It has been estimated that genital human papillomavirus (HPV) is the most common sexually transmitted infection in the US.1 Papillomaviruses are a family of DNA viruses that have a double-stranded, closed, circular genome of ≈8 kilobases (kb) and a nonenveloped, icosahedral capsid. HPVs have a human species-specific tropism and infect only mucosal or cutaneous epithelium. There are more than 100 HPV types, which are characterized further as mucosal or cutaneous: The cutaneous types can cause common skin warts; whereas the mucosal types have primary affinity for the genital and oral mucosa and can cause genital warts, recurrent respiratory papillomatosis, and certain anogenital and oropharyngeal cancers. Most infections are asymptomatic, cause no disease, and become undetectable within 2 years of acquisition.2, 3 Persistent HPV infection is the most important risk factor for the development of outcomes of HPV infection such as cervical cancer precursor lesions and cervical cancer.
Genital (or mucosal) HPV types are categorized further according to their epidemiologic association with cervical cancer. HPV types 16 (HPV-16), HPV-18, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-68, HPV-73, and HPV-82 are considered oncogenic HPV types, and another 3 types are considered most likely oncogenic.4 Nononcogenic types, such as HPV-6 and HPV-11, can cause benign or low-grade cervical cell changes, genital warts, and recurrent respiratory papillomatosis. Oncogenic types can cause cervical cancers and other anogenital cancers. Assessments of cervical cancers worldwide have demonstrated that 99% of cervical cancers are associated with high-risk HPV.5 Most cervical cancers (70%) are caused by 2 high-risk HPV types, HPV-16 and HPV-18.4
A quadrivalent (HPV-6, HPV-11, HPV-16, and HPV-18) HPV vaccine (Merck & Company, Inc.) was licensed for use in the US in June 2006.6 An application for US Food and Drug Administration (FDA) licensure was submitted for a bivalent (HPV-16 and HPV-18) HPV vaccine (GlaxoSmithKline) in March 2007. Both vaccines have been found to be highly effective in preventing infection and disease associated with the types included in the vaccine.7‒11 The Advisory Committee on Immunization Practices (ACIP) recommended the quadrivalent HPV vaccine for routine immunization of girls aged 11 and 12 years and for catch-up immunization of young women ages 13 through 26 years.12 Recommendations will be developed for the bivalent HPV vaccine when this vaccine is licensed by the FDA.
This report provides a review of published information on the epidemiology of HPV infection, on prophylactic HPV vaccines, and on recommendations for use of HPV vaccine in the US. In addition, we discuss vaccine implementation, including evaluation of safety and vaccine uptake and monitoring the impact of prophylactic HPV vaccines.
Epidemiology: Burden, Acquisition, Prevalence, and Natural History of Infection
Burden of cancers and precancers because of HPV
The attributable fraction of cancers and other conditions caused by HPV is based on a variety of information, including epidemiological data and studies evaluating biopsy specimens for HPV. HPV, specifically HPV-16 and HPV-18, are responsible for a considerable burden of cervical and other anogenital cancers, oropharyngeal cancers, and cervical, vaginal, and vulvar intraepithelial neoplasias (CIN, VaIN, and VIN, respectively).13 The available data for the contribution of HPV, and HPV-16, and HPV-18 to cervical cancers and precancers are substantial.5, 14, 15 Greater than 70% of cervical cancers are caused by HPV-16 and/or HPV-18 worldwide,5 and other HPV types, including HPV-31, HPV-33, HPV-39, HPV-45, HPV-52, and HPV-58, contribute to the majority of the remaining cervical cancers. The contribution of HPV types other than HPV-16/HPV-18 to cervical cancers varies geographically. HPV infection is the necessary but not sufficient cause of cervical cancer, because not all individuals with infection develop cancer. Approximately 50% of high-grade squamous intraepithelial lesions (HSIL), which are considered a precursors to cervical cancer, are caused by HPV-16 and/or HPV-18 worldwide.15 The most common type of cervical cancer is squamous cell carcinoma. The next most common type is adenocarcinoma, primarily caused by HPV-18.16 Recent data suggest an important role for HPV, and HPV-16 in particular, as a cause of vaginal and vulvar precancers; in 1 study, 91% of VIN-3 and 50% of VaIN-3 were associated with HPV-16.17 High proportions of oropharyngeal cancers, specifically oral and tonsillar cancers, are associated with HPV detection, primarily HPV-16.18 Substantial proportions of anal and penile cancers also are caused by HPV-16.19
