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Human papillomavirus vaccines

Author

Diane M Harper, MD, MPH, MS

Section Editor

S Hirsch, MD

Deputy Editor

Barbara H McGovern, MD

INTRODUCTION — Human papillomaviruses (HPV) are highly prevalent, tissue-specific, DNA viruses that infect epithelial cells [1]

.. Persistent viral infection with oncogenic types of HPV leads to cancer of the cervix, anus, vagina, vulva, penis, mouth, and sinuses [2-4]

.. Cervical cancer is the second most common malignant disease in women worldwide and has a bimodal onset in the third and sixth decades of life [2]

.. (See "Epidemiology; clinical features; and diagnosis of invasive cervical cancer").Use of cervical cytology has reduced the incidence of cervical cancer by 70 percent. However, cervical cancer remains a leading cause of death in countries without screening programs. Vaccines that prevent these persistent HPV infections have the potential to further reduce the burden of disease [5-8]

..Clinical data on the use of these candidate vaccines will be reviewed here. The epidemiology, virology, pathogenesis, clinical manifestations, and treatment of HPV are discussed separately. (See "Clinical presentation and diagnosis of human papillomavirus infections" and see "Epidemiology of human papillomavirus infections" and see "Virology of human papillomavirus infections and the link to cancer" and see "Treatment and prevention of human papillomavirus infections").

HPV TYPES — Specific HPV types are associated with squamous intraepithelial lesions. HPV 16, 18, 45, and 31 cause over half of the low grade lesions, and about 65 percent of the high grade lesions. HPV 6 and 11 cause 12 percent of low grade lesions [9]

and approximately 80 percent of genital warts [9-15]

.. Up to 40 percent of patients are infected with more than one HPV type. (See "Epidemiology of human papillomavirus infections").HPV 16 and HPV 18 are associated with approximately 50 and 20 percent of cervical cancers, respectively [16,17]

.. HPV 45 and 31 are the next most common HPV types associated with cervical cancer, accounting for another five percent each. The first peak of oncogenic HPV infection occurs between the ages of 15 to 25 years, with a secondary peak in the sixth decade of life [18]

..It is estimated that targeted HPV protection with the bivalent or quadrivalent vaccine would prevent half of the high-grade precancerous lesions (CIN 2 or 3) and two thirds of the invasive cancers. The quadrivalent vaccine would also prevent most genital warts [19]

..

LIFE CYCLE AND THE IMMUNE RESPONSE — Human papillomaviruses are small, nonenveloped viruses, whose circular genome encodes the encapsulating structural proteins, L1 and L2 [20]

.. The life cycle of the virus is integrally linked to the maturation of the keratinocyte. Initial infection occurs in the basal stem cell. Specific gene products are transcribed at every level of differentiation of the squamous keratinocyte [20]

.. At the most superficial level, the L1 protein coat is transcribed, and upon desquamation of this short-lived cell, HPV virions are infective for transmission to the next basal stem cell in the adjacent mucosal epithelium. (See "Virology of human papillomavirus infections and the link to cancer").HPV infection evades the immune system through a variety of mechanisms. HPV infection leads to down regulation of interferon expression and regulatory pathways, which subsequently prohibits the activation of cytotoxic T-lymphocytes [21]

.. No associated cytolysis or release of pro-inflammatory cytokines occurs as a result of basal cell infection [21]

.. In the absence of the usual signals that identify a virally-infected cell, the cellular immune system is not activated and HPV infection persists [21]

.. The importance of cellular immunity is clinically apparent in HIV-infected patients and in renal transplant patients, who have a higher incidence of HPV-related disease [22]

.. (See "Preinvasive and invasive cervical neoplasia in HIV-infected women").Approximately 75 to 90 percent of HPV infections will clear within a year of initial infection [17]

.. Clearance is mediated by the natural desquamation of epithelial cells, cell-mediated immunity and in part, by low-levels of neutralizing antibody responses to the specific HPV L1 epitope [23]

.. There is a limited antibody response from natural infection and a significant loss of these antibodies within three years [24,25]

..HPV infection induces a time-limited, type-specific immunity to HPV infections [26]

.. Individuals who are infected with one HPV type may develop protective antibodies against future infection for a period of time with that specific type, but remain immunologically naive to other HPV types. Thus, vaccine design strategies need to incorporate the most common disease-causing HPV types in order to protect against the majority of cervical intraepithelial neoplasias and cervical cancers. The interval between acquisition of incident HPV infection and malignancy usually takes ten years or longer [27]

..

