Human Papillomavirus (HPV) Vaccines

Overview This paper provides an overview of human papillomavirus (HPV), including its related diseases and health and economic burdens. The two currently available HPV vaccines, Gardasil and Cervavix, as well as challenges to HPV vaccination will also be discussed. Finally, new indications for the HPV vaccines will be presented. Introduction to HPV Human papillomavirus (HPV) is family of double-stranded DNA viruses. At minimum, there have been 120 serotypes identified. HPV is a type of oncogenic virus and is generally classified as high or low-risk. Low-risk oncogenic HPV strains consist of types 6 and 11 and are responsible for development of general skin warts, genital warts, low-grade dysplasia, and laryngeal papilloma [1]. Such lesions usually have no serious medical consequences and clear up without treatment [1]. High-risk oncogenic HPV strains consist of types 16, 18, 31, 33, 35, and 39 [1]. These strains are responsible for the development of high-grade dysplasia and carcinoma in the peritoneal areas and cervix [1]. In fact, these high-risk HPV strains are responsible for 99% of all cervical cancer cases; HPV types 16 and 18 are responsible for 70% of these cases [1]. There is also growing evidence of HPVs link to oropharyngeal cancer [1]. HPV is of considerable epidemiological concern, because it is easily transmissible. More than 75% of women and men will be affected by it at any one point in life. Consequently, it has a high financial burden on the healthcare system throughout the world. In the US, the estimated cost of the clinical management for HPV-related diseases is as high as $3 billion annually [2]. Cervical cancer is also the 2nd leading cause of cancer-related death in women due to the diseases poor prognosis [1]. The 5-year survival rate is as low as 63% starting in stage II [1]. HPV and Cancer Etiology

Not all HPV infections lead to the development of cancer [1]. Cancer progression tends to happen in the presence of chronic infection and inflammation. Following infection, HPV incorporates its genome into host human DNA and activates proto-oncogenes. There are two known mechanisms by which HPV infection leads to cancer. HPV-E6 protein can bind to p53 and induce its degradation. Alternatively, HPV-E7 protein can bind and inhibit retinoblastoma protein. The end-result of both mechanisms leads to uncontrolled cell proliferation and somatic cell proliferation, which eventually leads to cancer development. Risk factors that predispose an individual to HPV-related cancer development include: smoking, weak immune system, poor oral hygiene, and chronic inflammation [1]. Cervical cancer-related risk factors include: early age of sexual activity; multiple sexual partners; previous history of sexually transmitted infections, including genital warts; and long term contraceptive use [1]. Low socioeconomic groups are also at a higher risk due to decreased accessibility to timely healthcare resources for the prevention and early detection of cervical cancer. These factors contribute to cervical cancer being the most common gynecologic malignancy in the world, and an especially high incidence rate is observed in the developing countries [1]. Therefore, it is crucial to raise social awareness of HPV and HPV protection. HPV Screening Programs The best method to prevent HPV infections is through the practice of safe sex. Pap smear screening is not a preventative and only serves to detect precancerous lesions. However, through regular Pap smear screening, the incidence rate of invasive cervical diseases and ultimately, mortality can be decreased. The recommended routine is for women to have their first Pap smear at age 18 or as soon as the commencement of sexual activity [1]. A second test is then administered one year from the date of the initial test. If no abnormalities are found, Pap smear

screening is recommended every 3 years until the age of 70 [1]. After this, if there is the combination of more than 2 clear Pap tests, no cervical abnormalities for 9 years, and no history of cancer, regular screening is no longer recommended [1]. However, if an abnormality is found at any one Pap screening test, re-testing is performed every 6 months for 2 years [1]. There are pitfalls associated with the Pap smear screening program: the Pap-smear test has a 20% falsenegative result rate; the test result is dependent on the interpreting cyto-pathologist; and the test is not effective at detecting invasive cervical carcinoma [1]. Current HPV Vaccines Currently, there are two HPV vaccines available on the market: Gardasil and Cervavix. An overview of both vaccines, including their indications, supporting clinical evidence, and Canadian regulatory approval pathway is presented below. Gardasil Overview of Gardasil Gardasil is a quadrivalent vaccine that protect against HPV types 6, 11, 16 and 18. Manufactured by Merck, it been on the market since 2006 in Canada [3]. The vaccines active ingredient is the highly purified virus-like particle (VLP) made up of the recombinant major capsid (L1) proteins of HPV types 6, 11, 16, and 18 [3]. The prophylactic effect of the vaccine is due to fact that L1 proteins are required for viral entry into genital epithelial cells [4]. Since the VLPs do not contain any viral DNA, they cannot reproduce or infect cells [4]. Indications for Gardasil Gardasil is indicated for women between the ages of 9 to 26 years for the prevention of infections caused by HPV types 6, 11, 16 and 18 and their associated disease, which include cervical, vulvar, and vaginal cancer and genital warts and other genital abnormalities, such as all

