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Human papillomavirus vaccination
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Human papillomavirus vaccination
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Literature review current through: Sep 2017. | This topic last updated: Jul 26, 2017.

INTRODUCTION — Human papillomavirus (HPV) is a sexually transmitted pathogen that causes anogenital and oropharyngeal disease in males and females. Persistent viral infection with high-risk HPV genotypes causes virtually all cancers of the cervix. The high-risk HPV genotypes (or "types") 16 and 18 cause approximately 70 percent of all cervical cancers worldwide, and types 31, 33, 45, 52, and 58 cause an additional 20 percent. HPV types 16 and 18 also cause nearly 90 percent of anal cancers and a significant proportion of oropharyngeal cancer, vulvar and vaginal cancer, and penile cancer. HPV types 6 and 11 cause approximately 90 percent of anogenital warts.

Vaccines have been developed to protect against acquisition of HPV infection and development of subsequent HPV-associated disease. This topic will cover issues related to routine immunization recommendations, vaccination in special patient populations, and vaccine safety.

The natural history, epidemiology, and disease associations of HPV infection are discussed elsewhere. (See "Human papillomavirus infections: Epidemiology and disease associations".)

AVAILABLE VACCINES — Three different vaccines, which vary in the number of HPV types they contain and target, have been clinically developed, although not all are available in all locations:

Quadrivalent HPV vaccine (Gardasil) targets HPV types 6, 11, 16, and 18.

9-valent vaccine (Gardasil 9) targets the same HPV types as the quadrivalent vaccine (6, 11, 16, and 18) as well as types 31, 33, 45, 52, and 58.

Bivalent vaccine (Cervarix) targets HPV types 16 and 18.

In the United States, only the 9-valent vaccine is available. Practitioners in other locations should confirm vaccine availability locally.

Dosing and administration is discussed elsewhere. (See 'Administration' below.)

These are all prophylactic vaccines, designed to prevent initial HPV infection and subsequent HPV-associated lesions. Therapeutic vaccines, designed to induce regression of existing HPV-associated lesions, are in development but are not clinically available [1].

RATIONALE

Females — Vaccination with 9-valent, quadrivalent, or bivalent HPV vaccine provides a direct benefit to female recipients by safely protecting against cancers that can result from persistent HPV infection. This preventive effect is most notable and best studied with cervical cancer, which is one of the most common female cancers worldwide. HPV types 16 and 18, which are targeted by all three HPV vaccines, cause approximately 70 percent of all cervical cancers worldwide, and HPV types 31, 33, 45, 52, and 58, which are additionally targeted by the 9-valent vaccine, cause an additional 20 percent. HPV types 16 and 18 also cause nearly 90 percent of anal cancers and a substantial proportion of vaginal, vulvar, and oropharyngeal cancers. Vaccination with the quadrivalent or 9-valent HPV vaccine also protects against anogenital warts (90 percent of which are caused by HPV types 6 and 11); although they are benign lesions, they are associated with physical and psychological morbidity and have a high rate of treatment failure. The adverse effects of HPV vaccination are generally limited to mild local reactions. Vaccine efficacy and safety are discussed below. (See 'Efficacy' below and 'Vaccine safety' below.)

Details on HPV-associated diseases and the burden of HPV infection among females are found elsewhere. (See "Human papillomavirus infections: Epidemiology and disease associations".)

Various modeling studies have outlined the potential benefits of HPV vaccination, which appear to be cost effective for the recommended age range [2-6]. One study suggested that vaccination of the entire United States population of 12-year-old girls would annually 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 [2]. In settings where there has been high uptake of vaccine among females there is also evidence of herd immunity among males of similar age, reflected by a reduction in genital warts [7].

Males — HPV vaccination provides a direct benefit to male recipients by safely protecting against cancers that can result from persistent HPV infection. HPV types 16 and 18 cause nearly 90 percent of anal cancers and substantial proportion of oropharyngeal and penile cancers. Vaccination with 9-valent or quadrivalent vaccine also protects against anogenital warts (90 percent of which are caused by HPV types 6 and 11). The overall burden of HPV-associated cancers and precancers among males is less than the burden of cervical cancer in females. Nevertheless, despite a smaller direct absolute benefit of HPV vaccination in males compared with females, the overall benefit of vaccinating males outweighs its potential risks because of additional population benefits from herd immunity and the documented safety of HPV vaccines. (See 'Vaccine safety' below and 'Efficacy' below.).

Details on HPV-associated diseases and the burden of HPV infection among males are found elsewhere. (See "Human papillomavirus infections: Epidemiology and disease associations".)

Various models have indicated that vaccinating both males and females is more beneficial in reducing HPV infection and disease than by vaccinating only females, although male vaccination is less cost effective than female vaccination [8-14]. However, cost effectiveness analyses are limited by uncertainty regarding different variables that affect the impact of male vaccination. These include vaccine efficacy and duration of protection, vaccine coverage of females, the effect of herd immunity, the range of health outcomes included, and the effect of HPV-associated diseases on quality of life [15].

In particular, models have found that the cost effectiveness of male vaccination is higher in the setting of lower levels of female coverage. This is because there would be less herd protection from female vaccination, and thus males would have more direct benefit from vaccination. In one study that used population data from the Netherlands, the burden of HPV-associated cancers in men could be reduced by an estimated 37 and 66 percent if vaccine uptake among girls and young women reached 60 and 90 percent, respectively, but vaccine uptake among females is considerably less than 60 percent in many locations [13]. Furthermore, even if vaccine uptake were sufficiently high among females to confer protection against males, this would have minimal effect on men who have sex with men, who have substantially higher rates of HPV-associated anal cancer and precursor lesions than heterosexual males.

