Unger is involved in a material transfer agreement with Merck Research Laboratories to implement the competitive Luminex assay for HPV 6, 11, 16, and 18 serology. Presentations will not include any discussion of the unlabeled use of a product or a product under investigational use.# Introduction
and are self-limited, persistent genital HPV infection can cause cervical cancer in women and other types of anogenital can-Genital human papillomavirus (HPV) is the most com cers and genital warts in both men and women. mon sexually transmitted infection in the United States; an Approximately 100 HPV types have been identified, over estimated 6.2 million persons are newly infected every year 40 of which infect the genital area (2). Genital HPV types are (1). Although the majority of infections cause no symptoms categorized according to their epidemiologic association with cervical cancer. Infections with low-risk types (e.g., types 6
The material in this report originated in the National Center for HIV/ and 11) can cause benign or low-grade cervical cell changes, March 23, 2007 abnormalities, high-grade cervical cell abnormalities that are precursors to cancer, and anogenital cancers (5). High-risk HPV types are detected in 99% of cervical cancers (6); approximately 70% of cervical cancers worldwide are caused by types 16 and 18 (7). Although infection with high-risk types is considered necessary for the development of cervical cancer, it is not sufficient because the majority of women with high-risk HPV infection do not develop cancer (3,4).
In addition to cervical cancer, HPV infection also is associ ated with anogenital cancers such as cancer of the vulva, vagina, penis, and anus (Table 1) (8,9). Each of these is less common than cervical cancer (10)(11)(12)(13)(14). The association of genital types of HPV with nongenital cancer is less well established, but studies support a role in a subset of oral cavity and pharyn geal cancers (15).
In June 2006, the quadrivalent HPV vaccine types 6,11,16,18 (GARDASIL TM , manufactured by Merck and Co., Inc., Whitehouse Station, New Jersey) was licensed for use among females aged 9-26 years- for prevention of vaccine HPV-type-related cervical cancer, cervical cancer precursors, vaginal and vulvar cancer precursors, and anogenital warts. Efficacy studies are ongoing in men.
In the United States, cervical cancer prevention and con trol programs have reduced the number of cervical cancer cases and deaths through cervical cytology screening, which can detect precancerous lesions. The quadrivalent HPV vac cine will not eliminate the need for cervical cancer screening in the United States because not all HPV types that cause cervical cancer are included in the vaccine.

# Methods
The Advisory Committee on Immunization Practices (ACIP) HPV vaccine workgroup first met in February 2004 to begin reviewing data related to the quadrivalent HPV vac cine. The workgroup held monthly teleconferences and meet ings three times a year to review published and unpublished data from the HPV vaccine clinical trials, including data on safety, immunogenicity, and efficacy. Data on epidemiology and natural history of HPV, vaccine acceptability, and sexual behavior in the United States also were reviewed. Several eco nomic and cost effectiveness analyses were considered. Pre sentations on these topics were made to ACIP during meetings in June 2005, October 2005, and February 2006. Recom mendation options were developed and discussed by the ACIP HPV vaccine workgroup. When evidence was lacking, the recommendations incorporated expert opinion of the workgroup members. Options being considered by the workgroup were presented to ACIP in February 2006. The final recommendations were presented to ACIP at the June 2006 ACIP meeting. After discussions, minor modifications were made and the recommendations were approved at the June 2006 meeting. Modifications were made to the ACIP statement during the subsequent review process at CDC to update and clarify wording in the document.
The quadrivalent HPV vaccine is a new vaccine; additional data will be available in the near future from clinical trials. These data and any new information on epidemiology of HPV will be reviewed by ACIP as they become available, and rec ommendations will be updated as needed.

# Background Biology of HPV
HPVs are nonenveloped, double-stranded DNA viruses in the family Papillomaviridae. Isolates of HPV are classified as "types," and numbers are assigned in order of their discovery (16). Types are designated on the basis of the nucleotide se quence of specific regions of the genome. All HPVs have an 8 kb circular genome enclosed in a capsid shell composed of the major and minor capsid proteins L1 and L2, respectively. Purified L1 protein will self-assemble to form empty shells that resemble a virus, called virus-like particles (VLPs). In addition to the structural genes (L1 and L2), the genome en codes several early genes (E1, E2, E4, E5, E6, and E7) that enable viral transcription and replication and interact with the host genome. Immortalization and transformation func tions are associated with the E6 and E7 genes of high-risk HPV. E6 and E7 proteins from high-risk types are the pri mary oncoproteins; they manipulate cell cycle regulators, in duce chromosomal abnormalities, and block apoptosis (17).
Papillomaviruses initiate infection in the basal layer of the epithelium, and viral genome amplification occurs in differ entiating cells using the cellular replication machinery. After infection, differentiating epithelial cells that are normally nondividing remain in an active cell cycle. This can result in a thickened, sometimes exophytic, epithelial lesion. The vi rus is released as cells exfoliate from the epithelium. With neoplastic progression, the virus might integrate into the host chromosomes, and little virion production will occur.

# Immunology of HPV
HPV infections are largely shielded from the host immune response because they are restricted to the epithelium (18). Humoral and cellular immune responses have been docu mented, but correlates of immunity have not been established. Serum antibodies against many different viral products have been demonstrated. The best characterized and most typespecific antibodies are those directed against conformational epitopes of the L1 capsid protein assembled as VLPs. Not all infected persons have antibodies; in one study, 54%-69% of women with incident HPV 16, 6, or 18 infections had anti bodies (19). Among newly infected women, the median time to seroconversion is approximately 8 months (20,21).

