ReviewApproaches to monitoring biological outcomes for HPV vaccination: Challenges of early adopter countries☆
Introduction
Two prophylactic human papillomavirus (HPV) vaccines are currently available worldwide: a bivalent vaccine (HPV 16 and 18), and a quadrivalent vaccine (HPV 6, 11, 16, and 18). Randomized controlled trials conducted on several continents have demonstrated that these vaccines are highly efficacious in preventing vaccine-type high grade cervical intraepithelial neoplasia (CIN 2/3) [1], [2], [3], [4], [5], [6]. In addition, the quadrivalent vaccine has been shown to prevent vaccine-type vaginal and vulvar intraepithelial neoplasia and external genital lesions, including genital warts, in women and men [6], [7]. Worldwide, over 493,000 cervical cancers occur every year, most in settings where there is limited or no cervical cancer screening [8]. Current HPV vaccines have the potential to significantly reduce the burden of HPV-associated conditions, including prevention of up to 70% of cervical cancers [9].
The HPV vaccines have been licensed in over 100 countries and incorporated into national immunization programs in many high-income countries (as well as some low and middle-income countries) [10]. In April 2009, the World Health Organization (WHO) recommended inclusion of HPV vaccination in national immunization programs where cervical cancer and HPV-related disease are a public health priority and where vaccine introduction is feasible, sustainable financing secured, and cost-effectiveness considered [11]. In May and July 2009, respectively, both the quadrivalent vaccine and bivalent vaccine were awarded WHO pre-qualification, which denotes vaccine eligibility for procurement by organizations, such as United Nations Children's Fund (UNICEF) or Pan American Health Organization Revolving Fund, for use in national immunization programs [12]. In 2009, the Global Alliance for Vaccines and Immunization (GAVI) stated that it aims to make the HPV vaccine available to girls in developing nations, pending available funding [13].
With the WHO recommendation and pre-qualification status, implementation of HPV vaccine is expected to increase worldwide, although high cost and unique implementation challenges continue to impede HPV vaccine introduction in resource-constrained settings with competing public health priorities [14]. Along with addressing the challenges for vaccine implementation, a strategy for monitoring the impact of HPV vaccine on biologic outcomes merits discussion and planning [15], [16], [17], [18], [19], [20]. Impact monitoring cannot be interpreted without coverage and safety data; these components of comprehensive vaccine monitoring are addressed elsewhere [21], [22] and in a recent WHO technical guidance document on monitoring HPV vaccine coverage [23]. Thus, here, ‘vaccine impact monitoring’ refers to the monitoring of biologic outcomes.
For HPV vaccine impact monitoring, biologic outcomes include HPV infection and HPV-associated diseases. Each biologic endpoint has its own opportunities and challenges [16], [18], [19], [20], [24], [25], [26], [27], and the most appropriate outcomes to monitor, if any, may differ by setting. Cervical cancer develops in steps: HPV infection of the cervical epithelium, persistence of the infection, progression of the persistently infected epithelium to cervical intraepithelial neoplasia (CIN), and invasion through the basement membrane to result in invasive cervical cancer [28]. Hence, cervical cancer and high- and low-grade CIN lesions are outcomes that may be monitored. Vaccines directed against HPV types 16 and 18 also have the potential to reduce other HPV-associated cancers (vulvar, vaginal, anal, penile, and oropharyngeal). Anogenital warts and recurrent respiratory papillomatosis (RRP) are biologic outcomes that can be monitored in men and women for vaccines that prevent HPV types 6 and 11.
For several reasons, the ideal approach for monitoring vaccine impact must be carefully considered where HPV vaccine implementation is ongoing or soon will be. According to the WHO, surveillance of HPV outcomes is not a prerequisite to initiate HPV vaccination programs; however, monitoring, particularly for HPV infection and cervical cancer, should be considered [23]. Well done impact monitoring across each global region in at least some areas that have achieved a range of HPV vaccine coverage would be desirable for the benefit of all countries. Surveillance data for HPV-associated diseases collected at local or regional levels may help garner political will and public support in favor of implementation and sustain vaccination program policies by demonstrating HPV-associated disease burden. Baseline data may also establish benchmarks for monitoring vaccine impact [19]. In the present paper, we describe plans to monitor HPV vaccine impact on biologic outcomes in selected areas internationally (Australia, Canada, Mexico, Scotland, the Nordic countries, and the United States) as background for discussing the challenges of monitoring in settings where resources and capacity may vary.
Section snippets
Methods
From February to May 2009, 22 key stakeholders involved in HPV vaccination and/or cervical cancer from low-, middle- and high-resource countries were identified by the co-authors (MS, ED, SH) and interviewed (CW, MS, ED, SH) regarding vaccine monitoring activities. Additional information sources, including published manuscripts, unpublished documents, health ministry websites, press releases, plus websites and documents from public health authorities such as the WHO, were reviewed. Information
Summary of monitoring plans from selected jurisdictions
HPV vaccine implementation, infrastructure, and monitoring plans in selected jurisdictions that adopted HPV vaccine are presented in Table 1 to provide context in which to discuss the challenges of impact monitoring. These settings were chosen because they have developed at least preliminary plans for monitoring impact.