In resource-limited settings, expert groups recommend that public health efforts focus primarily on vaccinating young females, the group in which the absolute benefit and cost effectiveness of HPV vaccination is the highest.

ADMINISTRATION

Indications and age range — In accordance with the Advisory Committee on Immunization Practices (ACIP) in the United States, we recommend routine HPV vaccination for all females and males [16-19]. The ACIP recommended age ranges for vaccination are as follows:

Females – HPV vaccine is recommended at 11 to 12 years. It can be administered starting at 9 years of age, and catch-up vaccination is recommended for females aged 13 to 26 years who have not been previously vaccinated or who have not completed the vaccine series.

Males – HPV vaccine is recommended at 11 to 12 years. It can be administered as starting at 9 years of age, and catch-up vaccination is recommended for males aged 13 to 21 years who have not been previously vaccinated or who have not completed the vaccine series.

Among males 22 to 26 years old, catch-up HPV vaccination is recommended if they are men who have sex with men or immunocompromised (including HIV-infected males). Otherwise, "permissive use" of HPV vaccination is recommended for this age range. Permissive use means that the vaccine is recommended but not considered to be of sufficient priority to include on routine vaccination schedules. Vaccines recommended on a permissive basis may not be covered by a patient's health insurance provider.

The main reason that routine catch-up HPV vaccination is not recommended for individuals older than 26 years is the increased likelihood of prior exposure to HPV vaccine types with age, which reduces the potential individual benefit and thus the cost effectiveness of HPV vaccination. However, for some individuals in this age group, such as those with no prior sexual experience or certain lifelong sexual monogamy, the risk of prior HPV exposure may be very low. HPV vaccination is reasonable and likely beneficial in such individuals if they are deemed to have a future risk of HPV exposure; studies have suggested that HPV vaccination is immunogenic, efficacious, and safe in older women [20-23]. However, clinicians and patients should be aware that HPV vaccination of individuals older than 26 years may not be covered by insurance providers or other payers.

These recommendations are consistent with other expert groups in the United States, including the American Academy of Pediatrics (AAP), the American Academy of Family Practice (AAFP), the American College of Obstetricians and Gynecologists (ACOG), the American Cancer Society (ACS), and the International Papillomavirus Society [24-28]. These are also largely consistent with recommendations for resource-rich settings from the American Society of Clinical Oncology (ASCO) guidelines on cervical cancer prevention [29].

Recommendations for resource-limited settings are somewhat different. The World Health Organization (WHO) recommends that the primary target of HPV vaccination programs be females aged 9 to 14 years and that local public health programs should recommend vaccination of older females only if it is affordable and cost effective and does not divert resources from vaccinating the primary target population or screening for cervical cancer [30]. ASCO recommendations for resource-limited settings are similar [29].

Optimal timing — Within the recommended age range, the optimal time for HPV immunization is prior to an individual's sexual debut. Clinical trial data of vaccine efficacy in males and females suggest that immunization with HPV vaccine is most effective among individuals who have not been infected with HPV (eg, patients who are "HPV-naïve"). None of the available HPV vaccines treat or accelerate the clearance of preexisting vaccine-type HPV infections or related disease. (See 'Indications and age range' above.)

Individuals who are sexually active should still be vaccinated consistent with age-specific recommendations. A history of an abnormal Papanicolaou test, genital warts, or HPV infection is NOT a contraindication to HPV immunization [17]. However, immunization is less beneficial for those who have already been infected with one of more of the HPV vaccine types. (See 'Preexisting HPV-associated disease' below.)

Choice of vaccine — Not all HPV vaccines are available in all locations. If cost and availability are not an issue, we recommend the 9-valent vaccine. In the United States only the 9-valent vaccine is available (since 2017). The greater HPV-type coverage provided by the 9-valent compared with the quadrivalent and bivalent vaccines protects against additional cervical cancers. Although it is not clear that greater HPV-type coverage by vaccinating males with the 9-valent rather than quadrivalent vaccine would substantially improve male cancer prevention, it would likely further reduce the risk of cervical cancer in women indirectly through herd immunity.

In general, the same formulation should be used to complete the series, if possible. However, if the HPV vaccine formulation initially used is unknown or unavailable, or if the 9-valent vaccine is being introduced into the formulary, a different HPV vaccine formulation can be used to complete the series [18].

Revaccination with the 9-valent vaccine is likely of marginal individual benefit for those who have already completed the series with a different HPV vaccine.

Immunization schedule — In the United States, the recommended dosing schedule depends on the age of the patient at vaccine initiation [16,17,19]:

Individuals initiating the vaccine series before 15 years of age – Two doses of HPV vaccine should be given at 0 and at 6 to 12 months.

If the second dose was administered less than five months after the first, the dose should be repeated a minimum of 12 weeks after the second dose and a minimum of five months after the first.

Individuals initiating the vaccine series at 15 years of age or older – Three doses of HPV vaccine should be given at 0, 1 to 2 (typically 2), and 6 months.

The minimum intervals between the first two doses is four weeks, between the second and third doses is 12 weeks, and between the first and third dose is five months. If a dose was administered at a shorter interval, it should be repeated once the minimum recommended interval since the most recent dose has passed.