# Laboratory Testing for HPV
HPV cannot be cultured. Detecting HPV requires identifi cation of HPV genetic information (DNA in the majority of assay formats). Assays differ considerably in their sensitivity and type specificity. The anatomic region sampled and the method of specimen collection will impact detection.
Only Epidemiology and basic research studies of HPV typically use nucleic acid amplification methods that generate typespecific and, in certain formats, quantitative results. Polymerase chain reaction (PCR) assays used most commonly in epide miologic studies target genetically conserved regions of the L1 gene. These consensus assays are designed to amplify HPV, and types are then determined by type specific hybridization, re striction enzyme digestion, or sequencing. In the trials of quadrivalent HPV vaccine, multiplex assays were used that spe cifically detect the L1, E6, and E7 gene for each HPV type.
The most frequently used HPV serologic assays are VLPbased enzyme immunoassays, designed to detect antibodies to the L1 viral protein. The type-specificity of the assay de pends on preparation of conformationally intact VLPs in re combinant baculovirus or other eukaryotic expression systems (22). Serologic assays are available only in research settings. Key laboratory reagents are not standardized, and no gold standards exist for setting a threshold for a positive result (23). In trials of the quadrivalent HPV vaccine, a competitive ra dioimmunoassay or a quadriplex competitive immunoassay was used, both of which measure neutralizing antibodies in serum (24,25).

# Epidemiology of HPV Infection Transmission and Risk Factors
Genital HPV infection is primarily transmitted by genital contact, usually through sexual intercourse (2,26). In virtu ally all studies of HPV prevalence and incidence, the most consistent predictors of infection have been measures of sexual activity, most importantly the number of sex partners (life time and recent) (27)(28)(29)(30)(31)(32)(33)(34). For example, one study indicated that 14.3% of women aged 18-25 years with one lifetime sex partner, 22.3% with two lifetime sex partners, and 31.5% with more than three lifetime partners (33) had HPV infec tion. Transmission of HPV through other types of genital contact in the absence of penetrative intercourse (i.e., oralgenital, manual-genital, and genital-genital contact) has been described, but is less common than through sexual intercourse (26,35,36). Additional risk factors primarily identified for fe males include partner sexual behavior (26) and immune sta tus (37,38). Genital HPV infection also can be transmitted by nonsexual routes, but this is uncommon. Nonsexual routes of genital HPV transmission include transmission from a mother to a newborn baby (39,40).
Because HPV is transmitted by sexual activity, understand ing the epidemiology of HPV requires data on sexual behav ior. The 2002 National Survey of Family Growth (http:// www.cdc.gov/nchs/nsfg) indicated that 24% of females in the United States were sexually active by age 15 years (41). This percentage increased to 40% by age 16 years and to 70% by age 18 years. Among sexually active females aged 15-19 years and 20-24 years, the median number of lifetime male sex partners was 1.4 and 2.8, respectively (42). The 2005 Youth Behavioral Risk Survey (/ mmwrhtml/SS5505a1.htm) indicated that that 3.7% of female students had been sexually active before age 13 years (43). Of those sexually active, 5.7% of 9th-grade females and 20.2% of 12th-grade females had had four or more sex partners.

# Natural History of HPV Infection
The majority of HPV infections are transient and asymp tomatic and cause no clinical problems; 70% of new HPV infections clear within 1 year, and approximately 90% clear within 2 years (27,(44)(45)(46). The median duration of new in fections is 8 months (27,45). Persistent infection with highrisk types of HPV is the most important risk factor for cervical cancer precursors and invasive cervical cancer (45,(47)(48)(49)(50). The risk for persistence and progression to precancerous lesions varies by HPV type, with HPV 16 being more oncogenic than other high-risk HPV types (51,52). Factors associated with cervical cancer in epidemiologic studies include ciga rette smoking, increased parity, increased age, other sexually transmitted infections, immune suppression, long-term oral contraceptive use, and other host factors (53)(54)(55). The time between initial HPV infection and development of cervical cancer is usually decades. Many aspects of the natural history of HPV are poorly understood, including the role and dura tion of naturally acquired immunity after HPV infection.

# HPV Prevalence and Incidence in the United States
Overall in the United States, an estimated 6.2 million new HPV infections occur every year among persons aged 14-44 years (1). Of these, 74% occur among those aged 15-24 years. Modeling estimates suggest that >80% of sexually active women will have acquired genital HPV by age 50 years (56).
Routine reporting of HPV does not exist in the United States. Information on prevalence and incidence has been obtained primarily from clinic-based populations, such as family planning and sexually transmitted disease or univer sity health clinic patients. These evaluations have documented prevalence of HPV DNA ranging from 14% to 90% (57). Prevalence was highest among sexually active females aged <25 years and decreased with increasing age (31,32,58,59). Data from a multisite, clinic-based study of sexually active women in the United States indicated that prevalence was highest among those aged 14-19 years (60).
Two studies have reported prevalence in representative, population-based samples. In a study of sexually active women aged 18-25 years, prevalence of any HPV was 26.9% (33). Prevalence of types 6 or 11 was 2.2%, and prevalence of types 16 or 18 was 7.8%. In a study of females aged 14-59 years during 2003-2004, the prevalence of any HPV was 26.8% (61). Prevalence was highest among women aged 20-24 years (44.8%). Overall, prevalence of types 6, 11, 16, and 18 was 1.3%, 0.1%, 1.5%, and 0.8%, respectively.
Few data exist on cumulative risk for HPV infection. De tection of HPV DNA indicates infection and does not pro vide information on women who were infected but cleared the HPV. Seroprevalence data can provide a better estimate of cumulative risk but will also be an underestimate, because not all persons with natural HPV infection have detectable antibodies. In a representative sample of women aged 20-29 years in the United States, HPV 16 seroprevalence was 25% (62). Because as few as 60% of those infected with HPV have detectable antibodies, the seroprevalence is an underestimate, and true exposure to HPV 16 could be as high as 41% among women in that age group. Data also are available from the quadrivalent HPV vaccine phase III trials, in which both HPV PCR assays on cervical specimens and serologic tests were performed at enrollment. Participation was restricted to sexu ally active women who had no more than four lifetime part ners or were planning sexual debut. Among 5,996 North American females aged 16-24 years, 92% were sexually ac tive, and the median number of lifetime sex partners was two; 24% had evidence of previous or current infection with HPV 6,11,16, or 18 on the basis of serology and/or PCR at the time of enrollment; four (0.1%) had evidence of infection with all four vaccine types (Merck and Co., unpublished data, 2006).
Studies of incident HPV infection that have evaluated HPV DNA detection over time demonstrate that acquisition oc curs soon after sexual debut. In a prospective study of college women in the United States, the cumulative probability of incident infection was 38.9% by 24 months after first sexual intercourse. Of all HPV types, HPV 16 acquisition was high est (10.4%); 5.6% had acquired HPV 18 (26).
HPV infection also is common among men (63)(64)(65)(66)(67). Among heterosexual men in clinic-based studies, prevalence of geni tal HPV infection often is >20% and is highly dependent on the anatomic sites sampled and method of specimen collection (64,66,67).