grades of cervical intraepithelial neoplasia (CIN), cervical adenocarcinoma in situ (AIS), vulvar intraepithelial neoplasia (VIN) grades 2 and 3, and vaginal intraepithelial neoplasia (VaIN) grades 2 and 3 [3]. Clinical Evidence for Gardasil The efficacy of Gardasil was demonstrated in four pivotal (P005, P007, P013 and P015) Phase II and III clinical studies, which were all placebo-controlled, double-blinded, and randomized [3]. In total, over 20 000 women between the ages of 16-26 years were enrolled. The first pivotal study, P005, demonstrated the safety and tolerability of three doses of the HPV 16 L1 VLP vaccine [3]. The results suggested that the administration of three-doses reduced the risk for HPV 16 infection and prevents the development of HPV 16-related CIN 2/3. Another large pivotal study, P013, evaluated the efficacy of the quadrivalent HPV vaccine [3]. The results of this study showed that the vaccine prevented the development of HPV 6, 11, 16 and 18-related CIN; HPV 16 and 18-related CIN 2/3 or AIS, thereby, preventing the development of HPV 16 and 18-related cervical cancer. It also prevented HPV 6, 11, 16, 18-related external genital warts, HPV 6, 11, 16, 18-related VIN 2/3 and VaIN 2/3, therefore, preventing the development of HPV 16 and 18-related vulvar and vaginal cancer. Submission milestones for Gardasil Merck had a pre-submission meeting with Health Canada in late October 2005 [3]. Gardasil was reviewed under the Priority Review Policy as it offers a new protection against several different strains of HPV and the prevention of cervical cancer. Priority review status was requested and approved in mid December. A New Drug Submission (NDS) was filed on December 12, 2012, and it went through one scientific review. A Notice of Compliance (NOC) issued on July 20, 2006.

Cervavix Overview of Cervavix Cervarix is a bivalent HPV types 16 and 18 ASO4-adjuvanted recombinant vaccine and active immunizing agent [5]. Manufactured by GlaxoSmithKline, Inc. (GSK), it has been on the market since 2010 in Canada. The vaccines active ingredient is VLPs of recombinant major capsid (L1) proteins of HPV-16 and 18 [5]. Indications for Cervavix Cervavix is indicated for women between the ages 10 to 25 years for the prevention of infections caused by HPV-16 and 18 and their associated diseases: cervical cancer, adenocarcinoma in situ (AIS), and cervical intraepithelial neoplasia (CIN) [5]. The route of administration requires three intramuscular injections. Clinical Evidence for Cervavix Six studies were conducted to investigate the efficacy and immunogenicity of Cervarix. Of which, a total of 23, 281 subjects were vaccinated [5]. One pivotal study was submitted to Health Canada. The objective of the study was to demonstrate the efficacy of Cervarix compared with control. The study enrolled females who were vaccinated regardless of baseline HPV DNA status, serostatus or cytology. Cervarix significantly reduced the incidence of CIN2+ lesions due to HPV-16 and HPV-18, compared with the control [5]. Submission milestones for Cervavix Pre-submission meeting was hold between Health Canada and GSK in August 2005 [5]. However, NDS submission was submitted in March 2006, after Mercks submission of Gardasil. Therefore, no priority review status can be granted. Notice of Deficiency (NOD) was issued after first review, which means review cannot continue due to significant deficiencies or