Immunocompromised patients – Three doses of HPV vaccine should be given at 0, 1 to 2, and 6 months regardless of age. (See 'Immunocompromised hosts' below.)

This ACIP recommended vaccination schedule is the same as that recommended by the Strategic Advisory Group of Experts on Immunizations (SAGE) of the World Health Organization (WHO) [31]. The two-dose series is similarly recommended in many other countries. Practitioners outside the United States should consult local guidelines for the recommended immunization schedule in their country.

HPV vaccine can be safely administered at the same time as other age-appropriate vaccines at a different anatomic site. Administering HPV vaccine at the same time as certain other vaccines (ie, tetanus, acellular pertussis, and diphtheria vaccine and inactivated poliovirus vaccine) does not appear to adversely affect the immune response to either the HPV vaccine or the concomitant vaccine [32,33].

Although the initial clinical efficacy studies evaluated a three-dose schedule (see 'Efficacy' below), subsequent studies found that two vaccine doses in young individuals have similar or greater immunogenicity compared with three doses in older females (the group in whom vaccine efficacy was established in clinical trials) [34-38]. For the quadrivalent vaccine, furthermore, two doses are comparably effective as three doses for prevention of genital warts [39,40]. There have been no studies directly evaluating the efficacy of fewer than three doses for prevention of cervical neoplastic disease. Three doses of HPV vaccine are still recommended for individuals 15 and older because of the lower immunologic response to HPV vaccination in this population.

As an example of supportive evidence for the two-dose schedule, a trial of 1518 participants randomly assigned to receive the 9-valent vaccine at different dosing schedules demonstrated that antibody titers for HPV vaccine types were consistently higher among females and males aged 9 to 14 years who received two vaccine doses spaced 6 or 12 months apart compared with females aged 16 to 26 years who received three vaccine doses over six months [37]. One cohort of females aged 9 to 14 years in this trial was also assigned to receive three vaccine doses; among females in this age group, antibody responses were generally comparable with two- versus three-vaccine doses, and many vaccine-type titers trended higher with two doses.

While no efficacy studies have been conducted to directly evaluate a two-dose schedule, a post hoc analysis of data from two trials of the bivalent HPV vaccine in young women (aged 15 to 25 years) who had no HPV type 16 or 18 infection at baseline suggests that two vaccine doses can effectively protect against HPV infection [41]. Of those with at least 12 months of follow-up, vaccine efficacy against six-month persistent infection with HPV types 16 and 18 was no different in women who received the intended three doses compared with those who received only two (89 and 90 efficacy, respectively).

Observational studies have examined effectiveness by number of doses, but are difficult to evaluate primarily because of a number of unmeasured confounders. One observational study of over one million Swedish females suggested that two quadrivalent vaccine doses provided substantial protection against genital warts, although completion of three doses was slightly superior (128 versus 174 events per 100,000 person-years with two doses, compared with 528 events per 100,000 years without vaccination) [39]. In a similar study from Denmark, three quadrivalent vaccine doses were also associated with an overall lower risk of genital warts than two doses, but when the two vaccine doses were administered at least six months apart, the reduction in risk for genital warts appeared comparable to that with three doses [40].

Missed doses — Patients often do not follow up for their immunizations on schedule [42]. The ACIP recommends that if the vaccination series is interrupted for any length of time, it can be resumed without restarting the series.

Postvaccination instructions — Because of a potential for syncope with any vaccine, and particularly with the HPV vaccine, a routine 15-minute waiting period in a sitting or supine position following HPV vaccination is recommended [17]. This may decrease the risk of syncope with subsequent injury. (See 'Vaccine safety' below.)

Unnecessary evaluation

Prevaccination assessment — HPV vaccination can be administered without special evaluation. Serologic or HPV DNA testing is not warranted prior to immunization [17]. Pregnancy testing is also not necessary.

Postvaccination serology — There is no evidence that the measurement of postvaccination antibody titers to monitor immunity is useful for determining who is protected against infection by the vaccine-targeted types.

SPECIAL POPULATIONS

Pregnant or breastfeeding females — HPV vaccination during pregnancy is not recommended because of limited information about safety; however, data from inadvertent use in this setting are increasingly available and reassuring. Thus, if a woman is found to be pregnant after initiating the vaccination series, she can be reassured that available evidence does not indicate any increase in risk of adverse pregnancy outcome with vaccination. Nevertheless, the remainder of the series should be delayed until the woman is no longer pregnant. This is discussed in detail elsewhere. (See "Immunizations during pregnancy", section on 'Human papillomavirus'.)

Lactating females can receive the immunization series since subunit vaccines do not affect the safety of infant breastfeeding.

In the United States, the 9-valent vaccine manufacturer maintains a registry to monitor fetal outcomes of pregnant females exposed to HPV vaccine [17,18]; prenatal exposures to the 9-valent vaccine can be reported by calling 800-986-8999.

Preexisting HPV-associated disease — A history of genital warts, a positive HPV test result, or abnormal cervical, vaginal, vulvar, or anal cytology all indicate a prior HPV infection but not necessarily with the HPV types included in the vaccines. Vaccination is still recommended in individuals within the recommended age range who have evidence of prior HPV infection, as it can still provide protection against infection with HPV vaccine types not already acquired [16,17].

However, these patients should be advised that vaccination will have no therapeutic effect on preexisting HPV infection or HPV-associated disease, and the potential benefit of HPV vaccination is not as great as if they were vaccinated before their sexual debut. (See 'Optimal timing' above.)