Acquisition of HPV infection
Genital HPV is acquired most commonly through sexual contact.20 Studies evaluating young women after sexual debut have demonstrated that infection is acquired rapidly soon after the initiation of sexual intercourse. In 1 study, by 4 years after first intercourse, >50% of young women had acquired at least 1 HPV type; and, by 2 years, more than 10% had acquired HPV-6, HPV-11, HPV-16, or HPV-18.20 Although there are limited epidemiologic studies on HPV transmission, models evaluating the sexual transmissibility of genital HPV demonstrate that the per-act transmission probability is high (62.5% assuming that the man-to-woman prevalence rate ratio is equal).21
Prevalence of HPV infection
The prevalence of genital HPV differs by population, sampling, and laboratory methods. The prevalence of infection has been found to be high, although this does not indicate persistent infection: Infection that does not clear is a more relevant risk factor for developing cervical precancers or cancers than prevalent infection.
There are 2 studies that have used a representative sample of girls and women in the US: the National Health and Nutrition Examination Survey (NHANES) and the National Longitudinal Study of Adolescent Health (Wave III) Study. In NHANES, 26.8% (95% confidence interval [95% CI], 23.3%-30.9%) of women ages 14 to 59 years from 2003 through 2004 had HPV infection detected by polymerase chain reaction (PCR) analysis on vaginal swabs, corresponding to 24.9 million women with prevalent infection.22 In the National Longitudinal Study of Adolescent Health, 26.9% of women ages 18 to 26 years had HPV infection detected by PCR on urine specimens.23 To our knowledge, there are no representative studies of the prevalence of HPV infection among men.
Studies in various clinic populations have demonstrated that HPV prevalence ranges from 14% to 90% among women24 and the prevalence varies by venue and collection methods. In a Baltimore sexually transmitted disease (STD) clinic, a venue that serves high-risk, sexually active adolescents, 90% of the women who were evaluated had HPV detected.25 In studies of college health clinics, the prevalence of HPV infection generally was lower.26, 27 In a large, multisite study that sampled women from 26 primary care, family planning, and STD clinics throughout the US, oncogenic HPV prevalence ranged from 35% among young women ages 14 to 19 years and decreased with increasing age to 6% among women ages 50 to 65 years.28 HPV infection also is common among men: Most studies in men have demonstrated that >20% of men have HPV infection, depending on the site or specimen sampled and the methods used to assess infection.29, 30
In clinic-based studies, the prevalence of HPV infection usually is highest among women aged <20 years, and prevalence decreases with age. In some studies (mostly conducted outside the US), there is a second peak in older women (aged >45 years).31 In the US NHANES study, which was population based, HPV infection was most common in the group ages 20 to 24 years and decreased in the older age groups.22
The cumulative incidence of HPV infection is higher when repeat measures at short intervals are used to assess cumulative infection.20, 32 On the basis of cumulative incidence data and available models, most sexually active men and women will have acquired at least 1 type of HPV infection in their lifetime.33
Natural history of infection
Although most sexually active women acquire HPV infection, and many have prevalent infection detected, available studies demonstrate that, by 2 years, >90% of women do not have detectable virus.2, 3 Some women develop persistent infection with high-risk HPV types, and these women are at greatest risk for developing precancer lesions, such as HSIL of the cervix. HPV persistence is often defined as >1 visit at least 4 months apart with the same oncogenic HPV type detected; however, the definition varies in different studies. Factors such as smoking, older age, HPV type, duration of infection, and suppressed immunity have been identified as predictors of persistent infections.3, 34‒36 A recent study of persistent infection in a cohort in Costa Rica produced no evidence of interactions between detection of multiple HPV types and the incidence of new infection or persistent infection, implying that HPV types act independently.36 Despite the extensive studies evaluating the natural history of HPV infection, the dynamics of acquisition, clearance and immune response to infection, and transmission are incompletely understood. For example, little is known regarding the long-term protective effect of immune response to infection or how long antibody responses persist.