ANAMNESTIC RESPONSE — HPV infects only the epithelium and does not have a viremic phase. HPV actively evades immune recognition. In vaccinated women, therefore, it is unlikely there will be any antibody response with reinfection of type specific HPV. Protective antibody levels will be dependent on initial and sustained vaccine responses or requisite booster shots.At this time, most alum-based vaccinations have booster shots recommended at 7 to 10 year intervals, to maintain disease protection. This concept is important for HPV disease since the benefits of vaccination are to prevent long term cancer development, and not immediate epidemic protection as has been the standard for infectious diseases, such as pertussis, meningitis, or polio.Sustained antibody titers have been reported with use of an ASO4 adjuvant system in the bivalent vaccine, which specifically is designed to prime antigen presenting cells and may lengthen B cell memory response [28]

..

TOOLS FOR ASSESSMENT OF VACCINE EFFICACY — Vaccine efficacy is measured only by the prevention of virologic infection or clinical events. The immunogenicity of the vaccines are not equated with vaccine efficacy for three reasons:

The antibody titers are unique for each HPV type and not comparable across types.

The antibody titers for each vaccine are in different noncomparable assay units (milli-ELISA units/mL and milli-Merck units/mL).

There is no established correlate between a titer level and protection against HPV infection or the development of CIN/cancer.

Absolute values of antibody titers are not comparable within or between studies. Therefore, immunogenicity is measured by comparing type-specific, vaccine-induced titers to natural infection titers and then expressed as a ratio at a specific point in time after vaccination. HPV antibody titer levels at or above infection titers are generally considered to be protective.Vaccine efficacy for cervical cancer is defined for several natural history events that all serve as surrogate markers for the development of cervical cancer:

Incident HPV infection

Persistent type-specific HPV infection (>6 or >12 months)

Abnormal cytology

Abnormal histologic changes

VACCINE DEVELOPMENT — The HPV L1 major capsid protein self-assembles into virus-like particles (VLPs) for each HPV type [29]

.. Because the VLPs are hollow, without inner HPV DNA cores, the vaccine itself is not infectious. Preclinical research demonstrated that L1 is highly immunogenic with and without an adjuvant [29]

.. The major capsid protein, L1, is the only portion of HPV used in vaccine design [30]

..The proof-of-concept vaccine trial with HPV 16 VLP [31]

demonstrated that HPV infection could be prevented. This vaccine, which is no longer being used in clinical trials, led to the development of the following immunizations: the bivalent HPV 16/18 VLP vaccine, and the quadrivalent HPV 6/11/16/18 VLP vaccine.

BIVALENT HPV 16/18 L1 VIRUS-LIKE PARTICLE VACCINE

Safety and efficacy — The efficacy of a bivalent HPV 16/18 L1 virus-like particle vaccine was demonstrated in a double blind, randomized, placebo-controlled trial in 1113 women, 15 to 25 years of age [32,33]

.. Study participants were randomly assigned to receive 20 micrograms each of HPV type 16 and 18 VLPs with ASO4 adjuvant or placebo at months 0, 1 and 6 with follow-up to 5.5 years [34]

.. The trial results were significant for the following observations:

Protection against incident HPV 16/18 infection occurred in 96 percent of women who received vaccination according to protocol and in 91 percent of all participants, including those who received vaccine doses at irregular times.

Protection against persistent HPV 16 and 18 infections (≥ 12 months) occurred in 100 percent of women who received vaccination and follow up visits according to protocol; and in 96 percent of all participants.

The vaccine was generally safe and well tolerated; no new chronic diseases occurred during follow up.

Greater than 98 percent of the vaccine recipients sustained seroconversion for more than 5.5 years for both HPV types.

No cases of CIN caused by HPV 16/18 were reported in the vaccine group, compared to 11 cases in the placebo group.

Protection against incident HPV 45 and HPV 31 infections occurred in 88 and 53 percent of all women enrolled in the trial, respectively.

