Quadrivalent HPV vaccine safety review and safety monitoring plans for nine-valent HPV vaccine in the United States

Figures & data

Table 1. Post-licensure published quadrivalent human papillomavirus vaccine (4vHPV) safety studies.

System or review (country)	Year of Publication	Number of doses evaluated	Type of concern addressed	Description	Methods	Findings
VAERS (US)^a	2009	N/A	General safety	Summary of 12,424 VAERS reports following 4vHPV between 2006–2008	Spontaneous reporting; data mining for disproportional reporting	Disproportional reporting of syncope and VTE
Vaccine Safety Datalink (US)^b	2011	600,558	General safety	Large database used for active surveillance and research; safety assessment of 9 pre-specified health outcomes among females vaccine recipients aged 9–26 years	Cohort design with weekly sequential analyses of electronic medical data	No statistically significant increase in risk for the outcomes monitored; non-significant elevated risk detected for VTE
Institute of Medicine review (US)^c	2011	N/A	Review of safety data	Review of available 4vHPV safety data	Review of published studies, case reports, and surveillance systems	No evidence to support association among 12 outcomes; anaphylaxis causally associated with 4vHPV; syncope associated with all injectables
Post-marketing commitment to FDA (US)^d	2012	346,972	General safety, VTE, neurologic, death	General assessment of safety following routine administration of 4vHPV at two large managed care organizations	Self-controlled risk interval design supplemented with medical record review	4vHPV associated with syncope on the day of vaccination and skin infections in the two weeks after vaccination; no other vaccine safety signals detected
Post-marketing commitment to FDA (US)^e	2012	346,972	Autoimmune	Assessment of 16 pre-specified autoimmune conditions following routine use of 4vHPV at two large managed care organizations	Retrospective cohort using electronic medical data, supplemented with medical record review	No confirmed safety signals for monitored conditions
VAERS (US)^f	2013	N/A	General safety	Review of 21,194 VAERS reports following 4vHPV between 2006–2013	Spontaneous reporting; data mining for disproportional reporting	No disproportional reporting observed; no new concerns
Register-based cohort study (Denmark and Sweden)^g	2013	696,420	Autoimmune, Neurologic, VTE	Assessment of 23 different autoimmune, 5 neurologic conditions, and VTE following 4vHPV among females aged 10–17 years	Retrospective cohort using national patient registers	No consistent evidence of causal association between 4vHPV and the events monitored
VAERS (US)^h	2014	N/A	General safety	Review of 25,176 VAERS reports following 4vHPV between 2006–2014	Spontaneous reporting; data mining for disproportional reporting	No disproportional reporting observed; no new concerns
Pharmacoepidemiologic General Research Extension (France)^i	2014	N/A	Autoimmune	Assessment of 6 different autoimmune outcomes following 4vHPV among 211 cases and 875 controls aged 14–26 years	Case-control study with recruitment of cases and controls through registries	No increased risk for combined endpoint of six autoimmune disorders
Register-based cohort study (Denmark)^j	2014	500,345	VTE	Assessment of VTE following 4vHPV among women aged 10–44 years	Self-controlled case series using national patient registers	No increased risk for VTE
Register-based cohort study (Denmark and Sweden)^k	2015	1,927,581	Autoimmune	Assessment of multiple sclerosis and other demyelinating diseases of the central nervous system among females aged 10–44 years	Cohort design using data linked to national registers	No association with the development of multiple sclerosis and other demyelinating diseases
Vaccine Safety Datalink (US)^l	2015	1, 240, 000	VTE	Assessment of VTE among adolescents and young adults aged 9–26 years	Self-controlled case series; cases confirmed by medical record review	No increase risk for VTE
Sentinel System (US)^m	2015	1,423,399	VTE	Assessment of VTE among females aged 9–26 years	Self-controlled risk interval design; cases confirmed by medical record review	No increased risk for VTE
VAERS (US)^n	2015	N/A	Neurologic	Review of 21 CRPS-related VAERS reports following 4vHPV between 2006 and 2015	Spontaneous reporting; clinical review of CRPS cases	Lack of evidence to suggest an association; data suggest CRPS following HPV vaccine is rare
Post-marketing commitment to FDA (US)^o	2015	N/A	Pregnancy	Review of 4,919 reports of pregnancy following 4vHPV between 2006–2012	Voluntary reporting to pregnancy registry	Data were reassuring with no elevated reporting of adverse pregnancy outcomes
VAERS (US)^p	2015	N/A	Pregnancy	Review of 147 VAERS pregnancy reports following 4vHPV between 2006 and 2013	Spontaneous reporting; data mining for disproportional reporting	No unexpected patterns fetal adverse events after 4vHPV
Vaccine Safety Datalink (US)^q	2016	1,355,535	Death	Evaluation of deaths among individuals aged 9–26 years	Case-centered method; medical record review	Rate of death was lower than the national expected rate of death in this population

Abbreviations

CRPS- Chronic Regional Pain Syndrome, FDA- Food and Drug Administration, HIV- Human immunodeficiency virus, 4vHPV- Quadrivalent Human Papillomavirus vaccine, VAERS- Vaccine Adverse Event Reporting System, VTE- Venous thromboembolism

Sources

^a Slade, B.A., et al., Post-licensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA, 2009. 302(7): p. 750–757.

^b Gee, J., et al., Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink. Vaccine, 2011. 29(46): p. 8279–8284.

^c Institute of Medicine. Adverse Effects of Vaccines: Evidence and Causality. 2011.

^d Klein, N.P., et al., Safety of quadrivalent human papillomavirus vaccine administered routinely to females. Arch Pediatr Adolesc Med, 2012. 166(12): p. 1140–8.