omissions in NDS application [5]. The manufacturer responded within 90 days [5]. However, second review resulted in Notice of Non-Compliance (NON), which indicates that review process was completed, but submission is deficient or incomplete [5]. Health Canada cited safety and efficacy issues [5]. GSK responded the matter in 90 days [5]. Application underwent third review, including review with external advisory panel (EAP) on HPV being assembled [5]. NON withdrawal was issued on October 2008. NDS refiled on April 2009 [5]. With a considerable amount of additional information provided by GSK in response to the previous safety and efficacy concerns and a Product Monograph consistent with available scientific information, NOC was issued for Cervarix on February 2010 [5]. Recommendations for HPV Vaccination Following approval of the quadrivalent and bivalent HPV vaccines, a number of agencies have recommended that routine HPV vaccination for young women be integrated into preexisting national vaccination programs. The World Health Organization (WHO) recommends routine vaccination only if the following criteria are met: clinical management of cervical cancer is a public health priority; the vaccination program is feasible, can be sustained financially, and is targeted towards adolescents; and cost-effectiveness strategies are considered. In Canada, the National Advisory Committee on Immunization (NACI) has recommended routine vaccination for young women while in the United States (U.S.), the Advisory Committee on Immunization Practices (ACIP) recommended universal vaccination for young women. Effectiveness of HPV Vaccination Australia was the first country to implement a fully government funded, national HPV vaccination program [6]. In 2007, a school-based program was established to vaccinate young women ages 12-13 and was followed up with a catch-up program for women ages 13-26 in 2009.

Young women ages 12-17 are vaccinated in schools while women ages 18-26 can receive the quadrivalent HPV vaccine free of charge from general health practitioners [6]. The National HPV Vaccination Program Register (NHVPR) was set up to assist with monitoring vaccination coverage [6]. Coverage for all 3 doses was estimated to be moderately high (67-73%) in the school-age cohort, but was much lower (32-38%) in the older cohort. Coverage for the first dose was higher compared to coverage for all doses in both cohorts. Coverage for the first dose ranged from 81-84% and 52-64% for the school-age cohort and older cohort, respectively. Since establishing a national HPV vaccination program, declines in HPV-related disease incidence have already been observed. A study analysing genital wart presentations at sentinel sexual health clinics from 2004-2009 reported a 59% reduction in genital warts cases in women less than 27 years of age [7]. The trend continued in 2009-2010; a 73% decline in genital warts cases was reported for the same population group [8]. HPV Vaccination in the Developing World: Major Obstacles As of 2012, over 40 countries have added routine HPV vaccination to their national vaccination program [9]. However, only a few low- and middle-income countries, such as Mexico and Panama, have been able to do so because of the high vaccine prices [9-14]. At approximately 120 USD per dose, Gardasil and Cervavix are two of the most expensive vaccines available on the market [15]. These prices are prohibitive for the majority of developing countries, such as India and Uganda [10, 11]. The price of the HPV vaccines is predicted to decline due to increased market competition [9, 14]. Both Merck and GlaxoSmithKline have also stated their willingness to reduce prices for sale in developing countries [14, 15]. However, reports show that the price per

dose must be as low as 1-2 USD for the HPV vaccines to be affordable and cost-effective in countries with a gross domestic product (GDP) less than 1 000 USD per capita [13, 14]. As such, the vaccines are expected to remain beyond the reach of the poorest countries. A number of mechanisms have been implemented to increase accessibility of the HPV vaccines. The GAVI alliance (formerly, the Global Alliance for Vaccines and Immunisation) negotiated prices to 5 USD per dose and subsequently added the HPV vaccines to its list of vaccines that are subsidized for the poorest countries [9]. Countries have also pooled their resources to carry out collective pricing negotiations. The Pan-American Health Organisation Revolving Fund was able to reduce prices to 14 USD per dose for its participating members [9]. Finally, vaccine donations have been made to the poorest countries, such as Rwanda and Bhutan [9]. High vaccine prices are not the only obstacle encountered by developing countries. The cost of transportation, storage at 4oC, and appropriate waste removal must be factored into the total cost of vaccination [14]. Many countries also lack the infrastructure (facilities) and personnel (healthcare professionals, administrative support staff, vaccine monitoring teams) required to carry out a successful national vaccination program [14]. It is crucial for global public health that these barriers are removed. Currently, approximately 80% of all cervical cancer deaths occur in developing countries [13]. It is predicted that by 2020, as many as 90% of all cervical cancer deaths will occur in developing countries [13]. HPV vaccination is especially important in low- and middle-income countries as they also often lack the resources required for a national cervical cancer screening program [14]. HPV Vaccination in Developed Countries: Key Obstacles Status of HPV Vaccination Programs