Prophylactic HPV Vaccines
Two prophylactic HPV vaccines have been developed: One is a quadrivalent HPV vaccine (HPV-6, HPV-11, HPV-16, and HPV-18), and the other is a bivalent HPV vaccine (HPV-16 and HPV-18). Both vaccines use the L1 protein of the outer surface of the virus as the immunogen. These proteins self-assemble into conformational antigens called virus‒like particles (VLPs). The quadrivalent HPV vaccine was licensed for use in the US in June 2006. An application for FDA licensure was submitted for the bivalent HPV vaccine in March 2007. Both vaccines are licensed in multiple countries worldwide and are being used or considered for use.
Although both vaccines are L1 VLP vaccines, they differ in the HPV type VLPs and adjuvants (Table 1). Both vaccines are given intramuscularly as a 3-dose schedule, but the timing of the second dose differs slightly. The quadrivalent HPV vaccine contains an aluminum hydroxyphosphate sulfate adjuvant that also is used in other licensed vaccines in the US. The quadrivalent HPV vaccine consists of HPV-6, HPV-11, HPV-16, and HPV-18 VLPs produced in yeast. The adjuvant in the bivalent HPV vaccine is aluminum hydroxide and monophosphorolipid A (ASO4), a novel adjuvant that also is used in a hepatitis B vaccine licensed for use in dialysis patients in Europe. The bivalent HPV vaccine has HPV-16 and HPV-18 VLPs produced in a baculovirus expression system.
Table 1. Quadrivalent and Bivalent Prophylactic Human Papillomavirus Vaccine Characteristics
|Manufacturing||Yeast (Saccharomyces cerevisiae)||Baculovirus|
|Composition||20 μg HPV-6 VLP, 40 μg HPV-11 VLP, 40 μg HPV-16 VLP, 20 μg HPV-18 VLP||20 μg HPV-16 VLP, 20 μg HPV-18 VLP|
|Schedule||0 Mo, 2 mo, 6 mo||0 Mo, 1 mo, 6 mo|
|Adjuvant||Alum: 225 μg aluminum hydroxysulfate||AS04: 500 μg aluminum hydroxide, 50 μg deacylated monophosphoryl lipid A|
|Licensure||Licensed and approved for use in US June 2006||Application for licensure submitted in the US, March 2007|
|Price||$125 dose catalogue||Unknown|
Both vaccines have been identified as highly effective in preventing infection and disease associated with types included in the vaccine among young women ages 15 to 26 years. For the quadrivalent vaccine, efficacy was reported for the outcomes of VIN, VaIN, CIN, adenocarcinoma in situ (AIS), and external genital lesions, including condyloma. For the bivalent vaccine, efficacy was reported for the outcomes of CIN and AIS. For the quadrivalent HPV vaccine, 2 phase 3 efficacy studies included women from over 30 countries in North America, South America, Europe, Australia, and Asia who had a mean follow-up of 3 years.37, 38 For the bivalent HPV vaccine, to date, published analysis of the phase 3 efficacy study has included >18,000 women enrolled from 14 different countries with a mean follow-up of 14.8 months.11 All studies were randomized, double-blind clinical trials.