Immunocompromised hosts — Immunocompromised patients, particularly transplant recipients and HIV-infected patients with CD4 cell counts <200 cells/microL, are at especially high risk for HPV-related disease [43]. HPV vaccination with a three-dose schedule (at 0, 1 to 2, and 6 months) is recommended for all immunocompromised patients through 26 years of age if they have not already been vaccinated. Immunocompromising conditions that warrant this three-dose schedule include B-lymphocyte antibody deficiencies, complete or partial T-lymphocyte defects, HIV infection, malignant neoplasm, transplantation, autoimmune disease, and immunosuppressive therapy.

Direct efficacy data on HPV vaccination in immunocompromised hosts are lacking. However, studies of the HPV quadrivalent vaccine in HIV-infected adult men [44], HIV-infected women aged 16 to 23 years [45,46], and HIV-infected boys and girls aged 7 to 12 years [47] suggest that it is both immunogenic and safe in these populations. Studies in other immunocompromised populations are ongoing.

HPV vaccination in transplant recipients is discussed in detail elsewhere. (See "Immunizations in solid organ transplant candidates and recipients", section on 'Human papillomavirus' and "Immunizations in hematopoietic cell transplant candidates and recipients", section on 'Human papillomavirus'.)

Cancer screening continues to play an important role in detection and treatment of HPV-associated disease in these high-risk individuals. (See 'Importance of cancer screening' below.)

EFFICACY AND IMMUNOGENICITY

Immunogenicity — Excellent antibody responses have been reported following immunization with the 9-valent, quadrivalent, and bivalent vaccines, with seroconversion rates of 93 to 100 percent in females and 99 to 100 percent in males [48-52]. Elicited titers are generally higher in younger than in older individuals. Although there is no defined minimum threshold titer for protection, seroconversion from prior exposure has been shown to reduce the risk of incident HPV infection with the same HPV type [53,54]. This suggests that the titers resulting from natural infection, which are an order of magnitude lower than those elicited in vaccine studies, provide some level of protection against reinfection with the same HPV type.

Because initial efficacy trials were restricted to sexually active females 15 years of age and older, immunological "bridging" studies conducted in younger females and in males demonstrate safety and immunogenicity and thus support vaccine use in these other populations. With each of the three vaccines, the geometric mean titers (GMT) of postvaccination antibodies among females aged 9 to 15 years were generally twofold higher than those observed in females aged 16 to 26 for all targeted HPV types [50,55-59]. Similarly, GMT of postvaccination antibodies among males ages 9 to 26 were at least comparable to those in females aged 16 to 26 years [50-52,56].

In a head-to-head comparison of the immunogenicity of quadrivalent and bivalent HPV vaccines in females ages 18 to 45 years, immunization with the bivalent vaccine induced GMT of serum neutralizing antibodies 2.3- to 4.8-fold higher for HPV 16 and 6.8- to 9.1-fold higher for HPV 18 across all age strata compared with the quadrivalent vaccine [60]. However, whether the induction of higher serum titers against HPV 16 and 18 has any impact on the degree and duration of protection is unknown.

Efficacy

Cervical, vaginal, and vulvar disease — HPV vaccination is effective in preventing cervical disease, including cervical intraepithelial neoplasia (CIN2 or 3) and adenocarcinoma in situ. This has been demonstrated in large randomized trials of quadrivalent, 9-valent, and bivalent vaccines and, as discussed below, has been supported by population data from regions reporting declines in incidence of cervical disease following widespread quadrivalent HPV vaccination. In addition, quadrivalent and 9-valent HPV vaccines have been demonstrated to reduce the incidence of vaginal and vulvar intraepithelial neoplasia (VAIN and VIN 1-3). Vaccine efficacy is greatest in those who do not have prior HPV infection.

In the large licensing trials for the HPV vaccines, baseline HPV infection status was determined through serologic testing and DNA detection in cervical specimens. Efficacy in the overall trial populations was consistently lower than among the HPV-naïve population (those without baseline HPV infection), as presented below. This reflects the fact that many trial participants were already sexually active and previously infected with vaccine HPV types and highlights the importance of vaccination prior to the onset of sexual activity to maximize effectiveness. (See 'Optimal timing' above.)

Quadrivalent HPV vaccine – Two large, randomized, double-blind trials compared quadrivalent HPV vaccine with placebo among more than 17,000 females aged 15 to 26 [55,61]. After three years, the efficacy of quadrivalent HPV vaccine for preventing CIN2 or more severe disease due to HPV vaccine types was:

97 to 100 percent among HPV-naïve populations

44 percent among the overall population

Efficacy for preventing VIN2 or 3 and VaIN2 or 3 was similarly 100 percent among HPV-naïve populations and 62 percent among the overall population [55].

9-valent HPV vaccine – An international randomized trial compared the 9-valent vaccine with quadrivalent vaccine in approximately 14,000 females aged 16 to 26 years [62]. The efficacy of the 9-valent vaccine for preventing CIN2 or more severe disease, VIN2 or 3, and VaIN2 or 3 associated with HPV types 31, 33, 45, 52, and 58 (the types not contained in the quadrivalent vaccine) was:

97 percent among the HPV-naïve population

In the overall population of study participants, the rates of high-grade cervical, vaginal, and vulvar disease were the same among women who received the 9-valent vaccine and those who received the quadrivalent vaccine (14 cases/1000 person-years in both groups).