# Clinical Sequelae of HPV Infection
Clinical sequelae of HPV infection include cervical cancer and cervical cancer precursors, other anogenital cancers and their precursor lesions, anogenital warts, and recurrent respi ratory papillomatosis.

# Cervical Cancer and Precursor Lesions
HPV is a necessary but not sufficient cause of all cervical cancers. Approximately three fourths of all cervical cancers in the United States are squamous cell; the remaining are adeno carcinomas. HPV 16 and 18 account for approximately 68% of squamous cell cancers and 83% of adenocarcinomas (7).
Although HPV infection usually is asymptomatic, cervical infection can result in histologic changes that are classified as cervical intraepithelial neoplasias (CIN) grades 1, 2, or 3 on the basis of increasing degree of abnormality in the cervical epithelium or adenocarcinoma in situ (AIS). Spontaneous clearance or progression to cancer in the absence of treatment varies for CIN 1 and CIN 2, and CIN 3. CIN 1 usually clears spontaneously (60% of cases) and rarely progresses to cancer (1%); a lower percentage of CIN 2 and 3 spontaneously clears (30%-40%), and a higher percentage progresses to cancer if not treated (>12%) (68). Cervical cancer screening with the Pap test can detect cytologic changes that reflect the underly ing tissue changes. However, cytologic abnormalities detected by the Pap test can be ambiguous or equivocal. Abnormalities include ASC-US, atypical glandular cells, low-and high-grade squamous intraepithelial lesions (LSIL and HSIL), and AIS. HPV types 16 and 18 are more commonly found in associa tion with higher-grade lesions. In one study, the prevalence of HPV 16 was 13.3% among ASC-US, 23.6% among LSIL, and 60.7% among HSIL Pap tests (69).
No routine reporting or registry exists for abnormal Pap tests or cervical cancer precursor lesions in the United States; however, data are available from managed-care organizations and administrative data sets (70,71). Each year, approximately 50 million women undergo Pap testing; approximately 3.5-5.0 million of these Pap tests will require some follow-up, including 2-3 million ASC-US, 1.25 million LSIL, and 300,000 HSIL Pap tests (72)(73)(74).
In the United States, cases of cervical cancer are routinely reported to cancer registries such as the National Cancer In stitute Surveillance, Epidemiology, and End Results program, and CDC-administered National Program of Cancer Regis tries that cover approximately 96% of the U.S. population in 2003. Cervical cancer incidence rates have decreased approxi mately 75% and death rates approximately 70% since the 1950s, largely because of the introduction of Pap testing (74,75). However, the decrease in incidence is observed pri marily in squamous cell carcinomas; the incidence of adeno carcinomas has not changed appreciably (76). Adenocarcinomas are more difficult to detect because they are found in the endocervix; they account for approximately 20% of cervical cancer cases in the United States (77,78). In 2003, cervical cancer incidence in the United States was 8.1 per 100,000 women, with approximately 11,820 new cases reported (79). The median age of diagnosis for cervical can cer was 47 years.
Substantial differences exist in the cervical cancer incidence and mortality by racial/ethnic group in the United States (78). The incidence for black women was approximately 1.5 times higher than that for white women (Figure 1). Incidence for Hispanic women also was higher than that for white women (78). Death rates for black women were twice that for white women. Although incidence for Asian women overall is simi lar to that for white women (78), certain Asian subgroups, especially Vietnamese and Korean women, have higher rates of cervical cancer (80).
Geographic differences exist in incidence and mortality, with notably higher incidence and mortality in Southern states (Figures 2 and 3) and Appalachia (78,81). Mortality rates are  1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999  higher among specific groups, including Hispanic women living on the Texas-Mexico border; white women in Appala chia, rural New York State, and the northern part of the north east United States; and among American Indians in the Northern Plains and Alaska Native women (82).

# Vaginal and Vulvar Cancer and Precursor Lesions
HPV is associated with vaginal and vulvar cancer and vagi nal and vulvar intraepithelial neoplasias; however, unlike cer vical cancer, not all vaginal and vulvar cancers are associated with HPV. The natural history of vaginal and vulvar neopla sia is incompletely understood (83,84). No routine screening exists for vaginal or vulvar cancer in the United States.
The majority of vaginal cancers and vaginal intraepithelial neoplasias III (VaIN III) are positive for HPV (85); HPV 16 is the most common type (86,87). Approximately one third of women with VaIN or vaginal cancer had been treated pre viously for an anogenital cancer, usually cervical cancer (86). Vaginal cancer is rare, and incidence has decreased by 20% during the preceding two decades. In the United States in 2003, a total of 1,070 cases of invasive vaginal cancer (age adjusted incidence rate: 0.7 per 100,000 females) and 391 deaths (death rate: 0.2 per 100,000 females) occurred (79). The median age for diagnosis of vaginal cancer was 69 years.
HPV is associated with approximately half of vulvar squa mous cell cancers, the most common type of vulvar cancer.
HPV-associated vulvar cancer tends to occur in younger women and might be preceded by vulvar intraepithelial neo plasia (VIN). In a recent study, HPV types 16 or 18 were detected in 76% of the VIN 2/3 and 42% of vulvar carci noma samples (87). In 2003, a total of 3,507 cases of vulvar cancer (age-adjusted incidence rate: 2.2 per 100,000) and 775 deaths (death rate: 0.4 per 100,000 females) occurred in the United States (79). During 1973-2000, the incidence of in situ vulvar cancer increased by 400%, and the rate of invasive vulvar cancer increased by 20%. Changes in detection or re porting of in situ cancers might be responsible for the in creased rate of in situ cancers (88).

