Safety of human papillomavirus vaccines: a review

Figures & data

Table 1. Product information.

Name of the medicinal product	Cervarix®				Gardasil®/Silgard®
Producer	GlaxoSmithKline Biologics				Sanofi Pasteur MSD/Merck Sharp & Dohme
Qualitative and Quantitative composition	1 dose (0.5 ml) contains				1 dose (0.5 ml) contains approximately
	Human papillomavirus type 16 L1 protein			20 micrograms	Human papillomavirus type 6 L1 protein			20 micrograms
	Human papillomavirus type 18 L1 protein			20 micrograms	Human papillomavirus type 11 L1 protein			40 micrograms
	2 adjuvanted by AS04 containing: 3-O-desacyl-4’- monophosphoryl lipid A (MPL)			50 micrograms	Human papillomavirus type 16 L1 protein			40 micrograms
	Adsorbed on aluminium hydroxide, hydrated (Al(OH)3)			0.5 milligrams Al3+ in total	Human papillomavirus type 18 L1 protein			20 micrograms
					Adsorbed on amorphous aluminium hydroxyphosphate sulfate adjuvant.			0.225 milligrams Al
Pharmaceutical form	Suspension for injection. Turbid white suspension.				Suspension for injection. After thorough agitation, it is a white, cloudy liquid
Posology: age at the time of first injection and immunization schedule	EMA	FDA	TGA	PHAC	EMA	FDA	TGA	PHAC
	9 to and including 14 years = Two doses each of 0.5 ml at 0, 6 months From 15 years and above = Three doses each of 0,5 ml at 0, 1, 6 months	9 – 25 years of age = Three doses each of 0.5 ml at 0, 1, 6 months	Female from 10 – 45 years of age = Three doses each of 0.5 ml at 0, 1, 6 months	Recommended for females aged 9 – 26 years of age; may be administered to female over 26 years of age = Three doses each of 0.5 ml at 0, 1, 6 months	9 to and including 13 years of age = Two doses each of 0.5 ml at 0, 6 months From 14 years and above = Three doses each of 0,5 ml at 0, 2, 6, months	9 – 26 year of age = Three doses each of 0.5 ml at 0, 2, 6 months	Females aged 9 – 45 years and males aged 9 – 26 years = Three doses each of 0.5 ml at 0,2,6 months	Recommended for: females aged 9 – 26 years of age, males between 9 and 26 years of age. May be administered to female over 26 years of age = Three doses each of 0.5 ml at 0, 2, 6 months
Method of administration	Intramuscular injection				Intramuscular injection
Contraindications	Hypersensitivity to the active substances or to any of the excipients				Hypersensitivity to the active substances or to any of the excipients

EMA: European medicines agency; FDA: US food and drug administration; PHAC: Public health agency of Canada; TGA: Australian government department of Health - therapeutic goods administration.

Table 2. Characteristics of Phase II/III randomized control trials included in Lu et al. [39].

	FUTURE I [104]		FUTURE II [46]		PATRICIA [105]		Muñoz [35]		Koutsky and Mao 106, 107		Harper [27]		Villa [30]
Vaccine	Gardasil®		Gardasil®		Cervarix®		Gardasil®		Cervarix®		Cervarix®		Gardasil®
Phase	III		III		III		III		III		III		II
Funding source	Merk		Merk		GlaxoSmithKline		Merk		Merk		GlaxoSmithKline		Merk
No. study sites	62		90		135		38		16		32		5
Countries included	16		13		14		7		1		3		5
Control	225 µg Aluminium hydroxyphosphate sulfate		225 µg Aluminium hydroxyphosphate sulfate		Hepatitis A vaccine		Placebo		Placebo		Placebo		Placebo
Age	16 – 24		15 – 26		15 – 25		24 – 45		16 – 25		15 – 25		16 – 23
	Case (2673)	Control (2672)	Case (6019)	Control (6031)	Case (9319)	Control (9325)	Case (1908)	Control (1902)	Case (1194)	Control (1198)	Case (531)	Control (538)	Case (272)	Control (274)
Injection-related SAE	1	0	3	2	11	6	0	0	0	0	0	0	0	0
Risk ratio	3.0 (0.12,73.58)		1.50 (0.25,8.99)		1.83 (0.68,4.96)		Not estimable		Not estimable		Not estimable		Not estimable
SAE	48	45	45	54	701	699	3	7	4	3	22	19	2	2
Risk ratio	1.07 (0.71,1.60)		0.83 (0.56,1.24)		1.17 (0.64,2.14)		0.43 (0.11,1.65)		1.34 (0.30,5.96)		1.17 (0.64,2.14)		1.01 (0.91,1.09)

Table 3. Human papilloma virus vaccines safety reviews.

Author	Title	Year of publication	Type of study	Place	Population	Vaccine type	Results
							AE	SAE
Weber et al. [42]	Childhood vaccination-associated adverse events by sex: A literature review	2014	Review		12 studies	HPV16/18 and HPV6/11/16/18	The most frequent local adverse event was injection-site pain, the incidence of adverse events did not increase with increasing number of doses	No specific safety concern identified except for the Gee et al. [64] observation of an elevated risk of 1.98 for venous thromboembolism
Macartney et al. [41]	Safety of human papillomavirus vaccines: a review	2013	Review	/	/	HPV16/18 and HPV6/11/16/18	Injection-site adverse reaction (especially pain) and mild self-limited systemic symptoms (such as myalgia and headache) occur commonly after vaccination and should be anticipated. Some of these symptoms are more common in bHPVv	Consistent with the findings of the review no evidence supported an association of HPV vaccine with other outcomes, such new onset chronic diseases
Block et al. [43]	Clinical trial and post-licensure safety profile of a prophylactic Human Papillomavirus (types 6, 11, 16 and 18) L1 virus-like particle vaccine	2010	Review of five clinical trials	/	21,480 girls and boys	HPV6/11/16/18	Pain, the most common injection-site AE, occurred more frequently with vaccine (81% vaccine; 75% placebo aluminum; 45% placebo-saline). No differences were seen in the incidence of the most common non-serious AEs–headache and pyrexia	SAE occurred in 0.05% in vaccine group ad in 0.02% in placebo group. Of 18 deaths (0.1% vaccine; 0.1% placebo), all were considered unrelated to study treatment. New medical conditions which were potentially consistent with autoimmune phenomena were reported in 2.4% of both vaccine and placebo recipients
Agorastos et al. [40]	Safety of human papillomavirus (HPV) vaccines: A review of the international experience so far	2009	Review based on national and international agencies	US, Canada, Australia, Europe, Germany, France, UK		HPV6/11/16/18 and HPV16/18	Pre-licensure data: Injection site symptoms were the most reported symptoms in one of the studies they were reported more frequently in the vaccine group than in the control group. General symptoms was slightly higher in the vaccine group	Almost all the case-reports of SAE had weak or moderate strength of evidence for causality

AE: Adverse event; bHPVv: Bivalent HPV vaccine; SAE: Serious adverse event.

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.

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