Australia, the U.S., Canada, and 23 European countries were amongst the first to introduce the HPV vaccines into their national immunization programs [9]. Differences between the vaccination programs and estimated coverage rates exist (refer to Table 1). Barriers to Vaccination It is estimated that HPV vaccine coverage rates must be at least 80% to see a significant reduction in cervical cancer cases by 2025 [9]. However, many of the developed countries have failed to achieve that rate. Analyses of individual programs and their respective coverage rates resulted in the identification of several barriers to implementing a successful national HPV vaccination program. Cost Although cost is not a major obstacle for developed countries, it still impacts coverage rates for sub-groups. In the U.S., vaccination coverage rates are extremely low in high-risk populations where incomes are limited [16]. Although the Vaccine for Children (VFC) Program covers the cost for children in low-income families, certain eligibility criteria must be met [16, 17]. Alternate government programs, such as the Immunisation Grant Program and States Children Health Insurance Program, are more limited in their scope and cannot cover all children [17]. There is also no public funding for individuals over 21 years of age and private insurers decide whether or not to cover the cost of the vaccines [17]. Combined, these factors make the HPV vaccines cost-prohibitive to a large proportion of low-income individuals and families. Cost-prohibition is not a U.S. phenomenon. Of the European Union (EU) countries examined, France is the only one in which the vaccine is not free [18]; France also has the lowest vaccine coverage rates [14]. Lack of Awareness/Education

A study was conducted in the U.S. to investigate low vaccine coverage rates [14]. A survey of young women found that the majority of them did not understand the benefits of HPV vaccination. A similar finding was reported in Australia [6]. Lack of education about HPV and its link to cervical cancer is also thought to contribute to poor coverage rates in high-risk populations [16]. Furthermore, the U.S. study reported that families were more likely to get their children vaccinated if it was recommended by their health-care professional [14]. These findings suggest that better training/education of health care providers and a nation-wide campaign about the benefits of HPV vaccination is required to increase U.S. coverage rates. Treatment Regimen The European Centre for Disease Prevention and Control (EDEC) also conducted a study to investigate low coverage rates. Their report found the current treatment regimen of 3 doses over a 6-month period to be a major deterring factor [19]. This finding is supported by the decrease in coverage rates between the first dose and all 3 doses observed in Australia [6]. Preliminary studies suggest that a 2-dose regimen may be comparable to the standard regimen in terms of efficacy [9]. Additional testing is required, but a shift to a 2-dose regimen has the potential to increase coverage rates by reducing costs and streamlining the vaccination process. Medical/safety concerns In Canada, HPV vaccination is voluntary while in the U.S., children can be exempted from mandatory vaccination requirements due to medical, religious, or moral objections [17, 20]. Public health officials have expressed concerns that misinformation about HPV vaccine safety is being spread by the media and anti-immunisation groups [9]. A joint Centre for Disease Control (CDC) and Food and Drug Administration (FDA) study analysed adverse events (to Gardasil) reported to the Vaccine Adverse Event Reporting System (VAERS) [21]. This report showed

that the most common adverse events (fainting, pain/redness at the immunisation site, dizziness, nausea, and headaches) were similar to those reported for other paediatric/adolescent vaccines. Of the 32 deaths reported, no common pattern was found to suggest that Gardasil was responsible. Religious/moral/social objections The majority of the religious, moral, and social objections to HPV vaccination are due to its targeting towards young adolescent women. Parental and religious groups have expressed concerns that vaccination will result in promiscuity. These concerns have been a major obstacle in the U.S. Of the 27 states that proposed a HPV vaccination requirement for school entrance, only 1 state (Virginia) enacted such a requirement [17]. In Texas, an executive order issued by the governor mandating Gardasil vaccinations for sixth-grade girls was also quickly rescinded over objections from the state House of Representatives and Senate [15]. New Indications New Indications for Men Less than 25% of all HPV-related cancers occur in men [22]. However, the incidence of HPV-related diseases, such as anal cancer, is significantly higher in specific sub-groups, such as homosexual men. HPV types 16 and 18 are responsible for 90% of anal cancer cases and there are an estimated 340 000 genital warts cases reported in the U.S. annually [2, 22]. Vaccination of women and men is believed to confer herd immunity, thus reducing the incidence of HPVrelated diseases [23]. For these reasons, the quadrivalent Gardasil HPV vaccine has been approved for the prevention of genital warts and anal cancer in men 9-26 years of age in Canada, the U.S., Australia, Mexico, and other countries. [24].