General challenges
Monitoring HPV vaccine impact requires collaboration among several sectors [16], [18], [24]. Diverse experts in vaccination, cancer screening, cancer surveillance, infectious disease, virology, sexually transmitted infection, child and adolescent medicine, reproductive health, and policy-making bodies need to work together to consider the methodological, clinical, and feasibility issues surrounding various biologic outcomes to be monitored. Well-organized technical support and information
Discussion
Monitoring HPV vaccine impact on biologic outcomes is a complex and challenging task. However, it can also play an important role in documenting the benefit of vaccination, monitoring the progress of vaccination programs, and providing data to inform vaccination and disease prevention policies. Comprehensively monitoring vaccine impact at the population level requires a well-established surveillance infrastructure and sustained resources, and therefore may not be feasible in many settings.
Acknowledgements
We would like to thank Dr. Eduardo Franco and Dr. Elizabeth Unger for sharing their presentations from the CDC-sponsored satellite symposium at the 2009 IPV conference. Charlene Wong completed this project during her one-year fellowship The CDC Experience, a public/private partnership supported by a grant to the CDC Foundation from External Medical Affairs, Pfizer Inc.
References (83)
- et al.
Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial
Lancet
(2006) - et al.
Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial
Lancet
(2007) - et al.
Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials
Lancet
(2007) - et al.
Monitoring HPV vaccination
Vaccine
(2008) - et al.
Defining a strategy to evaluate cervical cancer prevention and early detection in the era of HPV vaccination
Prev Med
(2009) - et al.
Safety of human papillomavirus (HPV) vaccines: a review of the international experience so far
Vaccine
(2009) - et al.
Human papillomavirus and cervical cancer
Lancet
(2007) - et al.
A summary of the post-licensure surveillance initiatives for Gardasil/Silgard (R)
Vaccine
(2010) - et al.
Cervical cancer screening following prophylactic human papillomavirus vaccination
Vaccine
(2008) - et al.
Overview of human papillomavirus-based and other novel options for cervical cancer screening in developed and developing countries
Vaccine
(2008)
Editors’ introduction
J Clin Virol
Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis
Lancet Infect Dis
The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women
J Pediatr
WHO meeting on the standardization of HPV assays and the role of the WHO HPV laboratory network in supporting vaccine introduction held on 24–25 January 2008, Geneva, Switzerland
Vaccine
The challenges of organising cervical screening programmes in the 15 old member states of the European Union
Eur J Cancer
Challenges in starting organised screening programmes for cervical cancer in the new member states of the European Union
Eur J Cancer
Palliative aspects of recurrent respiratory papillomatosis
Otolaryngol Clin North Am
The current state of introduction of HPV vaccination into national immunisation schedules in Europe: results of the VENICE 2008 survey
Eur J Cancer
High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up
Br J Cancer
Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions
N Engl J Med
Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases
N Engl J Med
The efficacy of the quadrivalent HPV (types 6/11/16/18) vaccine in reducing the incidence of HPV infection and HPV-related genital disease in young men
Global cancer statistics, 2002
CA Cancer J Clin
Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis
Br J Cancer
Chapter 15: HPV vaccine use in the developing world
Vaccine.
Chapter 28: Studies to assess the long-term efficacy and effectiveness of HPV vaccination in developed and developing countries
Vaccine
Translational mini-review series on vaccines: monitoring of human papillomavirus vaccination
Clin Exp Immunol
Post-licensure monitoring of HPV vaccine in the United States
Vaccine
WHO/ICO (Institut Catala d’Oncologia) Information Centre on HPV and Cervical Cancer
Monitoring the coverage and impact of human papillomavirus vaccine – report of WHO meeting, November 2009
Wkly Epidemiol Rec
Evaluating the impact of human papillomavirus vaccines
Vaccine
Eurogin 2008 roadmap on cervical cancer prevention
Int J Cancer
Cancer registries and monitoring the impact of prophylactic human papillomavirus vaccines: the potential role
Cancer
LEM. A review of prophylactic human papillomavirus vaccines: recommendations and monitoring in the US
Cancer
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2016, Papillomavirus ResearchCitation Excerpt :Comprehensive sampling of multiple sites with one swab (e.g. shaft of penis, tip, coronal sulcus, scrotum ±anus) may better reflect the overall HPV burden at the external genitals but may not be needed for monitoring vaccine impact as long as a consistent method over time is used [43]. HPV-related diseases such as the pre-cancers and anogenital warts, are not routinely reportable conditions in most countries (except in the case of cervical pre-cancers reportable to screening registers in those countries with registers integrated as part of the screening program). [22] Furthermore, with an absence of screening programs for HPV-associated neoplasia to detect pre-cancers in males, measuring any reduction in these lesions will be challenging in most settings.
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2014, VaccineCitation Excerpt :Monitoring human papillomavirus (HPV) vaccines post-licensure to assess immunization programs, evaluate policies, and demonstrate population impact is essential [1–5].
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The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.