In another study in women 15 to 55 years of age, the bivalent HPV vaccine was safe and immunogenic for at least two years, including those women in the oldest age group (46 to 55 years of age) [35]

..An interim analysis of the phase III efficacy trial of the bivalent HPV vaccine was conducted when 23 cases of CIN2 or greater with HPV 16 or 18 DNA were identified among 18,644 women who had been randomly assigned to HPV vaccine or control vaccine (hepatitis A vaccine) [36]

.. Cases of CIN 2 or greater were noted in two participants in the HPV vaccine group and in 21 participants in the control group. Based on this interim analysis with a mean length of follow-up of 14.8 months, HPV vaccine efficacy was estimated to be greater than 90 percent among women who did not have evidence of HPV 16/18 infection at baseline.

QUADRIVALENT HPV 6/11/16/18 L1 VIRUS-LIKE PARTICLE VACCINE

Safety and efficacy — The efficacy of a quadrivalent HPV 6/11/16/18 L1 VLP vaccine has been demonstrated in a number of trials (show table 1A-1D), including a double blind, placebo-controlled trial in 552 women (mean age 20 years) [23]

.. Participants were given either alum placebo or vaccine, composed of 20 micrograms each of HPV types 6 and 18 VLPs and 40 micrograms each of HPV types 11 and 16 VLPs with alum, at months, 0, 2, and 6 with follow up through three years. The trial results were significant for the following results:

Overall protection against persistent HPV 16/18 infection (>4 months) occurred in 89 percent of women who received vaccination and follow up visits according to protocol, with 100 percent, 86 percent, and 89 percent efficacy for HPV 6, 16, and 18, respectively. There were no cases of HPV 11 infection reported.

Protection against CIN caused by HPV 6/11/16/18 occurred in 100 percent of all participants who were not infected with these types at first vaccination while seven cases occurred in the placebo group.

Protection against all external genital warts caused by HPV 6/11 occurred in 100 percent of all participants with four cases occurring in the placebo group.

The vaccine was generally safe and well tolerated.

After three vaccine doses, seroconversion rates were 94, 96, 100, and 76 percent for HPV types 6, 11, 16, and 18 at month 36, respectively [37]

..

Two hundred forty-one of these study participants were subsequently enrolled in an extension trial to obtain an additional two years of follow-up data [38]

.. The combined incidence of HPV 6/11/16/18-related persistent infection or disease was reduced by 96 percent in vaccine recipients (two cases in the vaccine group versus 46 in the placebo group).

FUTURE II trial — In a phase III, multinational prospective, double-blind, placebo-controlled trial (FUTURE II), more than 12,000 women, aged 15 to 26 years (with a lifetime number of no more than four sexual partners), were randomly assigned to receive a three-dose regimen of vaccine or placebo [39,40]

.. The majority of the study participants were from Europe (65 percent) and Latin America (26 percent). At baseline, cervical cytology was abnormal in 11 percent of both vaccine and placebo groups; approximately 16 and 7 percent had evidence of HPV 16 and 18 infection, respectively.The primary efficacy analysis was performed in those subjects who did not have evidence of either HPV-16 or 18 infection (by DNA or serologic testing) through one month after the third dose of vaccine; these patients were referred to as "HPV susceptible" per protocol. The primary composite end point was CIN 2 or 3, adenocarcinoma in situ, or cervical cancer related to HPV-16 or HPV-18. The mean duration of follow-up was three years. The study demonstrated the following results:

Vaccine efficacy for the prevention of the primary composite end point was 98 percent in study participants who were "HPV susceptible".

Vaccine efficacy remained high (95 percent) in those HPV-negative participants who did not receive all doses of vaccine according to protocol, suggesting some flexibility in the timing of the vaccine schedule.

Seroconversion rates at 24 months among 1512 vaccinated women in the immunogenicity substudy were 96, 97, 99, and 68 percent for HPV types 6, 11, 16, and 18, respectively.

The vaccine was well-tolerated and there were no serious adverse events.

However, vaccine efficacy for CIN2 or 3 disease due to all HPV types was significantly lower (44 percent) in the overall population of women who had undergone randomization, which included participants with baseline or incident HPV infection by one month after the last dose of vaccine.

FUTURE 1 trial — A similarly designed phase III placebo controlled trial was conducted in 5455 women aged 16 to 24 years to assess the efficacy of quadrivalent vaccine to prevent HPV-related anogenital disease (FUTURE I) [41]

.. The primary aim of the trial was to determine vaccine efficacy in reducing the combined incidence of anogenital warts, vulvar or vaginal intraepithelial neoplasia grades 1 to 3 or cancer associated with HPV vaccine types 6,11,16, or 18. A secondary aim was to observe whether the administration of vaccine reduced the combined incidence of CIN grades 1 to 3, adenocarcinoma in situ, or cancer associated with vaccine-type HPV.The following results were demonstrated after a mean follow-up of three years:

The vaccine was 100 percent effective in preventing anogenital disease in women who were "HPV susceptible" (ie, no cases were identified in the vaccine group versus 60 cases in the placebo group).