Studies have shown that Gardasil is safe, immunogenic in males, and has the potential to significantly decrease the incidence of genital warts and anogenital cancers [22]. One randomized, placebo-controlled, double-blind study with 458 male participants reported seroconversion rates of 97.8%, 99.3%, 99.3%, and 92.5% for HPV 6, 11, 16, and 18 respectively at 1 year following immunisation [25]. Another randomised, placebo-controlled, double-blind study involving 4 065 males aged 16-26 years reported vaccine efficacy to be 90.4% for the prevention of external genital lesions related to HPV types 6, 11, 16 and 18 [26]. Male HPV vaccination has yet to be incorporated into most national vaccination programs. In Australia, vaccines are not provided free of charge to men and in the U.S., permissive, not universal, male vaccination is recommended by the ACIP [6, 24]. This, in effect, puts the decision at the discretion of healthcare professionals. Austria is currently the only country to recommend HPV vaccination for both men and women [23]. A major barrier against male vaccination programs is studies indicating that male and female vaccination is less costeffective than female vaccination alone [23, 24, 27-29]. One cost-utility analysis study reported that the cost per quality-adjusted life year for 12-year-old girls was $20 990, but increased dramatically to $114 510 for 12-year-old girls and boys [27]. It is expected that male vaccination rates will remain low.

Country Canada [20]

Estimated Coverage Rate for All 3 Doses Differs between the provinces (53% in Ontario and 80-87% in Quebec and Atlantic Canada 35% (for 1 dose only)

Cost of Vaccine Free of charge

Delivery Program School-based

Campaign No

United States [16, 17] Australia [6]

66-73% in school-age cohort; 32-38% in older cohort

Free of charge for certain groups1 Free of charge

Primary careor clinic-based School- and primary care/clinic-

No

Nation-wide

France [14, 18]

17%

Luxembourg [14, 30% 18] Italy [14, 18, 19] Differs between regions (56-58%)

60% reimbursed Free of charge Free of charge

based Primary careor clinic-based Primary careor clinic-based Primary careor clinic-based

No Invitation letters Invitation letters (regionspecific) Nation-wide

Denmark [14, 18, 80-84% Free of charge Primary care19] or clinic-based Portugal [14, 18, 80-84% Free of charge Primary careInvitation 19] or clinic-based letters Sweden [14, 18, 80-84% Free of charge School-based Nation-wide 19] United Kingdom 80-84% Free of charge School-based Nation-wide (UK) [14, 18, 19] Table 1. Comparison of Estimated Coverage Rates and Details of National HPV Vaccination Programs in Selected Countries 1 Vaccine for Children Program: covers children under age of 18 years that are eligible for Medicaid, are uninsured or under-insured, or are First Nations Immunisation Grant Program: covers eligible children under 18 years of age and some eligible adults between 19-21 years of age States Children Health Insurance Program: in some states only; covers eligible children under 18 years of age