Bivalent HPV vaccine – Two large randomized trials compared bivalent HPV vaccine with placebo or a non-HPV comparator vaccine in females aged 15 to 25 years [63,64]. Vaccine efficacy was high in HPV-naïve populations in both of these trials. As an example, in one of the trials, which included nearly 16,000 females, efficacy in preventing CIN2 or more severe disease due to HPV vaccine types was:

93 percent among the HPV-naïve population

53 percent among the overall population

HPV vaccination also appears to be safe and effective in preventing subsequent infection and cervical disease in older women, but the overall benefit is less than in younger females [20,21,65]. In a trial of 5752 women older than 25 years who were randomly assigned to receive bivalent vaccine or placebo and followed for a mean of 84 months, vaccine efficacy for the combined endpoint (preventing six-month persistent cervical HPV type 16 or 18 infection or vaccine-type associated CIN grade 1 or more severe diagnoses) was 22 percent overall [20,21]. Among those who did not have a prior history of HPV infection and received three doses of vaccine, vaccine efficacy was 91 percent.

Data collected outside the clinical trial setting are also favorable, demonstrating decreased prevalence of HPV-related cervical disease following introduction of HPV vaccines into national immunization programs [66-72]. As an example, the 2007 implementation of a national program to administer the quadrivalent vaccine to women aged 12 to 26 years in Australia led to high rates of vaccine coverage, particularly among females under 18 years of age. In one study of the cervical cytology registry in Victoria, Australia, there was a progressive decrease in the incidence of high-grade cervical squamous intraepithelial lesions among girls 18 years of age or younger in the two years after the vaccination program compared with the four years preceding it [66]. Reductions in cervical disease have also been observed where vaccine uptake has been suboptimal. As an example, in a study from New Mexico in the United States, where vaccine uptake ranged from 17 to 40 percent, the incidence of CIN continually decreased among females aged 15 to 19 years between 2007 and 2014 (10 and 40 percent reduction annually for CIN2 and CIN3, respectively) [72]. Although many of these studies did not formally link individual vaccination status or implicated HPV type with disease occurrence, they suggest an association between widespread vaccination and population decreases in HPV-related disease that is consistent with the efficacy observed in clinical trials of the HPV vaccines and that may reflect vaccine-associated herd immunity.

All licensing trials and most observational data on HPV vaccination describe results with an intended three-dose series. Results with fewer than three doses are discussed elsewhere. (See 'Immunization schedule' above.)

Anal disease — Data informing the impact of HPV vaccine on anal intraepithelial neoplasia (AIN) and anal cancers are more limited than that for cervical disease but suggest efficacy in males and expected efficacy in females.

In a planned sub-study of 602 men who have sex with men aged 16 to 26 who participated in a large placebo-controlled trial of the quadrivalent vaccine, efficacy in preventing AIN secondary to the relevant HPV vaccine types was 78 percent among HPV-naïve males and 50 percent in the overall population [73].

Among females, there are no direct efficacy data regarding prevention of AIN, but bivalent HPV vaccination has been demonstrated to reduce the incidence of anal infection with HPV types 16 and 18 [74]. Since the majority of anal cancers in both females and males are related to HPV 16 and HPV 18, a beneficial impact of vaccination on AIN and anal cancer risk in females is anticipated [74].

Oral disease — Data informing the impact of HPV vaccine on oral disease are limited to studies demonstrating a reduction in oral HPV infection following vaccination. As an example, in a trial originally designed to evaluate bivalent HPV vaccine efficacy against cervical HPV disease among 7466 females in Costa Rica, fewer participants who were randomly assigned to receive bivalent HPV vaccination (1 of 2910) had detectable HPV types 16 or 18 on an oral specimen four years after vaccination compared with those who received the control hepatitis A vaccination (15 of 2924) [75]. Vaccine efficacy for the prevention of oral HPV infection was estimated to be 93 percent. Whether HPV vaccination can prevent the development of HPV-related oropharyngeal cancer has not yet been evaluated.

Anogenital warts — Clinical trials in females and males have demonstrated the efficacy of quadrivalent HPV vaccine for preventing anogenital warts (condylomata acuminata) which are most often caused by HPV types 6 and 11. Because 9-valent vaccine also targets these HPV types, it is expected to have similar efficacy. The bivalent HPV vaccine does not target these HPV types and thus does not prevent anogenital warts.

In a large randomized trial among females aged 16 to 24 years, quadrivalent HPV vaccine efficacy for preventing vulvar and vaginal condylomata was 100 percent among HPV-naïve participants (without evidence of HPV vaccine types at enrollment) and 70 to 78 percent among the overall population (with or without HPV infection at enrollment) [55]. Similarly, in a placebo-controlled randomized trial among over 4000 males aged 16 to 26, quadrivalent HPV vaccine efficacy for preventing external genital warts was 90 percent among HPV-naïve participants and 66 percent among the overall populations [73].

Observational studies have also suggested that quadrivalent HPV vaccination prevents anogenital warts [76-80]. As an example, in a study of nearly 400,000 females born between 1989 and 1999 in Denmark, quadrivalent HPV vaccination was associated with a substantially lower risk of developing genital warts (229 cases among 248,403 vaccinated versus 2241 cases among 151,367 unvaccinated individuals after an average of 3.5 years of follow-up) [79]. Declines in the incidence of anogenital warts have also been temporally associated with vaccine availability in both young women and men in various countries, including Australia [77,78] and the United States [80,81].