# Anal Cancer
HPV is associated with approximately 90% of anal squa mous cell cancers. Anal intraepithelial neoplasia (AIN) is rec ognized as a precursor of anal cancer, although the natural history of these lesions (i.e., rate of progression and regres sion) is less clear than for CIN (50). Anal cancer is more com mon in women (2,516 new cases in 2003 ) than in men (1,671 new cases ) (79). During the preceding three decades, the incidence of anal cancer in the United States has increased, especially among men (89). Women at high risk for anal can cer include those with high-grade cervical lesions and cervi cal and vulvar cancers. Men who have sex with men and persons who have human immunodeficiency virus (HIV) infection also are at high risk for anal cancer (90). No national recommenda tions exist for cytologic screening to prevent anal cancers.

# Genital Warts
All anogenital warts (condyloma) are caused by HPV, and approximately 90% are associated with HPV types 6 and 11 (91). The average time to development of new anogenital warts after infection with HPV types 6 or 11 is approximately 2-3 months (92). However, not all persons infected with HPV types 6 or 11 acquire genital warts. Anogenital warts can be treated, although many warts (20%-30%) regress spontane ously. Recurrence of anogenital warts is common (approxi mately 30%), whether clearance occurs spontaneously or following treatment (93). Anogenital warts are not routinely reported in the United States. The prevalence of genital warts has been examined using health-care claims data (94). An es timated 1% of sexually active adolescents and adults in the United States have clinically apparent genital warts (29).

# Recurrent Respiratory Papillomatosis
Infection with low-risk HPV types, primarily types 6 or 11, rarely results in recurrent respiratory papillomatosis (RRP), a disease that is characterized by recurrent warts or papillo mas in the upper respiratory tract, particularly the larynx. On the basis of age of onset, RRP is divided into juvenile onset (JORRP) and adult onset forms. JORRP, generally de fined as onset before age 18 years, is better characterized than the adult form. JORRP is believed to result from vertical trans mission of HPV from mother to baby during delivery, al though the median age of diagnosis is 4 years. A multicenter registry of JORRP in the United States that collected data during 1999-2003 ( 95) demonstrated that although the clini cal course of JORRP was variable, it is associated with exten sive morbidity, requiring a median of 13 lifetime surgeries to remove warts and maintain an open airway. Estimates of the incidence of JORRP are relatively imprecise but range from 0.12 to 2.1 cases per 100,000 children aged <18 years in two cities in the United States (96). The prevalence, incidence, and disease course of the adult form of RRP are less clear.

# Treatment of HPV Infection
HPV infections are not treated; treatment is directed at the HPV-associated lesions. Treatment options for genital warts and cervical, vaginal, and vulvar cancer precursors include various local approaches that remove the lesion (e.g., cryo therapy, electrocautery, laser therapy, and surgical excision). Genital warts also are treated with topical pharmacologic agents (97). On the basis of limited existing data, available therapies for HPV-related lesions might reduce but probably do not eliminate infectiousness.

# TABLE 2. Cervical cancer screening guidelines -United States

# Prevention HPV Infection
Condom use might reduce the risk for HPV and HPVassociated diseases (e.g., genital warts and cervical cancer). A limited number of prospective studies have demonstrated a protective effect of condoms on acquisition of genital HPV. A study among newly sexually active college women demon strated a 70% reduction in HPV infection when their part ners used condoms consistently and correctly (98). Abstaining from sexual activity (i.e., refraining from any genital contact with another persons) is the surest way to prevent genital HPV infection. For those who choose to be sexually active, a mo nogamous relationship with an uninfected partner is the strat egy most likely to prevent future genital HPV infections.
Neither routine surveillance for HPV infection nor part ner notification is useful for HPV prevention (97). Genital HPV infection is so prevalent that the majority of partners of persons found to have HPV infection are infected already; no prevention or treatment strategies have been recom mended for partners.

# Cervical Cancer Screening
The majority of cervical cancer cases and deaths can be pre vented through detection of pre-cancerous changes in the cervix by cytology using the Pap test. Pap test screening includes a con ventional Pap or a liquid-based cytology (99). CDC does not issue recommendations for cervical cancer screening, but certain professional groups have published recommendations (Table 2).  (102). USPSTF concluded that evidence is insufficient to recommend for or against routine use of HPV tests (100).

# Guidelines
An estimated 82% of women in the United States have had a Pap test during the preceding 3 years (103). Pap test rates for all age and ethnic populations have increased during the preceding two decades. However, certain groups continue to have lower screening rates. These include women with less than a high school education (77%); foreign-born women, especially women who have been in the United States for <10 years (61%); women without health insurance (62%); and certain racial/ethnic populations such as Hispanics (77%) and Asians (71%). Approximately half of women who had cervi cal cancer diagnosed in the United States had not had a Pap test in the 3 years before diagnosis (104).

# Quadrivalent Human Papillomavirus Vaccine Composition
The licensed vaccine is a quadrivalent HPV vaccine (GARDASIL TM , produced by Merck and Co, Inc.). The L1 major capsid protein of HPV is the antigen used for HPV vaccination (105) The vaccine should be stored at 2C-8C (36F-46F) and not frozen.

# Dose and Administration
Quadrivalent HPV vaccine is administered intramuscularly as three separate 0.5-mL doses. The second dose should be administered 2 months after the first dose and the third dose 6 months after the first dose. The vaccine is available as a sterile suspension for injection in a single-dose vial or a prefilled syringe.