References Rubin P: Clinical oncology: A multidisciplinary approach for physicians and students, 8 edn; 2001. 2. McLaughlin-Drubin ME, Munger K: Oncogenic activities of human papillomaviruses. Virus Research 2009, 143:195-208. 3. Summary Basis of Decision (SBD) for Gardasil(). In. Edited by Canada H. Ottawa; 2007. 4. Brotherton JML, Gertig DM: Primary prophylactic human papillomavirus vaccination programs: future perspective on global impact. Expert Review of Anti-Infective Therapy 2011, 9(8):627-639. 5. Canada H: Summary Basis of Decision (SBD): CERVARIX Human Papillomavirus Types 16 and 18 Recombinant AS04 adjuvanted vaccine GlaxoSmithKline Inc. Submission Control Number: 127987. In.; 2010. 6. Garland SM, Skinner SR, Brotherton JML: Adolescent and young adult HPV vaccination in Australia: Achievements and challenges. Preventive Medicine 2011, 53:S29-S35. 7. Donovan B, Franklin N, Guy R, Grulich AE, Regan DG, Ali H, Wand H, Fairley CK: Quadrivalent human papillomavirus vaccination and trends in genital warts in Australia: analysis of national sentinel surveillance data. Lancet Infectious Diseases 2011, 11(1):39-44. 8. Read T, Hocking J, Gurrin L, Chen M, Donovan B, Bradshaw C, Fairley C: Continued decline in genital warts three years after introduction of quadrivalent human papillomavirus (HPV) vaccination program. In: The International Society for Sexually Transmitted Diseases Research: 2011; Quebec City; 2011. 9. Poljak M: Prophylactic human papillomavirus vaccination and primary prevention of cervical cancer: issues and challenges. Clinical Microbiology and Infection 2012, 18:64-69. 10. Banura C, Mirembe FM, Katahoire AR, Namujju PB, Mbidde EK: Universal routine HPV vaccination for young girls in Uganda: a review of opportunities and potential obstacles. Infectious Agents and Cancer 2012, 7(24). 11. Farooqui HH, Zodpey S: Cervical cancer control in India: Taking evidence to action. Journal of Public Health Policy 2012, 33(2):165-172. 12. Kaarthigeyan K: Cervical cancer in India and HPV vaccination. Indian Journal of Medical and Paediatric Oncology 2012, 33(1):7-12. 13. Kling M, Zeichner JA: Role of the HPV vaccine in the developing countries. International Journal of Dermatology 2010, 49:377-379. 14. Woo YL, Omar SZ: Human papillomavirus vaccination in the resourced and resource-constrained world. Best Practices & Research Clinical Obstetrics and Gynaecology 2011, 25:597-693. 15. Unknown: The debate over HPV inoculations. In. Ottawa: CBC News; 2009. 1.

16.

17.

18. 19.

20.

21.

22. 23.

24. 25.

26.

27.

28. 29.

Downs LS, Scarinci I, Einstein MH, Collins Y, Flowers L: Overcoming the barriers to HPV vaccination in high-risk populations in the US. Gynecologic Oncology 2010, 117:486-490. Unknown: HPV vaccine: implementation and financing policy in the US. In: Women's Health Policy Fact Sheet. Edited by Foundation THJKF. Menlo Park; 2008. Davies P: HPV vaccinations around Europe. In: online. Edited by Association ECC. Brussels; 2009. team Ee: Updated version of ECDC guidance on human papillomavirus vaccines in Europe available. In. Stockholm: European Centre for Disease Prevention and Control (ECDC); 2012. Colucci R, Hryniuk W, Savage C: HPV vaccination programs in Canada: Are we hitting the mark? In: Report card on cancer in Canada. Toronto: Cancer Advocacy Coalition of Canada; 2008. Slade BA, Leidel L, Vellozzi C, Woo EJ, Hua W, Sutherland A, Izurieta HS, Ball R, Miller N, Braun MM et al: Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. Journal of the American Medical Association 2009, 302(7):750-757. Mendoza N, Hernandez PO, Tyring S: HPV vaccine update: new indications and controversies. Skin Therapy Letter 2011, 16. Yancey AM, Pitlick JM, Forinash AB: The prophylactic role for the human papillomavirus quadrivalent vaccine in males. The Annuals of Pharmacotherapy 2010, 44:1314-1318. Zimet GD, Rosenthal SL: HPV vaccine and males: issues and challenges. Gynecologic Oncology 2010, 117:S26-S31. Reisinger KS, Block SL, Lazcano-Ponce E, Samakoses R, Esser MT, Erick J, Puchalski D, Giacoletti KE, Sings HL, Lukac S et al: Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial. Pediatric Infectious Disease Journal 2007, 26(3):201-209. Giuliano AR, Palefsky JM, Goldstone S, Moreira ED, Penny ME, Aranda C, Vardas E, Moi H, Jessen H, Hillman R et al: Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. New England Journal of Medicine 2011, 364:401-411. Kim JJ, Goldie SJ: Cost effectiveness analysis of including boys in human papillomavirus programme in the United States. British Medical Journal 2009, 339:b3884. Elbasha EH, J. DE, Insinga RP: Model for assessing human papillomavirus vaccination strategies. Emerging Infectious Diseases 2007, 13:28-36. Kim JJ, Andres-Beck B, Goldie SJ: The value of including boys in an HPV vaccination programme: a cost-effectiveness analysis in a low-resource setting. British Journal of Cancer 2007, 97:1322-1328.