Strategies for continuous evaluation of the benefit–risk profile of HPV-16/18-AS04-adjuvanted vaccine

Figures & data

Figure 1. Determinants of the HPV-16/18-vaccine benefit–risk with highlights of investigative strategies.

Table 1. Summary of post-licensure studies to evaluate the benefit–risk of HPV-16/18-vaccination.

Study number (country)	Design	Population	Primary end points	Secondary end points	Status	Results anticipated	Ref.
NCT01953822/116239 (UK)	Observational cohort study (CPRD GOLD)	Women aged 9–25 years	Neuro-inflammatory/ophthalmic autoimmune diseases and other autoimmune diseases within 12 months following the first HPV-16/18-vaccine dose	Specific autoimmune diseases within 2, 6 and 12 months of vaccination with HPV-16/18-vaccine	Ongoing	2015	[53]
NCT01905462/114101 (UK)	Observational cohort study (CPRD GOLD)	Women aged 15–25 years	Spontaneous abortion during weeks 1–23 of gestation with the first day of the LMP -30 to +45 days after any dose of HPV-16/18-vaccine	Spontaneous abortion: weeks 1–23 (and 1–19) with a risk window of exposure of –30 to +45 (and –30 to +90) days. Other pregnancy outcomes	Completed	In analysis	[55]
NCT00586339/107863 (South Africa)	RCT	HIV+ (WHO stage I) and HIV– women aged 18–25 years	Safety and reactogenicity, CD4^+ T-cell counts and viral load, immunogenicity and cell-mediated immune responses to month 12	Not applicable	Completed	Available	[22]
NCT01031069/109823 (India, Thailand, Brazil)	RCT	HIV+ and HIV– women aged 15–25 years	Safety and reactogenicity, Non-inferiority (and then superiority) of HPV-16/18-vaccine to HPV-6/11/16/18-vaccine in terms of HPV-16/18 GMTs in HIV+ women	Superiority of HPV-16/18-vaccine to HPV-6/11/16/18-vaccine in terms of HPV-16/18 GMTs in HIV– women. Persistence of the immune response until month 24. Cell-mediated immune responses until month 12	Ongoing	2014	[23]
NCT00534638/106636 (Finland)	Community-RCT	Healthy females and males aged 12–15 years	Demonstration of direct and indirect effectiveness against HPV-16/18 prevalence at 18.5 years of age following community-based vaccination of a) only females b) females and males	Cross-protection, safety, immunogenicity (tertiary end points: herd protection, descriptive epidemiology of type-specific infections, CIN3+, risk factors for breakthrough infection, oropharyngeal infection	Recruitment complete	2015	[31]
NCT00369824/107682 (USA)	Open RCT	Healthy girls aged 11–18 years	Non-inferiority in terms of immunogenicity when HPV-16/18-vaccine was co-administered with Boostrix™ or Menactra™	Non-inferiority in terms of immunogenicity Safety and reactogenicity	Completed	Available	[28]
NCT00652938/111507 (The Netherlands, Sweden)	Open RCT	Healthy girls aged 9–15 years	Non-inferiority in terms of immunogenicity when HPV-16/18-vaccine was co-administered with Engerix™ B	Immunogenicity, safety and reactogenicity	Completed	Available	[29]
NCT00426361/108464 (Spain, Germany, France)	Open RCT	Healthy girls aged 9–15 years	Non-inferiority in terms of immunogenicity when HPV-16/18-vaccine was co-administered with Boostrix™polio	Immunogenicity, safety and reactogenicity	Completed	Available	[27]
NCT00578227/110886 (Canada, Denmark, Hungary, Sweden)	Open RCT	Healthy girls aged 9–15 years	Non-inferiority in terms of immunogenicity when HPV-16/18-vaccine was co-administered with Twinrix™	Immunogenicity, safety and reactogenicity	Completed	Available	[26]

CRPD: Clinical practice research datalink general practitioner online database; RCT: Randomized controlled trial.

Table 2. Summary of post-licensure national surveillance activities to evaluate the benefit–risk of HPV-16/18-vaccination.

Study number (country)	Design	Population	Primary end points	Secondary endpoint	Status	Results anticipated
National surveillance
PHE national HPV surveillance		Females 16–24 years	Type-specific HPV infections	Not applicable	Ongoing	2015
		Samples from females aged 25 years undergoing routine cervical screening	Type-specific infections (by cytology/histology)	Assessment of vaccine failures	Planned	Pending
RIVM 09/022 (The Netherlands)	Longitudinal observational study (5 years)	Females born in 1993	Impact of HPV-16/18-vaccine on HPV infections and epigenetic alterations suggestive of high-grade CIN lesions	Gain insight into immune mechanisms of infection and vaccination	Ongoing	2014

CIN: Cervical intraepithelial neoplasia; PHE: Public Health England; RIVM: National Institute for Public Health and the Environment.

Study assessing risk of autoimmune diseases in females (9–25 Years) exposed to Cervarix® in United Kingdom. Available from: http://clinicaltrials.gov/show/NCT01953822

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Post-marketing safety study to assess the risk of spontaneous abortions in women exposed to Cervarix residing in UK. Available from: http://clinicaltrials.gov/show/NCT01905462

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Evaluation of safety and immunogenicity of a human papillomavirus (HPV) vaccine in human immunodeficiency virus (HIV) infected females. Available from: http://clinicaltrials.gov/show/NCT01031069

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