A variety of different clinical outcomes were evaluated in HPV vaccine phase 3 trials including HPV-16– and HPV-18–related CIN-2/CIN-3, HPV vaccine type-related CIN. For the quadrivalent HPV vaccine, data also have been presented on HPV-6–, HPV-11–, HPV-16–, and HPV-18–related VIN-2/VIN-3 or VaIN-2/VaIN-3 and on HPV-6–, HPV-11–, HPV-16–, and HPV-18–related condyloma (Table 2).
Table 2. Prophylactic Vaccine Efficacy: Quadrivalent and Bivalent Human Papillomavirus Vaccines
|HPV-16– and HPV-18–related CIN-2/CIN-3|| || || |
| Per protocol*||98 (86-00)||NA||The Future II Study Group 200738|
| Unrestricted susceptible†||95 (85-9)||90.4 (53.4-99.3)||Paavonen 200711|
|HPV vaccine type-related CIN‡|| || || |
| Per protocol||100 (94-00)||NA||Garland 200737|
| Unrestricted susceptible||98 (92-100)||89.2 (59.4-98.5)||Paavonen 200711|
|HPV-6–, HPV-11–, HPV-16–, and HPV-18–related VIN-2/VIN-3 or VaIN-2/VaIN-3|| || || |
| Per protocol||100 (49-100)||NA||Garland 200737|
| Unrestricted susceptible||91 (37-100)|| || |
|HPV-6–, HPV-11–, HPV-16–, and HPV-18–related condyloma|| || || |
| Per protocol||100 (92-100)||NA||Garland 200737|
| Unrestricted susceptible||96 (86-99)|| || |
Published analyses have included several different study populations from the trials. The per-protocol population included participants with no evidence of the relevant HPV type infection based on DNA or serologic assessments (naive women) at baseline and through 1 month after the third dose, and cases were counted after the third vaccine dose, at Month 7. The unrestricted susceptible or total vaccinated cohort population was naive to the relevant HPV types at baseline, and cases were counted after the first dose; this population was the only population that was reported for both vaccines in phase 3 trials. The efficacy for prevention of HPV-16/HPV-18–related CIN-2/CIN-3 ranged from 90.4% to 98% for the vaccines.11, 38 The overall HPV vaccine type-related CIN efficacy ranged from 89.2% to 100%.11, 37 The quadrivalent vaccine also demonstrated 91% to 100% efficacy against HPV-6–, HPV-11–, HPV-16–, HPV-18–related VIN-2/VIN-3 or VaIN-2/VaIN-3 and 96% to 100% efficacy against HPV-6–, HPV-11–, HPV-16–, HPV-18–related condyloma.37
Current data do not indicate that the vaccines have any therapeutic effect among women who are infected at the time of vaccination: The quadrivalent vaccine did not prevent progression to disease or the regression of existing lesions.38 In the bivalent vaccine trial, women with existing HPV infection who were enrolled into the vaccine group did not have any improved clearance of HPV infection.39 Thus, the vaccine would have maximum benefit when given before sexual debut.
Intent-to-treat analyses or analyses that included all study participants in the vaccine and placebo groups, regardless of HPV status at baseline, demonstrated that the efficacy of the HPV vaccine was less than among naive women. This was expected, because the vaccines do not have any therapeutic effect, and some women were infected at the time of study enrollment and were included in these analyses. The efficacy for prevention of HPV-16/HPV-18–related CIN-2/CIN-3 or AIS in the intent-to-treat population was 44% (95% CI, 31%-55%).38 When the women who were included in this analysis were followed to 36 months, all but 3 cases of HPV-16/HPV-18–related CIN-2/CIN-3 or AIS occurred in participants who were infected with HPV-16/HPV-18 at baseline.38 The efficacy for prevention of any HPV-related CIN-2/CIN-3 or AIS in the intent-to-treat population for the quadrivalent HPV vaccine was 18% (95% CI, 7%-29%). The difference in efficacy among the intent-to-treat population and the per-protocol population most likely was caused by existing vaccine type infection at the beginning of the study.
