adolescents and young adults. Hum Vaccines. 2011;7:768-75.^] (2011/5)	RCT, DB, PC	HPV QV (n=1945) vs. Placebo (n=1950)	M (16–26 yrs)	Local pain
Kim et al. ^[²³23 Kim YJ, Kim KT, Kim JH, et al. Vaccination with a human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine in Korean girls aged 10–14 years. J Korean Med Sci. 2010;25:1197-204.^] (2010/5)	RCT	HPV DV (n=474) vs. hepatitis A vaccine (n=483)	F (10–14 yrs)	Local pain, erythema, edema and myalgia
Sow et al. ^[³⁵35 Sow PS, Watson-Jones D, Kiviat N, et al. Safety and immunogenicity of human papillomavirus-16/18 AS04-adjuvanted vaccine: a randomized trial in 10–25-year-old HIV seronegative African girls and young women. J Infect Dis. 2013;207:1753-63.^] (2013/5)	RCT IIIb, DB, PC, MULTI (aluminum hydroxide)	HPV DV (n=1298) vs. Placebo (n=643)	F (10–25 yrs)	Local pain
Reisinger et al. ^[³⁶36 Reisinger KS, Block SL, Lazcano-Ponce E, et al. Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial. Pediatr Infect Dis J. 2007;26:201-9.^] (2007/5)	RCT, DB, PC	HPV QV (n=1165) vs. Placebo (n=584)	M and F (1:1) (9–15 yrs)	Local pain, erythema and edema
Szarewski et al. ^[³⁷37 Szarewski A, Poppe WA, Skinner SR, et al. Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15–25 years with and without serological evidence of previous exposure to HPV-16/18. Int J Cancer. 2012;131:106-16.^] (2012/5)	RCT, DB	HPV DV (n=9319) vs. hepatitis A vaccine (n=9325)	F exposed to HPV (15–25 yrs)	Local pain, erythema and edema
Petäjä et al. ^[³⁸38 Petäjä T, Keränen H, Karppa T, et al. Immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in healthy boys aged 10–18 years. J Adolesc Health. 2009;44:33-40.^] (2009/3)	RCT, phase I/II, blind observer	HPV DV (n=181) vs. hepatitis B vaccine (n=89)	M (10–18 yrs)	Local pain, edema and myalgia
FUTURE II ^[³³33 The FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007;356:1915-27.^] (2007/5)	RCT, DB, PC	HPV QV (n=448) vs. Placebo (n=447)	F (15–26 yrs)	Local pain, seasonal allergies
Medina et al. ^[³⁹39 Medina DM, Valencia A, de Velasquez A, et al. Safety and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine: a randomized, controlled trial in adolescent girls. J Adolesc Health. 2010;46:414-21.^] (2010/3)	RCT, MULTI	HPV DV (n=1017) vs. hepatitis A vaccine (n=1010)	F (10–14 yrs)	Local pain, erythema, edema, headache, myalgia, fatigue, hives and syncope
Romanowski et al. ^[⁴⁰40 Romanowski B, Schwarz TF, Ferguson LM, et al. Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose schedule compared with the licensed 3-dose schedule: results from a randomized study. Hum Vaccines. 2011;7:1374-86.^] (2011/3)	RCT phase I/II, PB; 2 vs. 3 doses of divalent HPV	2 Doses FOR20/20 M0/6 (n=240); 2 doses FOR40/40 M0/6 (n=241); 2 doses FOR40/40 M0/2 (n=240); 3 doses FOR20/20 0/1/6 (n=239)	F (9–25 yrs)	–
Garland et al. ^[³²32 Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007;356:1928-43.^] (2007/5)	RCT, DB, PC, MULTI	HPV QV (n=2673) vs. Placebo (n=2672)	F (16–24 yrs)	Local pain, erythema, edema and local pruritus, fever >38.9 °C, bronchospasm
Petäjä et al. ^[⁴¹41 Petäjä T, Pedersen C, Poder A, et al. Long-term persistence of systemic and mucosal immune response to HPV-16/18 AS04-adjuvanted vaccine in preteen/adolescent girls and young women. Int J Cancer. 2011;129:2147-57.^] (2011/3)	RCT phase III, MULTI	HPV DV (n=616)	F (10–25 yrs)	–
Esposito et al. ^[⁴²42 Esposito S, Birlutiu V, Jarcuska P, et al. Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted vaccine administered according to an alternative dosing schedule compared with the standard dosing schedule in healthy women aged 15 to 25 years: results from a randomized study. Pediatr Infect Dis J. 2011;30:e49-55.^] (2011/3)	RCT, standard schedule (0/1/6 m) vs. alternative (0/1/12 m)	HPV DV standard (n=1195) vs. HPV DV alternative (n=1188)	F (15–25 yrs)	–
Kang et al. ^[⁴³43 Kang S, Kim KH, Kim YT, et al. Safety and immunogenicity of a vaccine targeting human papillomavirus types 6, 11, 16 and 18: a randomized, placebo-controlled trial in 176 Korean subjects. Int J Gynecol Cancer. 2007;18:1013-9.^] (2008/5)	RCT, DB, PC	HPV QV (n=117) vs. Placebo (n=59)	F (9–23 yrs)	Local pain, erythema, edema and fever
Li et al. ^[⁴⁴44 Li R, Li Y, Radley D, et al. Safety and immunogenicity of a vaccine targeting human papillomavirus types 6, 11, 16 and 18: a randomized, double-blind, placebo-controlled trial in Chinese males and females. Vaccine. 2012;30:4284-91.^] (2011/3)	RCT, DB, PC	HPV QV (n=302) vs. Placebo (n=298)	M (9–15 yrs) and F (9–45 yrs)	Local pain, edema and pruritus

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[1] * Corresponding author. E-mail:plsc.fcms@gmail.com (P.L.S. Coelho).