Vaccine efficacy was 100 percent in preventing CIN grades 1 to 3 or adenocarcinoma in situ with vaccine type HPV in those women who were "HPV susceptible" (ie, no cases were diagnosed in the vaccine group, whereas 65 cases were diagnosed in placebo group).

As noted in the FUTURE II trial, vaccine efficacy was lower when women with baseline HPV infection were included in the intent-to-treat analysis (ie, 73 percent efficacy in prevention of external anogenital or vaginal lesions and 55 percent efficacy in the prevention of CIN).

There was no clear evidence that vaccination altered the course of disease or infection present before administration of the first dose of vaccine in both FUTURE I and II trials. These data reinforce the use of the HPV vaccine as a prophylactic, and not a therapeutic immunization. (See "Vaccine utilization" below).A summary of the efficacy data from four placebo controlled, double-blind, randomized Phase II and III clinical studies of the quadrivalent vaccine may also be viewed on the website for the US Food and Drug Administration (www.fda.gov).

Recommendations — The Advisory Committee on Immunization Practices (ACIP) and the American College of Obstetricians and Gynecologists (ACOG) have recommended that quadrivalent HPV 6/11/16/18 L1 VLP vaccine should be administered in girls and women 9 to 26 years of age [42,43]

.. (See "Human papillomavirus quadrivalent (types 6, 11, 16, 18) recombinant vaccine: Drug information").Other vaccine approaches have been considered for immunotherapy of cervical cancer as well as prevention of the acquisition of HPV infection. (See "Virology of human papillomavirus infections and the link to cancer").

SPECIFIC ISSUES

Vaccine safety — Since virus-like particles (VLPs) are recombinant proteins, manufactured in benign biologic systems (yeast and Baculovirus), they have no known oncogenic or disease-causing potential [19]

..The clinical trials of the bivalent and quadrivalent vaccines have demonstrated mild injection site reactions [23,32]

; no serious adverse events have been recorded, including one study with more than five years of follow-up [34]

.. Furthermore, HPV vaccine has been studied in diverse populations of women in both developed and developing countries [39,41]

..The vaccine adverse events reporting system (VAERS) has registered five cases and confirmed two cases of Guillain-Barre syndrome (GBS) after quadrivalent vaccine administration. Ongoing reporting continues for adverse events from coadministration of the quadrivalent vaccine with other vaccines, as there has been limited data available prior to regulatory approval.Anaphylaxis has been reported following administration of the quadrivalent vaccine and the incidence appears to be higher than that of most other routinely-administered vaccines, although this complication is still rare. (See "Anaphylactic reactions to vaccines").Neither HPV vaccine contains live virus: the quadrivalent vaccine has been classified as a category B drug by the FDA. However, use in pregnancy is not recommended because of limited data on safety in this setting. In the FUTURE II trial, pregnancy occurred in 1053 women in the vaccine group and 1106 in the placebo group; no obvious anomalies attributable to vaccine were observed [39]

..The manufacturer maintains a pregnancy registry to monitor fetal outcomes of pregnant women exposed to the vaccine. Exposures can be reported by calling [44]

.. However, lactating women can receive the immunization series since subunit vaccines do not affect the safety of infant breast-feeding. (See "Immunizations in pregnant women").

Cost-effectiveness — Mathematical models have examined the cost-effectiveness of HPV vaccination [45-48]

.. One study suggested that vaccination of the entire United States population of 12 year-old girls would prevent more than 200,000 HPV infections, 100,000 abnormal cervical cytology examinations, and 3300 cases of cervical cancer if cervical cancer screening continued as currently recommended [45]

.. Studies have demonstrated that the effectiveness of HPV vaccination will depend on the duration of vaccine immunity, including one study which supported continued cost-effectiveness when the vaccine was given to 12 to 26 year-old females [49]

..Vaccinating both men and women is predicted to be more beneficial in reducing HPV infection and disease than by vaccinating only women, but at a higher cost [50,51]

.. However, models of cost-effectiveness are plagued by substantial uncertainty regarding major issues such as duration of protection [52]

, the effect of herd immunity, and the prevalence of vaccine-specific HPV types circulating in the population [53]

.. (See "Epidemiology of human papillomavirus infections").

