Long-term efficacy and safety of human papillomavirus vaccination

Figures & data

Table 1 Anti-HPV-vaccine types and characteristics

	Quadrivalent vaccine (qHPV)	Bivalent vaccine (bHPV)
Commercial name and HPV types	Gardasil^®	Cervarix^®
	HPV 6/11/16/18	HPV 16/18
Administration schedule	9–13 years: 0, 6 months	9–14 years: 0, 6 months
	Over 13 years: 0, 2, 6 months	Over 14 years: 0, 1, 6 months
VLP dose and producer cells	L1 dose 20/40/40/20 μg	L1 dose 20/20 μg
	Saccharomyces cerevisiae (baker’s yeast) expressing L1	Trichoplusia ni (Hi 5) insect cell line infected with L1 recombinant baculovirus
Adjuvant	225 μg aluminum hydroxyphosphate sulfate (ASO4)	500 μg aluminum hydroxide, 50 μg 3-O-deacylated-4-monophosphoryl lipid A (MPLA)

Notes: Gardasil^® (Merck and Co., Whitehouse Station, NJ USA). Cervarix^® (GlaxoSmithKline plc, London, UK).

Abbreviations: HPV, human papillomavirus; VLP, virus-like particle.

Table 2 Long-term studies on quadrivalent vaccine (qHPV)

Study	Study subjects	Efficacy	Seropositivity	Follow-up
P007 (villa et al^Citation28)	Young women (age 16–23 years)	No cases of HPV 6/11/16/18-related CIN	Maintained up to 5 years	5 years
Nordic Study P015 (Nygard et al^Citation29)	Young women (age 16–23 years)	No cases of HPV 6/11/16/18-related CIN	Trend up to 9 years	8 years
Extension P018 (Iversen^Citation32)	Females and males (age 9–15 years)	No cases of HPV 6/11/16/18-related CIN	Maintained up to 8 years	6.8 years
Extension P019 (Luna et al^Citation35)	Adult women (age 24–45 years)	One case of HPV 6/11/16/18-related CIN	Maintained up to 6 years	6 years
P020 (Giuliano et al^Citation36)	Males (age 16–26 years)	Three cases of EGLs	–	3 years
P020 – AIN substudy (Palefsky et al^Citation37)	Males – MSM (age 16–26 years)	Five cases of AIN due to HPV 6/11/16/18	–	3 years

Abbreviations: HPV, human papillomavirus; CIN, cervical intraepithelial neoplasia; EGLs, external genital lesions; AIN, anal intraepithelial neoplasia; MSM, men who have sex with men.

Table 3 Long-term studies on bivalent vaccine (bHPV)

Study	Study subjects	Efficacy	Seropositivity	Follow-up
Extension HPV-013 NCT00196924 (Huang et al^Citation38)	Females (age 10–14 years)	–	Maintained up to 7 years	7 years
Extension HPV001/007/023 combined (Naud et al^Citation42)	Young women (age 15–25 years)	No cases in vaccine arm	Maintained up to 9.4 years	9.4 years
NCT00196937 (Schwarz et al^Citation43)	Young and adult women (age 15–55 years)	–	Maintained up to 4 years	4 years
Extension NCT00196937 (Schwarz et al^Citation44)	Young and adult women (age 15–55 years)	–	Maintained up to 7 years	8 years
P 011-NCT00309166 (Petäjä et al^Citation45)	Males (age 10–18 years)	–	Maintained up to 7 months	7 months

Abbreviation: HPV, human papillomavirus.

Figure 1 Long-term clinical efficacy in follow-up studies in naïve populations.

Abbreviations: HPV, human papillomavirus; qHPV, quadrivalent vaccine; bHPV, bivalent vaccine; CI, confidence interval; CIN, cervical intraepithelial neoplasia; NA, not applicable; FU, follow-up; M, months.

Table 4 HPV vaccines: serious AEs in long-term safety evaluation

Study (vaccine type)	Assessment (sample)	End points	Results
Slade et al^Citation55 (qHPV)	Postmarketing US passive surveillance reports (VAERS) (12,424 AE reports/23 million doses)	Syncope, dizziness, nausea, headache, local injection-site reactions, hypersensitivity reactions including anaphylaxis, Guillain–Barré syndrome (GBS), transverse myelitis, pancreatitis, venous thromboembolic events (VTEs), deaths, and pregnancy outcomes	Most AE rates not greater than background rates Syncope was reported with higher frequency, but only in 5% lead to a serious AE
Descamps et al^Citation59 (bHPV)	Pooled analysis of eleven clinical trials (16,142 subjects/45,988 doses)	Serious AEs and medically significant conditions	No difference from placebo group
Gee et al^Citation60 (qHPV)	Longitudinal cohort in seven MCOs (600,558 doses)	GBS, stroke, VTE, appendicitis, anaphylaxis, seizure, syncope, or allergic reaction	No statistically significant increased risk
Chao et al^Citation61 (qHPV)	Longitudinal cohort in two MCOs (189,629 subjects)	Autoimmune conditions	No autoimmune safety signals
Klein et al^Citation62 (qHPV)	Longitudinal cohort in two MCOs (189,629 subjects/346,972 doses), same cohort as Chao et al^Citation61	Emergency department admission and hospitalization	Association with syncope and skin infection, but not with autoimmune diseases and VTEs
Arnheim-Dahlström et al^Citation63 (qHPV)	Register-based cohort study (296,826 subjects/696,420 doses)	Behçet’s syndrome, Raynaud’s disease, and type 1 diabetes; VTEs	No-temporal relationship with Behçet’s, Raynaud’s, or type I diabetes; no association with VTEs
Grimaldi-Bensouda et al^Citation64 (qHPV)	Case-control study (211 cases and 875 matched controls)	Six types of autoimmune disorders (ADs): idiopathic thrombocytopenic purpura, connective tissue disorders, central demyelination and multiple sclerosis (MS), GBS, type 1 diabetes, and thyroid disorders	No evidence of an increase in the risk of the studied ADs, except for a lower OR for central demyelination/MS
Angelo et al^Citation58 (bHPV)	Pooled analysis of AEs in 42 clinical trials (31,173 subjects/96,704 doses)	Spontaneous abortion, appendicitis	No differences of incidence and distribution with placebo group. No increased risk of any immunologic disease
Naud et al^Citation42 (bHPV)	Clinical trial safety extension study (224 subjects)	Adverse events, chronic and autoimmune diseases: five cases each for gastritis, spontaneous abortion, depression, and hypertension; two cases of hypothyroidism; one case each for rheumatoid arthritis and vitiligo	No difference with placebo group

Abbreviations: HPV, human papillomavirus; qHPV, quadrivalent vaccine; AE, adverse event; VAERS, Vaccine Adverse Event Reporting System; MCOs, managed care organizations; OR, odds ratio; bHPV, bivalent vaccine.

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