Table 4.

Post-surveillance studies on human papilloma virus vaccines safety.

Author	Title	Year of publication	Type of study	Place	Population	Vaccine type	Results
							AE	SAE
Angelo et al. [55]	Pooled analysis of large and long-term safety data from the human papillomavirus-16/18-AS04-adjuvanted vaccine clinical trial programme.	2014	Post-licensure passive surveillance	UK		HPV16/18	Ten most frequent AEs are non-serious AE and representing 86% of all reports	No specific safety concern identified from more than 4 years of HPV16/18 vaccine use in routine clinical practice
Markowitz et al. [10]	Human Papillomavirus Vaccination Recommendations of the advisory committee on immunization practices (ACIP)	2014	VAERS passive surveillance data	USA	18.083 person (male and female)for qHPVv and different pooled of safety analysis (from 12,000 to 57,323 females) for bHPVv	HPV16/18 and HPV6/11/16/18	qHPVv: Pain 83% of women and 61.4% men in vaccine group, 62% of women and 46.2% of men in control group. Systemic clinical AEs were reported by similar proportion of vaccine and control groups among both females and males. bHPVv: pain 91.9% in vaccine group and 76,5% in control group, redness 25.7% in vaccine group and 25.7% in control group, swelling 44.3% in vaccine group and 19.5% in control group. No differences were observed between the two groups for general symptoms	qHPVv: < 0.1% of person suffered serious AEs. bHPVv 5.3%in vaccine group and 5.9% in control group. New autoimmune disorder incidence was 0.8% in both groups. None of the deaths reported was considered to be vaccine-related
Harris et al. [68]	Adverse events following immunization in Ontario’s female school-based HPV program	2014	Reports of confirmed AEs following immunization	Canada	Over the reporting period 691,994 vaccine doses were distributed	HPV6/11/16/18	213 HPV4 vaccine AEFI reports. In total there were 152 AEs associated with the 133 individual qHPVv vaccine AEFI reports. The majority of reports included a single AE (114/133; 86%) and the remaining included two or more distinct events (14%,19/133). The most frequently reported AEs were allergic reaction–dermatologic/mucosa’ (25%), ‘rash’ (22%), and local/injection site reaction’ (20%).	26% of reports had a non-specific event of ‘other severe/unusual events’ selected. Among 133 confirmed qHPVv vaccine AEFI reports, 7.5% (n = 10) were serious including two reports of anaphylaxis, two reports of seizure, one report of thrombocytopenia and one report of death (cardiac condition was responsible)
Levi et al. [60]	Evaluation of bivalent human papillomavirus (HPV) vaccine safety and tolerability in a sample of 25 year old Tuscan women	2013	Post marketing monitoring	Italy	271 participants	HPV16/18	The most frequently reported adverse reaction proved to be pain at the site of injection (83.4% of doses), followed by local swelling (20.8%) and pyrexia (14.6%).	No severe symptoms were registered.
Labadie [63]	Post licensure safety evaluation of human papillomavirus vaccine	2012	Passive surveillance from VigiBase, VAERS and RIVM databases	Global safety surveillance	/	HPV16/18 and HPV6/11/16/18	qHPVv: Syncope was the most reported symptom both in VARES (15%), in VigiBase the incidence was 12%. Local reaction was described in 14% of reports in VARES and 18% in VigiBase. bHPVv Local reaction were the most reported symptoms (16.2%) in RIVM and (12.8%) in VigiBase, followed by Syncope 8.7% in RIVM and 8.7% in Vigibase. Headache was frequently reported in VigiBase database: 21.1% of all reports	For all databases and for both vaccines SAE were reported in < 1% of cases, except for hypersensitivity reaction and urticaria that were between 1% and 4%, and Venus thromboembolic event that was reported in 1.5% of subjects who received bHPVv
Gold et al. [9]	Human papillomavirus vaccine safety in Australia: experience to date and issues for surveillance	2011	Surveillance	Australia	1394 reports of suspected AEFI on > 5.8 million doses of vaccine	HPV6/11/16/18	A total of 1394 suspected AEs following immunization (AEFI) have been reported. Most reports are of common and expected reactions.	Case series of more uncommon and serious AEs, both known to be potentially vaccine related (anaphylaxis, conversion disorders and lipoatrophy) and otherwise (multiple sclerosis and pancreatitis) have been published.
Gee et al. [64]	Monitoring the safety of quadrivalent human papillomavirus vaccine: Findings from the Vaccine Safety Datalink	2011	Prospective cohort study (prespecified AEs were selected based on safety data from prelicensure clinical trials)	US	600,558 females	HPV6/11/16/18	/	No statistically significant increased risk for the outcomes studied (Guillan-Barre’ syndrome, stroke, venous thromboembolism (VTE), appendicitis, seizures, syncope, allergic reaction and anaphylaxis. For venous thromboembolism an elevated risk of 1.98 among the youth could be observed.
Slade et al. [62]	Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine	2009	Post-licensure passive surveillance	US	More than 23 million doses distributed. 12,424 AEFI reports	HPV6/11/16/18	Most common local reaction reports included injection site pain (53%), erythema (28%) and swelling (22%). Syncope was the most frequent general SAE (74% of reports)	Disproportional reporting of venous thromboembolic events was noted.

AE: Adverse event; AEFI: Adverse events following immunization; bHPVv: Bivalent HPV vaccine; qHPVv: Quadrivalent HPV vaccine; SAE: Serious adverse event.