Vaccine utilization — Clinical trials of the HPV vaccines suggest high efficacy and an excellent safety profile in women who do not have abnormal cervical cytology or HPV infection at the time of immunization.Several questions remain regarding vaccine utilization including [19]

:

The duration of protection is unknown; protective antibodies persist for at least five years. Duration of protection is important in determining when booster vaccines will be needed [54]

..

The precise level of antibody needed for protection against infection is also unknown.

HPV exposure occurs at all ages of life, starting in infancy [55,56]

.. The risk of HPV exposure increases with the number of sexual partners, regardless of the age at which new partners are acquired [57]

.. Decisions about the age at which to initiate HPV immunization have been guided by epidemiologic data regarding ages of peak HPV acquisition and estimated duration of vaccine protection [4,18,26]

.. HPV vaccination has been recommended by the ACIP in girls and women 9 to 26 years of age.

The American Cancer Society (ACS) guidelines are in general agreement with the ACIP recommendations about the need for vaccination in young females [57]

..Effective vaccination strategies will require further education of the public on the importance of HPV infection and its consequences [58]

.. A study of 400 women in a university setting demonstrated that awareness and knowledge of HPV was very limited [59]

.. Vaccination against cervical cancer will be especially important in developing countries, where nearly 80 percent of cancer cases are reported, and where screening cytologies are rarely used [60]

..Molecular-based testing for HPV detection is NOT recommended prior to immunization [61]

.. (See "Clinical presentation and diagnosis of human papillomavirus infections", section on Diagnosis).

Efficacy in established infection — Since there are many HPV types that can infect the cervix, there are important distinctions that need to be made about the efficacy of the HPV vaccine in women with prior versus current HPV infection.

The HPV vaccine does not clear HPV infection that is present at the time of vaccination [61]

..

The absence of therapeutic efficacy for established infection was illustrated in a trial of 2189 women with cervical HPV DNA who were randomly assigned to receive either three doses of bivalent HPV-16/18 L1 virus-like particle vaccine or a control (hepatitis A) vaccine [62]

.. There was no evidence of increased viral clearance of established infection at 6 or 12 months in the group that received HPV vaccine.

The HPV vaccine can still protect women with current HPV infections from acquisition of additional HPV types (ie, HPV 6,11,16,18) [63]

..

The vaccine was effective in preventing CIN 2/3 or adenocarcinoma in situ in a subgroup of 4722 women from the FUTURE 1 and FUTURE 2 studies who had evidence of current infection with at least one cancer-causing HPV vaccine type (16 or 18) at the time of vaccination, but were naive to the other vaccine type [63]

.. These data suggest that vaccinating a woman currently infected with 16 or 18 can still confer benefit in preventing infection with the other oncogenic HPV types.

IMPORTANCE OF CERVICAL SCREENING — Appropriate use of cervical cytology has reduced the death rate from cervical cancer by 70 percent in the past five decades [64]

.. However, there are limitations to cervical screening:

Many women do not seek or receive cervical screening, especially minority groups and recent immigrants.

The results of cervical cytology smears cannot be used to make a definitive diagnosis or to initiate treatment (See "The cervical cytology report").

Despite optimal cytologic screening strategies, cervical cancers still occur [65]

..

Cytologic screening is of paramount importance since HPV immunization is NOT effective in clearing cytologically evident disease or infection. Furthermore, one large US-based prevalence study found that although HPV infection was highly prevalent, specific HPV vaccine types were not [66]

.. Strategic linking of immunization initiatives to cervical screening programs may be effective in reducing the number of abnormal cytology results and in reducing the number of cervical cancers not detected by cervical cytology [10]

.. (See "The cervical cytology report" and see "Epidemiology of human papillomavirus infections", section on Prevalence).Cytologic screening is recommended for any woman who has been sexually active for three or more years or is 21 years of age. A preventive health care visit in which vaccination is discussed or offered represents an ideal opportunity to offer Pap screening to sexually active patients as well [57]

..In contrast, in the young child or adolescent, the pubertal, physiologic, and psychological development of the young child or adolescent needs to be considered; thus cervical screening should not be considered until at least three years have passed after the onset of sexual activity.