Both vaccines produce a vigorous immune response, with essentially all vaccinees developing an antibody response after vaccination.40, 41 Antibody titers were measured by different methods for the 2 vaccines: For the quadrivalent HPV vaccine, a multiplexed luminex assay was used.42 For the bivalent HPV vaccine, a VLP enzyme-linked immunoadsorbent assay was used.43 Results from immunogenicity studies reported geometric mean titers (GMTs) and seroconversion. By Month 7 in trials of the quadrivalent HPV vaccine, seroconversion rates were ≥99% for all 4 HPV types.44 On completion of a 3-dose regimen, anti-HPV–6, anti-HPV–11, anti-HPV–16, and anti-HPV–18 antibody levels were ≈10- to 104-fold higher than those observed in these placebo recipients who were vaccine-type HPV seropositive and PCR negative at enrollment (assumed to represent antibody titers after natural infection).45 Through 5 years, vaccine-induced anti-HPV GMTs remained at or above those observed after natural infection.10 In phase 3 studies of the bivalent HPV vaccine, >99.5% of women had detectable HPV-16 and HPV-18 antibody after the second and third doses.11 In the bivalent vaccine trials, vaccinees had detectable antibody at the end of a 4.5-year follow-up, and the GMTs at 51 to 53 months were 17-fold and 14-fold higher than the HPV-16 and HPV-18 GMTs after natural infections.43 The longevity of immune response and the minimum protective antibody response both remain unknown. It is unclear whether differing antibody titers indicate better disease protection or longer duration of immune protection.
Bridging immunogenicity studies have been conducted in women who were younger than the women who were included in the efficacy studies. For the quadrivalent vaccine, the antibody responses among girls ages 10 to 15 years were not inferior and were 1.7- to 2.7-fold higher than the antibody responses observed in young women ages 16 to 23 years.44 Data from the bivalent vaccine demonstrated that 100% of women in both age groups (10-14 years and 15-25 years) who received the vaccine developed antibodies after vaccination. GMTs in the group ages 10 to 14 years were not inferior to those in the group ages 15 to 25 years and were 2 times higher.41
Studies have also been conducted in women older than the women who were included in the phase 3 efficacy studies. In a study of 3800 women ages 24 to 45 years, the quadrivalent HPV vaccine prevented 91% of cases of persistent infection, low-grade cervical abnormalities, precancers, and genital warts caused by HPV-6, HPV-11, HPV-16, or HPV-18.46 In studies of the immune response to bivalent vaccine in women ages >25 years to 55 years, the immune response was not inferior to that demonstrated for the women ages 15 to 25 years.47
Both vaccines have demonstrated cross-protection to types other than those in the vaccine. HPV types are organized by phylogenetic relatedness, and certain types have a close relation to types in the vaccines, HPV-16 and HPV-18. Types related to HPV-16 include HPV-31, HPV-33, HPV-35, HPV-52, and HPV-58. Types related to HPV-18 include HPV-39, HPV-45, HPV-59, and HPV-68. Evaluations of the quadrivalent HPV vaccine found cross-protection against CIN-2/3 and AIS due to HPV 31/33/45/52 and 58 (efficacy, 45%; 95% CI, 10, 68).48 Studies of the bivalent HPV vaccine found statistically significant reductions in 6-month persistent infections due to types 45, 31, and 52 and an efficacy of 27% (97.9% CI, 0.5-46.8) for prevention of 12-month persistent infection due to 12 oncogenic types (not including 16 or 18).11 There is limited understanding of what cross-protection will mean in the population. Reductions in persistent infections do not necessarily imply reductions in disease; also, reductions in CIN-2/CIN-3 and AIS were unclear, because many individuals had multiple infections, and it was unclear which HPV type contributed to disease.