# Efficacy
One clinical study evaluated efficacy of monovalent HPV 16 vaccine, and three studies evaluated efficacy of quadriva lent HPV vaccine: a phase II study of a monovalent HPV 16 vaccine (protocol 005) (106,107), a phase II study of quadriva lent HPV vaccine (protocol 007) (108-110), both among females aged 16-23 years, and two phase III studies of quadrivalent HPV vaccine (protocols 013 and 015) among females aged 16-23 and 16-26 years, respectively. All were randomized, double-blind, placebo-controlled studies.
The studies used prespecified endpoints to evaluate the impact of the quadrivalent vaccine in preventing HPV-related infection and disease. Phase II studies were primarily proof of-concept studies that evaluated the efficacy of vaccine using a persistent infection endpoint. Phase III studies evaluated the efficacy of vaccine on clinical lesions. Predefined combi nations of phase II and III studies were used to improve the precision of the efficacy findings. Various endpoints were as sessed in the different studies, including vaccine type-related persistent HPV infection, CIN, VIN and VaIN, and genital warts. The primary endpoint and the basis for licensure was the combined incidence of HPV 16-and 18-related CIN 2/3 or AIS. These endpoints served as surrogate markers for cer vical cancer. Studies using an invasive cervical cancer end point were not feasible because the standard of care is to screen for and treat CIN 2/3 and AIS lesions to prevent invasive cervical cancer. Furthermore, the time from acquisition of infection to the development of cancer can exceed 20 years. The two phase III efficacy studies of quadrivalent HPV vac cine (protocols 013 and 015) were international studies, which included persons from North America, South America, Eu rope, Australia, and Asia. Data on efficacy against CIN end points also are available from the phase II study (protocol when analyses were restricted to participants who received all 007) (108,110) and of monovalent HPV-16 vaccine (protocol 3 doses of vaccine, had no protocol violations, and no evi 005) (107).
dence of infection with the relevant vaccine HPV type (se-The quadrivalent HPV vaccine has a high efficacy for pre-ronegative and HPV PCR-negative through 1 month after vention of vaccine HPV type HPV 6-, 11-, 16-, and 18-dose 3) (Tables 3 and 4) (111). No evidence exists of protec related persistent infection, vaccine type-related CIN, CIN tion against disease caused by vaccine types for which partici 2/3, and external genital lesions (genital warts, VIN and VaIN) pants were PCR positive at baseline. Participants infected with  one or more vaccine HPV types before vaccination were pro tected against disease caused by the other vaccine HPV types.
No evidence exists that the vaccine protects against disease caused by nonvaccine HPV types.

# Persistent HPV Infection
Two phase II studies evaluated persistent infection, defined as a vaccine HPV type detected by PCR at two or more con secutive visits 4 months apart or at a single visit if it was the last visit of record. In the phase II quadrivalent vaccine study (pro tocol 007), 276 women received the 20/40/40/20 g dose for mulation of vaccine, and 275 received a placebo. The efficacy for prevention of persistent HPV 6, 11, 16, or 18 infection or disease at the end of study (approximately 2.5 years after dose 3) was 89.5% (95% confidence interval  = 70.7%-97.3%). Of the vaccinated persons with persistent infection endpoints, three had HPV 16 detected at the last visit (without observed persistence), and one had persistent infection with HPV 18 (detected at both 12 and 18 months) but not at months 24, 30, or 36 (108). In the phase II study of a monovalent HPV 16 vaccine (protocol 005), the efficacy against persistent HPV 16 infection was 100% at a midpoint analysis (106) and 94.3% (CI = 87.8%-97.7%) at the end of the study (107). All seven cases in the vaccine group had HPV 16 DNA detected on the person's last study visit (without observed persistence).

# Cervical Disease
Two phase III trials evaluated efficacy against cervical disease. Protocol 015 included 12,157 women aged 16-26 years. Par ticipants had a Pap test, cervicovaginal sampling for HPV DNA testing, and detailed genital inspection at day 1 and months 7, 12, 24, 36, and 48, and were referred to colposcopy using a pro tocol specified algorithm based on Pap test results. The primary study endpoint was incidence of HPV 16-or 18-related CIN 2, CIN 3, AIS, or cervical cancer. In a per protocol analysis, the vaccine efficacy was 100% (CI = 80.9%-100%) for prevention of HPV 16 or 18 related CIN 2/3 or AIS (Table 3).
Protocol 013 included 5,442 females aged 16-23 years. Par ticipants had a Pap test at day 1 and at months 7, 12, 18, 24, 30, 36, and 48 and were referred to colposcopy according to protocol. In addition, participants had detailed genital in spection, with biopsy of abnormalities and cervicovaginal sam pling for HPV DNA sampling. The study had two primary efficacy endpoints: 1) external genital lesions related to HPV 6, 11, 16, or 18, including genital warts, VIN, VaIN, vulvar cancer, or vaginal cancer; and 2) cervical endpoints related to HPV 6, 11, 16, or 18, including CIN, AIS, or cervical can cer. In a per protocol analysis, the vaccine efficacy was 100% (CI = 89.5%-100%) for prevention of any grade CIN re lated to vaccine types (Table 3).
In a planned combined efficacy analysis, including data from four clinical studies (protocol 005, 007, 013, and 015), pro tection against HPV 16-or 18-related CIN 2/3 or AIS was 100% (CI = 92.9%-100%) (111). In a planned combined analy sis, including data from three studies (protocol 007, 013, and 015), protection against any CIN attributed to HPV 6, 11, 16, or 18, the efficacy was 95.2% (CI = 87.2%-98.7%). Four cases of CIN occurred in the vaccine group; all were CIN 1.

# External Genital Lesions
Data from three studies (protocol 007, 013, and 015) pro vide data on efficacy against external genital lesions. In a com bined analysis, the efficacy of quadrivalent HPV vaccine against HPV 6-, 11-, 16-, or 18-related external genital warts was 98.9% (CI = 93.7%-100%) in a per protocol analysis (Table 3). Efficacy against HPV 16-or 18-related VIN 2/3 or VaIN 2/3 was 100% (CI = 55.5-100.0) (Table 4).