PREVENTION OF VULVAL AND VAGINAL LESIONS — Vulvar and vaginal cancers are uncommon complications of HPV infection, which are preceded by vulva intraepithelial neoplasia (VIN2-3) and vaginal intraepithelial neoplasia (VaIN2-3). Data from three placebo-controlled clinical trials evaluating the quadrivalent HPV vaccine for cervical cancer were combined to assess the potential effect of immunization on the prevention of moderate to severe vulvar intraepithelial neoplasia (VIN-2 and VIN-3) [36]

.. Among 15,596 women who were naive to HPV 16 or 18 infection through one month after the final dose of vaccine, immunization was 100 percent effective against the development of VaIN-2/3 and VIN-2/3 caused by HPV 16/18 over a mean follow-up time of three years (ie, no cases demonstrated in vaccinated group; 13 in the placebo group). In the intention to treat population of 18,174 women, vaccine efficacy was 49 percent for VaIN or VIN grades 2 or 3, irrespective of HPV type (27 cases in the vaccinated group; 53 cases in the placebo group).

VACCINATION IN MEN — The potential strategy of using HPV vaccine in men to prevent cervical cancer in women is being planned [30]

.. Studies of male vaccination to prevent HPV-associated genital warts and cancers occurring in men are underway [19,67]

..Excellent immunogenicity of the HPV vaccine has been demonstrated in male adolescents [68,69]

.. In one randomized, double-blind trial 1781 children, ranging in age from 9 to 15 years, were assigned 2:1 to quadrivalent HPV vaccine or placebo. Approximately half of the study participants were young boys. The trial was significant for the following results:

At month seven, seroconversion rates were ≥ 99.5 percent for the four vaccine types in both genders.

Although geometric mean titers declined by month 18, antibody levels were comparable for each HPV type when comparing responses between genders.

The vaccine was well-tolerated.

Mathematical models suggest that male vaccination may not be cost-effective for the prevention of cervical cancer in women [45,57,70]

..

FUTURE IMPACT OF HPV VACCINE — The impact of HPV vaccination programs on reduction of cervical cancer in the future will be dependent on multiple issues, such as the amount of circulating HPV types in the population, the percent of patients vaccinated, and the duration of protection [57]

.. Another important factor will be whether patients and providers continue to adhere to recommendations for cervical screening, since premature cessation of these preventive interventions could lead to an increase in cervical cancer rates.

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Human papillomavirus (HPV) vaccine", see "Patient information: Condyloma (genital warts) in women", and see "Patient information: Cervical cancer screening"). We encourage you to print or e-mail these topic reviews, or to refer patients to our public web site, www.uptodate.com/patients, which includes these and other topics.

SUMMARY AND RECOMMENDATIONS

Persistent infection with high-risk oncogenic HPV types leads to cervical cancer, the second most common malignant disease in women worldwide. (See "Introduction" above).

Multicenter, double-blind, placebo-controlled trials for both quadrivalent and bivalent HPV vaccines demonstrate efficacy against incident and persistent HPV infection and abnormal cervical cytology and histology. Bivalent HPV 16/18 L1 VLP AS04 adjuvanted vaccine has been submitted to the FDA for approval; quadrivalent HPV 6/11/16/18 L1 VLP vaccine is available for use and distribution. The quadrivalent vaccine also prevents most genital warts. (See "Vaccine development" above).

Both vaccines have an excellent safety profile. (See "Vaccine safety" above).

We recommend immunization with HPV vaccine, as suggested by the ACIP and ACOG (Grade 1A). The currently suggested immunization schedule is in girls and women 9 to 26 years of age. Quadrivalent HPV 6/11/16/18 L1 VLP vaccine (Gardasil™ ) is administered in three doses at 0, 2, and 6 months. The duration of immunity is unknown. (See "Vaccine development" above).

Cytologic screening is recommended for any woman who has been sexually active for three or more years or is 21 years of age. Clinicians need to be aware that HPV immunization is NOT effective in clearing cytologically evident disease or infection. A preventive health care visit in which vaccination is discussed or offered represents an ideal opportunity to offer Pap screening to sexually active patients as well. (See "Vaccine utilization" above).

Vaccination can be offered to females as young as nine years of age. Cervical screening is not appropriate until pubertal, physiologic, and psychological development has been established and at least three years from onset of sexual activity has passed.

HPV vaccine is a major advance in the prevention of cervical cancer, but it will not replace the need for other preventive strategies, such as cervical screening. (See "Importance of cervical screening" above).

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