Vaccine safety evaluations during the clinical trials of the quadrivalent vaccine demonstrated that the most commonly reported systemic, adverse events were headaches (23.2%) and fever (13.1%).44 The majority of infection-site adverse events were mild to moderate in intensity (79.4% of girls ages 10-15 years reported pain/tenderness or soreness at the site of injection).44
Injection site symptoms (pain, redness, and swelling) also were more frequently reported in the vaccine group than in the control group in trials of the bivalent vaccine.11 Most local symptoms lasted from 2.2 days to 3.4 days.11 Neither the bivalent or quadrivalent clinical trial protocols included pregnant women; however, some women became pregnant during the trial and were evaluated for outcomes of the pregnancy. There was no overall difference in pregnancy outcomes between the HPV vaccine and control groups for either vaccine.9, 11
Recommendations for Quadrivalent HPV Vaccine Use
The quadrivalent HPV vaccine has been recommended for routine immunization of girls aged 11 and 12 years and for catch-up immunization of young women ages 13 through 26 years in the US by the ACIP and other organizations12 (Table 3). Recommendations will be developed for the bivalent HPV vaccine when this vaccine is licensed by the FDA. The rationale for recommending the routine immunization of girls aged 11 and 12 years is that they are less likely to have had a sexual debut and would be naive to vaccine type infections. In addition, immune responses were vigorous in this age group. Several professional groups recommend a routine adolescent healthcare visit at ages 11 and 12 years, and the routine immunization of girls at this age with the HPV vaccine would fit into this platform.
Table 3. Recommendations for Prophylactic Human Papillomavirus Vaccine Use: Advisory Committee on Immunization Practices, 2006
|Routine use||Girls ages 11-12 y; the series can be started as young as age 9 y|
|Catch-up||Women/girls aged 13-26 y who have not been vaccinated previously or who have not completed the full series|
|Administration issues||Vaccine should be shaken before administration; the dose is 0.5 mL and is administered intramuscularly, preferably in the deltoid muscle|
|Dosing||Three-dose schedule; the second and third doses should be administered 2 mo and 6 mo after the first dose|
|Precautions||Individuals with moderate or severe acute illnesses should defer vaccination until improvement|
|Contraindications||Individuals with a history of immediate hypersensitivity to yeast or to any vaccine component|
|Pregnancy||Not recommended for use in pregnancy|
|Human immunodeficiency virus||The vaccine can be administered to women/girls who are immunosuppressed as a result of disease or medications; however, the immune response and vaccine efficacy may be less than that in individuals who are immunocompetent|
|Not recommended for||Quadrivalent HPV vaccine is not licensed for use among girls aged <9 y, or women aged >26 y, or men/boys|
Recommendations for vaccine use have been published by a variety of professional and academic organizations, including the American College of Obstetrics and Gynecology, the American Academy of Pediatrics, and the American Cancer Society (ACS).49‒52 Many of these recommendations do not differ from those published by the ACIP. The ACS-published recommendations differ, in that they recommend basing the decision to vaccinate women ages 19 to 26 years on an informed discussion between the woman and her healthcare provider.50, 51
Vaccination is not a substitute for routine cervical cancer screening, and vaccinated individuals should have cervical cancer screening as currently recommended. HPV vaccination may result in changes in cervical cancer screening in the future.52 Because the quadrivalent HPV vaccine is not a live vaccine, it can be administered to immunocompromised individuals; however, vaccine efficacy may be less than that in individuals who are immunocompetent. The quadrivalent vaccine is not recommended for use in pregnancy. If it is determined that a woman is pregnant after initiating the vaccination series, then the remainder of the 3-dose regimen should be delayed until after completion of the pregnancy. The precautions for administration include minor acute illnesses, and the vaccine should be deferred until after the illness improves. Quadrivalent HPV vaccine is contraindicated for individuals who have a history of immediate hypersensitivity to yeast or any vaccine component. Although it is possible that vaccination of men with the quadrivalent vaccine may offer direct health benefits to men and indirect health benefits to women, there are currently no efficacy data available to support the use of HPV vaccine in men. Efficacy studies in men are ongoing.