Duration of protection — HPV vaccines have shown excellent duration of protection for the time periods through which they have been studied. Continued protection against high-grade cervical, vaginal, and vulvar neoplasia has been observed through at least 84 months following vaccination among female trial participants [21,82-84]. Persistent antibody levels and protection against HPV infection have been reported up to 10 years following vaccination [85-88]. Of note, the precise level of antibody needed for protection against infection is unknown. Further data will become available in the future as female and male participants in vaccine studies are followed over time.

VACCINE SAFETY — All vaccines use virus-like particles (VLPs), which mimic the viral capsid. VLPs do not contain genetic material and are produced in biologic systems, which have well-established safety records [89]. All HPV vaccines have documented safety in large clinical trials, and extensive post-licensure data (following approval and clinical use) on the quadrivalent vaccine support this safety profile.

In light of the growing data on the safety of the HPV vaccine, the World Health Organization (WHO) Global Advisory Committee on Vaccine Safety stated that the benefit-risk profile remains favorable [90]. Additionally, it warned against claims of harm that are raised on the basis of anecdotal reports in the absence of biological or epidemiological substantiation.

Quadrivalent vaccine (Gardasil) — Data from both registration trials and post-licensure safety surveillance systems demonstrate that the vaccine is safe and well tolerated apart from mild injection site reactions. Postvaccination syncopal events have emerged as a potential serious adverse effect, although it does not appear unique to HPV vaccination, since syncope after vaccination occurs with other vaccines administered to adolescents [91,92]. A waiting time after vaccination is recommended to try to reduce the likelihood of injury from possible syncope. (See 'Postvaccination instructions' above.)

In the large licensing trials, the safety profile of the quadrivalent vaccine was evaluated in diverse populations of females from both resource-rich and resource-limited settings [55,61]. Mild injection site reactions were the most commonly observed adverse events in these studies as well as in trials in males [73].

Subsequently, surveillance systems and observational studies of vaccinated populations have supported the safety of quadrivalent vaccination []. As an example, in the United States, reports of adverse events to the Vaccine Adverse Event Reporting System (VAERS) have been consistent with the pre-licensure data [91,93]. Between June 2006 and March 2013, approximately 57 million doses of quadrivalent HPV vaccines were distributed in the United States. Over this time, VAERS received 21,194 reports of adverse events following HPV immunization among females; the vast majority (92 percent) were considered mild [93]. Among serious events, headache, nausea, vomiting, fatigue, dizziness, syncope, and generalized weakness were the most frequently reported. There was no increased risk of Guillain-Barré Syndrome compared with other vaccines in similar age groups [91].

There does appear to be an increased risk of syncope with the quadrivalent vaccine, but whether this is unique to this vaccine is unclear. In the United States, a disproportionate number of syncopal events following quadrivalent vaccine administration had been reported to the VAERS [91]. Among the 1896 syncopal events reported, 15 percent resulted in a fall or injury. Similarly, in an industry-sponsored study of almost 190,000 females in a large health care system who received at least one vaccine dose, emergency department visits or hospitalizations were higher during the postvaccine period compared with a subsequent control period for 10 of 265 diagnostic categories evaluated, including viral, bacterial, and skin infections and congenital anomalies [94]. An independent safety committee concluded that same-day syncopal events (OR 6.0, 95% CI 3.9-9.2) and local skin infections within two weeks of vaccination (OR 1.8, 95% CI 1.3-2.4) were the only adverse events likely associated with vaccine administration. The incidence of syncope among adolescents has increased overall with the introduction of other routine immunizations as well, such as meningococcal vaccine [91,92].

Other adverse events that initially appeared to be vaccine related have not been substantiated by further study. Although venous thromboembolism (VTE) rates reported to the VAERS in the United States were higher for quadrivalent vaccine than other vaccines, of the 31 patients with thromboembolism reported through 2008, 28 (90 percent) had a known risk factor (ie, estrogen-containing birth control pills or a family history of clotting disorder) [91]. In a study of adverse events following over 600,000 quadrivalent vaccine doses administered to females in seven large managed care organizations, there was a nonsignificant increase in the risk of VTE following vaccination among females aged 9 to 17 years, but individual review of the eight potential VTE cases indicated that only five met the standard case definition and all had other known risk factors for VTE (eg, oral contraceptive use, coagulation disorders, smoking, obesity, or prolonged hospitalization) [95]. Additionally, in a study of 1.6 million Danish women, of whom 30 percent had received quadrivalent HPV vaccine, there were over 4000 cases of incident VTE, but there was no association between vaccine receipt and VTE [96].

Anaphylaxis had also been reported following administration of the quadrivalent vaccine [91,97], although this risk has not been confirmed in other studies. In a mass school-based national vaccination program in Australia, the incidence of anaphylaxis was 2.6 per 100,000 doses [97]. However, some of those cases were subsequently thought not to have represented anaphylaxis and other studies from Australia did not confirm this high rate [98,99]. In the United States VAERS surveillance system, only 10 cases met predefined criteria for anaphylaxis; the overall risk ratio was 0.1 case per 100,000 doses distributed [91]. (See "Allergic reactions to vaccines".)

Although anecdotal and sporadic case reports had raised concerns about a potential causal relationship between HPV vaccination and development of multiple sclerosis and other demyelinating disorders, larger studies have refuted this. In a study of nearly four million Swedish and Danish females aged 10 to 44 years, receipt of quadrivalent vaccination was not associated with demyelinating diseases, including multiple sclerosis, optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis, as documented by billing codes [100].