# Efficacy in Females with Current or Previous Vaccine HPV-Type Infection
Because participants were enrolled into the clinical trials even if they were HPV DNA or antibody positive, evaluating efficacy in females infected with a vaccine HPV type at the time of vaccination was possible. Overall, 27% of the study population had evidence of previous exposure to or infection with a vaccine HPV type. Among these participants, 74% were positive to only one vaccine HPV type and did not have evidence of infection with the other three types. Among par ticipants positive to one or more vaccine HPV types, the vac cine had high efficacy for prevention of disease caused by the remaining vaccine HPV types (112).
The vaccine's impact on the course of infection present at the time of infection was evaluated using data from four clini cal studies (protocols 005, 007, 013, and 015). Three differ ent groups were analyzed on the basis of antibody and HPV DNA detection at the time of vaccination (Table 5). Among persons seropositive to the relevant HPV type but HPV DNA negative, efficacy against CIN 2/3 or AIS caused by that type was 100% (CI = -63.6%-100%). Among women who were HPV DNA positive but seronegative, efficacy was 31.2% (CI = -4.5-54.9). Among women who were both seropostive and HPV DNA positive, efficacy against CIN 2/3 caused by that type was -25.8% (CI = -76.4%-10.1%). Because of the small numbers and wide confidence intervals around efficacy estimates, limited conclusions can be drawn from these estimates.

# Efficacy in the Intent-to-Treat Population
Analyses among all women who received at least 1 dose of vaccine and had any follow-up 1 month after the first dose, regardless of initial PCR or serology, provide information on ). The lower efficacy in these analyses compared with the per protocol population indicates that certain women were infected with vaccine types before vaccination. A 12.2% (CI = -3.2%-25.3%) reduction occurred in any CIN 2/3 in the vaccinated group compared with the placebo group at a median follow-up time of 1.9 years (111).

# Duration of Protection
A subset of participants (n = 241) in the phase II quadriva lent HPV vaccine study (protocol 007) is being followed for 60 months after dose one. In a combined analysis of all partici pants through year 3 and a subset through 60 months, the effi cacy against vaccine HPV type persistent infection or disease was 95.8% (CI = 83.8%-99.5%) and efficacy against vaccine type-related CIN or external genital lesions was 100% (CI = 12.4%-100%) (110).
Follow-up studies are planned by Merck and Co., Inc. to determine duration of protection among women enrolled in the phase III studies through 3 years after dose 3. Additional data on duration of protection will be available from followup of approximately 5,500 women enrolled in one of the phase III quadrivalent HPV vaccine studies in the Nordic coun tries. These women will be followed for at least 14 years; sero logic testing will be conducted 5 and 10 years after vaccination; and Pap testing results will be linked to data from vaccine registries to monitor outcomes.

# Immunogenicity Immunogenicity in Persons Aged 9-26 Years
The immunogenicity of the quadrivalent HPV vaccine has been measured by detection of IgG antibody to the HPV L1 by a type-specific competitive Luminex-based immunoassay (cLIA) in the majority of the studies (24,25). This assay mea sures antibodies against neutralizing epitopes for each HPV type. The units (milliMerck units) are internally consistent but cannot be directly compared across HPV types or with results from other HPV antibody assays. The height of the antibody titers (geometric mean titers ) for the dif ferent types cannot be directly compared.
Data on immunogenicity are available from Phase II (109) and Phase III double-blind, randomized, placebo-controlled trials conducted among females aged 16-26 years and immu nogenicity studies conducted among males and females aged 9-15 years (113). In all studies conducted to date, >99% of study participants had an antibody response to all four HPV types in the vaccine 1 month after completing the 3-dose se ries (109,113). High seropositivity rates were observed after vaccination regardless of sex, ethnicity, country of origin, smoking status, or body mass index.
Vaccination produced antibody titers higher than those after natural infection. Among females aged 16-23 years, anti-HPV 6, 11, 16, and 18 GMTs 1 month after the third dose of vaccine were higher than those observed in participants who were HPV seropositive and PCR negative at enrollment in the placebo group (109).
Vaccination of females who were seropositive to a specific vaccine HPV type at enrollment resulted in higher antibody titers to that type, particularly after the first dose, compared with those seronegative at enrollment (109), suggesting a boosting of naturally acquired antibody by vaccination. In studies among females aged 16-26 years, the interval between the first and second dose of vaccine ranged from 6 to 12 weeks. Variation in the interval did not diminish the GMTs post-vac cination. Likewise, little impact of intervals was observed be tween the second and third dose ranging from 12 to 23 weeks.
A serologic correlative of immunity has not been identified and no known minimal titer determined to be protective. The high efficacy found in the clinical trials to date has precluded identification of a minimum protective antibody titer. Fur ther follow-up of vaccinated cohorts might allow determina tion of serologic correlates of immunity.

# Immunogenicity Bridge to Efficacy Among Females
Immunogenicity studies provide data, allowing compari son of seropositivity and GMTs among females aged 9-15 years with those among females aged 16-26 years who were in the efficacy studies (Table 6) (111). Seropositivity rates in all age groups were approximately 99% for HPV 6, 11, 16, and 18. Anti-HPV responses 1 month post dose 3 among females aged 9-15 years were noninferior to those aged 16-26 years. At month 18, anti-HPV GMTs in females aged 9-15 years remained two to three fold higher than those observed at the same time point in females aged 16-26 years in the vaccine efficacy trials.

# Duration of Antibody
The longest follow-up to date is 60 months in the phase II trial of quadrivalent HPV vaccine (110). Antibody titers de cline over time after the third dose but plateau by 24 months. At 36 months, anti-HPV 16 GMT among vaccinees remained higher than those in participants in the placebo group who were seropositive at baseline, and anti-HPV 6, 11, and 18 titers were similar to those seropositive in the placebo group (109). At 36 months, seropositivity rates were 94%, 96%, 100%, and 76% to HPV 6, 11, 16, and 18, respectively. No evidence exists of waning efficacy among participants who become seronegative during follow-up (110). Data from a revaccination study in which vaccinated women were given a challenge dose 5 years after enrollment into the study dem onstrated an augmented rise in antibody titer consistent with immune memory (114).