Postlicensure monitoring includes evaluation of vaccine coverage, vaccine safety, and impact on disease outcomes.
Evaluation of vaccine uptake in the community is important for understanding implementation challenges and to measure the impact of vaccination on disease and infection endpoints. Vaccine coverage traditionally has been measured in the US through national surveys, such as the National Immunization Survey, the National Survey of Children's Health, and the National Health Interview Survey. Some surveys have been expanded to collect additional data on adolescent immunizations, including HPV vaccine.54 Vaccine registries and local studies will provide additional detailed and local information on vaccine uptake.
Ongoing monitoring of vaccine safety occurs through 2 main mechanisms at the Centers for Disease Control and Prevention (CDC): passive reporting through the Vaccine Adverse Events Reporting System (VAERS) and special studies and evaluations through the Vaccine Safety Datalink (VSD) Project.55 Both of these systems are a collaboration between the CDC and the FDA. VAERS reports are useful to document associated serious or moderate adverse events after vaccination; however, as a passive reporting system, it is insufficient to provide detailed information on the association with vaccination. The VSD Project is a collaboration between the CDC and a group of managed care organizations (MCOs) that investigate possible vaccine-related events through systematic studies and evaluations of data collected in the MCOs.56 Both of these systems provide periodic updated information on safety to the general public, the FDA, and advisory committees. In special cases, studies evaluating specific hypotheses can be conducted in the VSD Project.
Monitoring the impact of the HPV vaccine will be important to describe the population level impact of vaccination, and duration of protection after vaccination. In addition, ongoing systems to monitor impact of the vaccine may answer questions concerning the effect of this vaccine on other HPV types (type replacement). A potentially important limitation to the collection of surveillance data on many outcomes of interest is the lack of a system that routinely collects these data (either as a nationally notifiable condition or as a routine surveillance activity).
Proximal measures of vaccine impact include outcomes such as HPV infection, cervical cancer precursors, vaginal and vulvar cancer precursors, and anogenital warts. Proximal measures are optimal for monitoring because they will detect an impact (either disease reduction or vaccine type infection reduction) earlier than cancer outcomes. Planned CDC evaluations for cervical cancer precursors such as CIN-2/CIN-3, carcinoma in situ, or AIS include population-based assessments of CIN-2/CIN-3 and evaluation of administrative databases, cancer registries, and sentinel sites with specific populations.
An advantage to monitoring anogenital warts as an early marker of vaccine impact is that most genital warts are caused by HPV-6 or HPV-11, and widespread use of the quadrivalent HPV vaccine in appropriate age groups could have a dramatic effect on the incidence of genital warts. The CDC plans to monitor genital warts through sentinel surveillance in STD clinics and administrative databases.
A distal measure of vaccine impact includes cervical cancer cases that are reported routinely through a system of state-based cancer registries (the National Program of Cancer Registries and the Surveillance, Epidemiology, and End Results Program), covering up to 100% of the US population. However, it may take as long as 20 or 30 years before an impact on this outcome is detected. Vaginal, vulvar, other anogenital, and oropharyngeal cancers are also reported routinely as a part of these cancer registries; however, the impact of the prophylactic HPV vaccine on these outcomes may be difficult to monitor because these cancers are relatively rare.
Planned evaluations of HPV types in cervical specimens may be useful to measure the expected reduction in HPV-16 and HPV-18 as well as the theoretical concern of type replacement. Evaluations of HPV types are occurring in several ongoing or completed projects including the NHANES, a sentinel network of cervical cancer screening clinics, 2 managed care organizations, demonstration projects in areas with high cervical cancer morbidity, and population-based studies of CIN 2/3. In addition, projects evaluating HPV types in anogenital cancers are planned. Finally, studies on the duration of immune response and special studies to evaluate long-term efficacy are planned to address questions about booster immunizations.