^e Chao, C., et al., Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine. J Intern Med, 2012. 271(2): p. 193–203.

^f Stokley S, et al., Human Papillomavirus Vaccination Coverage Among Adolescent Girls, 2007–2012, and Postlicensure Vaccine Safety Monitoring, 2006–2013 — United States. MMWR Recomm Rep, 2013. 62(29); p. 591–595

^g Arnheim-Dahlstrom, L., et al., Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study. BMJ, 2013. 347: p. f5906.

^h Stokley S, et al., Human papillomavirus vaccination coverage among adolescent girls, 2007–2012, and post-licensure vaccine safety monitoring, 2006–2013 — United States. MMWR Recomm Rep. 2014. 63(29); p. 620–4.

ⁱ Grimaldi-Bensouda, L., et al., Autoimmune disorders and quadrivalent human papissllomavirus vaccination of young female subjects. J Intern Med, 2014. 275(4): p. 398–408.

^j Scheller, N.M., et al., Quadrivalent human papillomavirus vaccine and the risk of venous thromboembolism. JAMA, 2014. 312(2): p. 187–8.

^k Scheller, N.M., et al., Quadrivalent HPV vaccination and risk of multiple sclerosis and other demyelinating diseases of the central nervous system. JAMA, 2015. 313(1): p. 54–61.

^l Naleway, A.L., et al., Absence of venous thromboembolism risk following quadrivalent human papillomavirus vaccination, Vaccine Safety Datalink, 2008–2011. Vaccine, 2016; 34(1): p. 167–71.

^m Yih, W.K., et al., Evaluation of the risk of venous thromboembolism after quadrivalent human papillomavirus vaccination among US females. Vaccine, 2016; 34(1): p. 172–8.

ⁿ Weinbaum C, et al.. HPV Vaccination and Complex Regional Pain Syndrome: Lack of Evidence. EBioMed, 2015. 2(9): p. 1014–1015.

^o Goss, M.A., et al., Final report on exposure during pregnancy from a pregnancy registry for quadrivalent human papillomavirus vaccine. Vaccine, 2015. 33(29): p. 3422–8.

^p Moro, P.L., et al., Safety of quadrivalent human papillomavirus vaccine (Gardasil) in pregnancy: adverse events among non-manufacturer reports in the Vaccine Adverse Event Reporting System, 2006–2013. Vaccine, 2015. 33(4): p. 519–22.

^q McCarthy, N.L., et al. Lack of association between vaccination and death in individuals 9–26 years of age. Pediatrics, 2016; 137(3): p. 1–8.

Table 2. Post-licensure clinical trials of the safety of quadrivalent human papillomavirus vaccine (4vHPV) among HIV-infected persons.

Year of Publication	Description	Methods	Findings
2010^a	Assessment of safety of 4vHPV among 126 HIV-infected children 7–12 years	Randomized, placebo-controlled, double-blinded study; observation post-vaccination; diary cards and telephone response	Adverse events were similar between treatment arms
2010^b	Assessment of safety of 4vHPV among 112 HIV-infected men 18 years and older	Single arm, open label, multicenter clinical trial; clinical assessment post vaccination and at defined time points; diary card	No severe adverse events related to vaccination
2013^c	Assessment of safety of 4vHPV among 99 HIV-infected women 16–23 years	Open-label, multicenter clinical trial; clinical assessment post-vaccination and at defined time points; diary card and telephone response	4vHPV well tolerated; pain most common report
2014^d	Assessment of safety of 4vHPV among 319 HIV-infected women 13–45 years	International phase 2, open label, single-arm study with stratification by CD4+ cell count; clinical assessments post vaccination and at defined time points	No significant safety issues observed
2014^e	Assessment of safety of 4vHPV among 46 HIV-infected and 46 HIV-uninfected males and females aged 13–27 years	Non-randomized, open label clinical trial; observation post-vaccination; diary card	4vHPV safe and well tolerated among HIV-infected and HIV-uninfected participants
2014^f	Assessment of the safety of 4vHPV versus 2vHPV among 92 HIV-infected men and women	Randomized, double-blind, head-to-head clinical trial of 2vHPV and 4vHPV	No serious adverse events were detected; both vaccines were well tolerated with very few mild systemic reactions observed

Abbreviation: HIV- Human immunodeficiency virus; 2vHPV- bivalent human papillomavirus vaccine

Sources:

^a Levin, M.J., et al., Safety and immunogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine in HIV-infected children 7 to 12 years old. J Acquir Immune Defic Syndr, 2010. 55(2): p. 197–204.

^b Wilkin, T., et al., Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in HIV-1-infected men. J Infect Dis, 2010. 202(8): p. 1246–53.

^c Kahn, J.A., et al., Immunogenicity and safety of the human papillomavirus 6, 11, 16, 18 vaccine in HIV-infected young women. Clin Infect Dis, 2013. 57(5): p. 735–44.

^d Kojic, E.M., et al., Immunogenicity and safety of the quadrivalent human papillomavirus vaccine in HIV-1-infected women. Clin Infect Dis, 2014. 59(1): p. 127–35.

^e Giacomet V., et al., Safety and immunogenicity of a quadrivalent human papillomavirus vaccine in HIV-infected and HIV-negative adolescents and young adults. Vaccine. 2014; 32(43): p. 5657–61.

^f Toft L., et al., Comparison of the immunogenicity and reactogenicity of Cervarix and Gardasil human papillomavirus vaccines in HIV-1 infected adults: a randomized, double-blind clinical trial. J Infect Dis. 2014; 209 (8): p. 1165–73.