9-valent vaccine (Gardasil 9) — Fewer post-licensure safety data are available for the 9-valent vaccine than the quadrivalent vaccine. The overall safety profile appears similar, although the frequency of mild local reactions might be higher with the 9-valent vaccine. (See 'Quadrivalent vaccine (Gardasil)' above.)

In an analysis of seven trials in which over 15,000 individuals received at least one dose of the 9-valent vaccine, the most common adverse effects were mild or moderate injection site reactions (pain, erythema, and swelling) [101]. These occurred slightly more often than with the quadrivalent vaccine. The frequency of systemic adverse effects (eg, headache, fever, nausea, dizziness) was similar with the 9-valent and quadrivalent vaccines. Serious adverse effects occurred in <0.1 percent.

Bivalent vaccine (Cervarix) — Data from large placebo-controlled randomized trials indicate that bivalent HPV vaccine is safe. As an example, in one trial of more than 18,000 females aged 15 to 25 years, there were no differences in serious adverse events between vaccine and placebo recipients. Post-licensure data are sparse from the United States, where almost all HPV vaccine used through 2015 was quadrivalent vaccine. In the United States, there were 52 reports to VAERS of adverse events following administration of bivalent vaccine through September 2011, and 98 percent were considered nonserious.

Behavioral impact — Some surveys of parents of adolescent girls identified a concern for sexual disinhibition following HPV vaccine receipt, particularly among older and ethnic minority parents [102,103]. Studies have not supported an increase in risky sexual behavior following vaccination [104-106]. In a retrospective study of preteenage girls enrolled in a large health care system, the combined incidence of pregnancy testing, chlamydia testing, and contraception counseling was determined among those girls who did (n = 493) and did not (n = 905) receive at least one HPV vaccine dose [104]. After adjustment for baseline health care utilization, race, and socioeconomic status, HPV vaccination was not associated with an increased rate of these sexual activity-related outcomes.

Where to report adverse events — Additional data on the Vaccine Adverse Event Reporting System are available on the web. Instructions for reporting adverse events to the Vaccine Adverse Event Reporting System are available at www.vaers.hhs.gov or by calling 800-822-7967 in the United States.

STRATEGIES TO IMPROVE VACCINE COVERAGE — Some countries, such as Australia, the United Kingdom, and Denmark, have achieved relatively high full-dose uptake of HPV vaccination (>60 percent) through inclusion of the vaccine in national vaccination programs [107-109]. In the United States, uptake of HPV vaccination has been suboptimal [110,111]. In 2015, based on results of a national survey among adolescents who had provider-reported vaccination records, estimated vaccine coverage among females and males aged 13 to 17 was 63 and 50 percent for at least one dose and only 42 and 28 percent for at least three doses (at a time when three doses was the recommended schedule for all recipients) [110]. In an earlier survey, parents who did not intend to have their daughters vaccinated gave the following as their top five reasons: the vaccine was not needed, the vaccine was not recommended, concern about vaccine safety, lack of knowledge about the vaccine or disease, and lack of sexual activity by their daughter [93]. This highlights a lack of understanding about the rationale for HPV vaccination on the part of the parent and the important role of the health care provider in consistently and clearly educating parents about vaccination.

Lack of opportunity did not appear to be a major reason for low vaccine coverage. Of the unvaccinated females in the survey, 84 percent had at least one medical visit at which they were given a different vaccine but not the HPV vaccine [93]. Vaccination rates may be particularly low among certain demographic subgroups. As an example, in a survey of 3253 females aged 15 to 25 years, only 29 percent reported initiating HPV vaccination despite 84 percent being aware of it [112]. Among self-described lesbians, only 9 percent of those aware of HPV vaccination had received it.

The implications of these findings are significant. Some experts estimate that by increasing complete-dose HPV vaccination coverage (with either bivalent or quadrivalent vaccine) to 80 percent in females, approximately 53,000 additional cases of cervical cancer could be prevented in the United States over the lifetimes of those currently aged ≤12 years [113]. More cervical cancers would conceivably be prevented with similar coverage with the 9-valent vaccine.

Attempted community- or practice-based interventions to improve uptake of HPV vaccine include patient reminders, physician-focused interventions (auditing and feedback or alerts to remind physicians to offer vaccination), school-based vaccination programs, and social marketing strategies. In a systematic review of studies evaluating the efficacy of such interventions, most suggested an improvement in at least one HPV vaccination outcome (eg, initiation or completion of greater number of doses) with these strategies [114].

IMPORTANCE OF CANCER SCREENING

Cervical screening — Clinicians should be aware that HPV immunization is not effective in clearing HPV infection, genital warts, or cervical intraepithelial neoplasia that is already present, and the vaccine does not protect against 100 percent of types known to cause cervical cancer. Thus, HPV vaccination status does not impact cervical cancer screening recommendations. In the United States, cervical cancer screening is recommended for all females beginning at age 21 (table 1). A preventive health care visit is an opportune time to discuss and offer HPV vaccination and/or cervical screening depending on the age of the woman [115]. Detailed information regarding screening for cervical cancer is found elsewhere. (See "Screening for cervical cancer".)

The optimal approach to cervical cancer screening in HPV-naïve females who have received the 9-valent vaccine and are thus protected against 90 percent of cervical cancer is unclear, but until further data are available and new screening guidelines issued, screening should continue for all vaccinated females.