# Concomitant Administration of HPV Vaccine with Other Vaccines
GMTs after concomitant administration of quadrivalent HPV vaccine and hepatitis B vaccine at all 3 doses were noninferior to GMTs after administration at separate visits. Studies are planned to evaluate concomitant administration with meningococcal conjugate vaccine and with the adolescent/adult formulation of tetanus, diphtheria and acellular pertussis (Tdap) vaccine.

# Safety and Adverse Events
The quadrivalent HPV vaccine was evaluated for injectionsite and systemic adverse events, new medical conditions re ported during the follow-up period, and safety during pregnancy and lactation. Safety data on quadrivalent HPV vaccine are available from seven clinical trials and include 11,778 persons aged 9-26 years who received quadrivalent vaccine and 9,686 who received placebo. Detailed data were collected using vaccination report cards for 14 days following each injection of study vaccine on a subset of participants aged 9-23 years. The population with detailed safety data included 5,088 females who received quadrivalent HPV vac cine and 3,790 who received placebo (Tables 7-9) (111).

# Local Adverse Events
In the study population with detailed safety data, a larger proportion of persons reported injection-site adverse events (for all persons except those aged 100F (>38C) after dose one, two, or three (Table 9).

# TABLE 7. Injection-site adverse events among female participants aged 9-23 years in the detailed safety data, days 1-5 after any vaccination with quadrivalent human papillomavirus (HPV) vaccine

# Serious Adverse Events in All Safety Studies
Vaccine-related serious adverse events occurred in <0.1% of persons. The proportions of persons reporting a serious adverse event were similar in the vaccine and placebo groups, as were the types of serious adverse events reported. Seven persons had events that were determined to be possibly, prob ably, or definitely related to the vaccine or placebo. Five events occurred among quadrivalent HPV vaccine recipients and two among placebo recipients. The five in the quadrivalent HPV vaccine group included bronchospasm, gastroenteritis, head ache/hypertension, vaginal hemorrhage, and injection site pain/movement impairment.
In the overall safety evaluation, 10 persons in the group that received quadrivalent HPV vaccine and seven persons in the placebo group died during the course of the trials. None of the deaths was considered to be vaccine related. Two deaths in the vaccine group and one death in the placebo group oc curred within 15 days following vaccination. Seven deaths were attributed to motor-vehicle accidents (four in vaccine group and three in placebo group), three were caused by in tentional overdose (nonstudy medications) or suicide (one in vaccine group and two in placebo group), two were attrib uted to pulmonary embolus or deep venous thrombosis (one each in vaccine and placebo group), two were attributed to sepsis, one case each attributed to cancer and arrhythmia (in vaccine group), and one case caused by asphyxia (placebo group).

# New Medical History
Information was collected on new medical conditions that occurred in up to 4 years of follow-up. Overall, nine (0.08%) participants in the vaccine group and three (0.03%) partici pants in the placebo group had conditions potentially indica tive of autoimmune disorders, including various arthritis diagnoses (nine in vaccine group and two in placebo group) and systemic lupus erythematosis (none in vaccine group and one in placebo group) (111). No statistically significant dif ferences exist between vaccine and placebo recipients for the incidence of these conditions.

# Vaccination During Pregnancy
The quadrivalent clinical trial protocols excluded women who were pregnant. Human beta gonadotropin testing was conducted before administration of each vaccine dose, and if women were found to be pregnant, vaccination was delayed until completion of pregnancy. Nevertheless, among clinical trial participants, 1,244 pregnancies occurred in the vaccine group and 1,272 occurred in the placebo group (Table 10) (111). Among those with known outcomes (996 and 1,018), the percentage with spontaneous loss was similar in both groups (25%). A total of 15 and 16 congenital abnormalities occurred in the vaccine and placebo groups, respectively, in cluding five in the vaccine group and none in the placebo group among infants born to women who received vaccine or placebo within 30 days of estimated onset of pregnancy. The five congenital abnormalities were determined by an expert panel to be unrelated (one pyloric stenosis with ankyloglos sia, one congenital hydronephrosis, one congenital megaco lon, one club foot, and one hip dysplasia). Rates of congenital abnormalities in the study were consistent with those in sur veillance registries. Quadrivalent HPV vaccine has been clas sified as Category B on the basis of animal studies in rats showing no evidence of impaired fertility or harm to the fetus.

# Vaccination During Lactation
In the clinical trials, 995 women in the evaluated popula tion (500 and 495 persons in the group that received quadriva lent HPV vaccine or placebo, respectively) were breast feeding during the vaccination period. A total of 17 (3.4%) and nine (1.8%) infants of women who breastfed who received quadrivalent HPV vaccine or placebo, respectively, experi enced a serious adverse event. Of the 23 experiences among the 17 infants of women who received vaccine, 12 were respi ratory infections, five were gastroenteritis or diarrhea, and the remaining included various other single events. None was considered vaccine related.

# Impact of Vaccination and Cost Effectiveness Economic Burden of HPV
The prevention and treatment of anogenital warts and cer vical HPV-related disease imposes an estimated burden of $4 billion or more (2004 dollars) in direct costs in the United States each year (70,71,115). Of this, approximately $200 million is attributable to the management of genital warts; approximately $300-$400 million to invasive cervical can cer; and the remainder to routine cervical cancer screening, the follow-up of abnormal Pap tests, and pre-invasive cervi cal cancer (71,115). The estimated economic burden associ ated with HPV would be more substantial if the cost of other HPV-related diseases (e.g., vaginal and anal cancer and RRP) were included.