Anal screening — Although there are no formal guidelines regarding screening for precancerous anal lesions, some specialists recommend anal cytologic screening for HIV-infected males and females and other populations known to be at increased risk of anal cancer. (See "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and prevention" and "HIV and women" and "Immunizations in HIV-infected patients" and "Anal squamous intraepithelial lesions: Diagnosis, screening, prevention, and treatment", section on 'Screening for anal SIL'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Immunizations in children and adolescents" and "Society guideline links: Immunizations in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Human papillomavirus (HPV) vaccine (The Basics)" and "Patient education: Anogenital warts (The Basics)" and "Patient education: Pap tests (The Basics)" and "Patient education: Vaccines for children age 7 to 18 years (The Basics)")

Beyond the Basics topics (see "Patient education: Human papillomavirus (HPV) vaccine (Beyond the Basics)" and "Patient education: Genital warts in women (Beyond the Basics)" and "Patient education: Cervical cancer screening (Beyond the Basics)" and "Patient education: Vaccines for children age 7 to 18 years (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Three HPV vaccines have been clinically developed, although not all are available in all locations:

Quadrivalent vaccine (Gardasil) targets HPV types 6, 11, 16, and 18.

9-valent vaccine (Gardasil 9) targets HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.

Bivalent vaccine (Cervarix) targets HPV types 16 and 18.

In the United States, only the 9-valent vaccine has been available since the end of 2016. (See 'Available vaccines' above.)

Vaccination with 9-valent, quadrivalent, or bivalent HPV vaccine provides a direct benefit to female and male recipients by safely protecting against cancers that can result from persistent high-risk HPV infection. HPV types 16 and 18 cause approximately 70 percent of all cervical cancers worldwide and nearly 90 percent of anal cancers, as well as a significant proportion of oropharyngeal cancer, vulvar and vaginal cancer, and penile cancer. Quadrivalent and 9-valent vaccine also protect against anogenital warts, 90 percent of which are caused by HPV types 6 and 11. Although the burden of HPV-associated disease is lower in males than females and thus the direct absolute benefit to males is smaller, the indirect benefit to males from vaccinating females only is incomplete and vaccinating males provides additional population benefits from herd immunity. (See 'Rationale' above.)

In accordance with the Advisory Committee on Immunization Practices (ACIP) in the United States, we recommend routine HPV vaccination for females (Grade 1A) and males (Grade 1B). The recommended age ranges for administration are as follows (See 'Indications and age range' above.):

For females – Routine immunization should be offered at 11 to 12 years of age, but can be administered starting at 9 years. Catch-up vaccination should be offered for females aged 13 to 26 years who have not been previously vaccinated.

For males – Routine immunization should be offered at 11 to 12 years of age, but can be administered starting at 9 years. Catch-up vaccination should be offered for males between the ages of 13 to 21 who have not been previously vaccinated. For men who have sex with men (MSM) and immunocompromised males, catch-up vaccination should be offered up to age 26.

Within the recommended age range, the optimal time for HPV immunization is prior to an individual's sexual debut. (See 'Optimal timing' above.)

If cost and availability are not issues, we recommend the 9-valent HPV vaccine rather than other HPV vaccines (Grade 1B). For individuals starting any HPV vaccine series when they are younger than 15 years old, we suggest administering a two- rather than a three-dose vaccine series (Grade 2C). In such patients, the two doses are administered at least six months apart. For individuals starting any HPV vaccine series at 15 years and older, the HPV vaccine is administered in three doses at 0, at 1 to 2 months, and at 6 months. Immunocompromised patients should also receive a three-dose series. (See 'Immunization schedule' above.)

HPV vaccination during pregnancy is typically avoided because of limited information about safety; however, data from inadvertent use in this setting are increasingly available and reassuring. (See 'Pregnant or breastfeeding females' above.)

Excellent antibody responses have been reported following immunization with the 9-valent, quadrivalent, and bivalent vaccines, with seroconversion rates of 93 to 100 percent in females and 99 to 100 percent in males. Elicited titers are generally higher in younger than in older individuals. (See 'Immunogenicity' above.)

Multicenter, double-blind, placebo-controlled trials have demonstrated the efficacy of quadrivalent, 9-valent, and bivalent HPV vaccines against incident and persistent cervical HPV infection due to vaccine types and the development of cervical intraepithelial neoplasia. Quadrivalent and 9-valent HPV vaccines have also demonstrated high efficacy against vaccine type-associated vaginal and vulvar intraepithelial neoplasia. They have demonstrated efficacy against genital warts associated with HPV 6 and HPV 11. Reduction in anal intraepithelial neoplasia in MSM, anal HPV infection in females, and oral HPV infection in females has also been demonstrated in trials. (See 'Efficacy' above.)

Data from both registration trials and post-licensure safety surveillance systems demonstrate that the vaccine is safe and well tolerated apart from mild injection site reactions. Postvaccination syncopal events have emerged as a potential serious adverse effect, although it does not appear unique to HPV vaccination. (See 'Vaccine safety' above.)

Clinicians should be aware that HPV immunization is not effective in clearing HPV infection, genital warts, or anogenital intraepithelial neoplasia that is already present. HPV vaccination status does not impact cervical cancer screening recommendations. (See 'Importance of cancer screening' above and "Screening for cervical cancer".)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Philip Castle, PhD, MPH, who contributed to an earlier version of this topic review.

Use of UpToDate is subject to the  Subscription and License Agreement.

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