# Expected Impact of Vaccination
Various different models have been developed to evaluate the impact of HPV vaccine (116). Markov models have sug gested that vaccination of an entire cohort of females aged 12 years could reduce the lifetime risk for cervical cancer by 20%-66% (117,118) in that cohort, depending on the efficacy of the vaccine and the duration of vaccine protection. Models also project decreases in Pap test abnormalities and cervical cancer precursor lesions as a result of vaccination. For ex ample, incidence of low-grade Pap test abnormalities would decrease by 21% over the life of a vaccinated cohort of fe males aged 12 years (117). Models that incorporate HPV trans mission dynamics suggest an even greater potential impact of HPV vaccination on cervical cancer and cervical cancer pre cursors (119)(120)(121). Decreases in cervical cancer incidence and precursor lesions would occur more quickly with catch-up vaccination according to models that evaluated catch-up for females aged 12-24 years (121,122).

# Cost Effectiveness of HPV Vaccine
Since 2003, four studies have estimated the potential cost effectiveness of HPV vaccination in the context of cervical cancer screening practices in the United States (117)(118)(119)121). Two of these studies applied Markov models to estimate the cost per quality-adjusted life year (QALY), focusing on the costs and impact of HPV vaccination for a given cohort, with out considering the effect of vaccination on HPV transmis sion in the population (herd immunity). The other studies applied dynamic transmission models to incorporate the ben efits of herd immunity in estimating the cost effectiveness of HPV vaccination.
The two studies based on Markov models of the natural history of HPV infection examined the cost effectiveness of vaccinating females aged 12 years. One study assumed 100% vaccine coverage, 90% vaccine efficacy against HPV 16/18, lifetime duration of protection, and a cost of $377 per vac cine series (118). Under these assumptions, an estimated 58% reduction was achieved in the lifetime risk for cervical cancer for the vaccinated cohort at a cost of $24,300 (2002 dollars) per QALY compared with no vaccination. A second study assumed 70% vaccine coverage, 75% efficacy against all highrisk HPV types, 10 years duration of protection plus 10 addi tional years of protection with a booster, and a cost of $300 per vaccine series plus $100 per booster (117). Under these assump tions, an estimated 20% reduction in cervical cancer incidence was achieved in the vaccinated cohort at a cost of $22,800 per QALY (2001 dollars) compared with no vaccination.
The two cost effectiveness analyses based on dynamic trans mission models examined the cost effectiveness of vaccinat ing females. One study assumed vaccination at age 12 years with 70% vaccine coverage. The vaccine cost $300 per series plus $100 per booster and targeted HPV 16/18 with 90% efficacy and 10-year duration of protection plus 10 additional years with a booster (119). Under these assumptions, the life time risk for cervical cancer among vaccinated females would be reduced by 62% at a cost per QALY of $14,600 (2001 dollars) compared with no vaccination. A second study as sumed vaccination at or before age 12 years with 70% vac cine coverage (121). The vaccine cost $360 per series and targeted HPV types 6, 11, 16, and 18, with 90% efficacy against infection and 100% efficacy against HPV-related dis eases attributable to these HPV types, with lifelong duration of protection. Under these assumptions, over the long term, a reduction of approximately 75% was achieved in the cervical cancer incidence rate attributable to HPV 16 and 18 at a cost of $3,000 per QALY in 2005 dollars compared with no vac cination. This model also suggested that a catch-up program for females aged 12-24 years would cost $4,700 per QALY compared with vaccination of females aged 12 years only.
The cost per QALY gained by routine vaccination of fe males at age 12 years in the published studies ranged from $3,000 to $24,300. The results summarized are calculated using base-case scenarios, which vary across studies. In the sensitivity analyses, when base-case assumptions were modi fied, the estimated cost effectiveness ratios changed substan tially. For example, factors such as duration of vaccine-induced protection, duration of natural immunity, frequency of cervi cal cancer screening, vaccine coverage, and vaccine cost im pacted the estimated cost effectiveness of HPV vaccination (116)(117)(118)(119)121,123).

# MMWR March 23, 2007

# Summary of Rationale for Quadrivalent HPV Vaccine Recommendations
The availability of a quadrivalent HPV vaccine offers an opportunity to decrease the burden of HPV infection and its sequelae, including cervical cancer precursors, cervical can cer, other anogenital cancers, and genital warts in the United States. Quadrivalent HPV vaccine is licensed for use among females aged 9-26 years. In this age group, clinical trials indi cate that the vaccine is safe and immunogenic. Trials among females aged 16-26 years indicated the vaccine to be effective against HPV types 6-, 11-, 16-, and 18-related cervical, vaginal and vulvar cancer precursor and dysplastic lesions, and genital warts. HPV 16 and 18 are the cause of approxi mately 70% of cervical cancers; HPV 6 and 11 are the cause of approximately 90% of genital warts. Because HPV is sexu ally transmitted and often acquired soon after onset of sexual activity, vaccination should ideally occur before sexual debut. The recommended age for vaccination is 11-12 years; vaccine can be administered to females as young as age 9 years. At the beginning of a vaccination program, females aged >12 years will exist who did not have the opportunity to receive vaccine at age 11-12 years. Catch-up vaccination is recommended for females aged 13-26 years who have not yet been vaccinated.
The recommendation for routine vaccination of females aged 11-12 years is based on several considerations, includ ing studies suggesting that quadrivalent HPV vaccine among adolescents will be safe and effective; high antibody titers achieved after vaccination at age 11-12 years; data on HPV epidemiology and age of sexual debut in the United States; and the high probability of HPV acquisition within several years of sexual debut. Ideally, HPV vaccine should be admin istered before sexual debut, and duration of protection should extend for many years, providing protection when exposure through sexual activity might occur. The vaccine has been demonstrated to provide protection for at least 5 years with out evidence of waning protection. Long-term follow-up stud ies are underway to determine duration of protection. The recommendation also considered cost effectiveness evaluations and the established young adolescent health-care visit at age 11-12 years recommended by several professional organiza tions, when other vaccines are also recommended.
Although routine vaccination is recommended at age 11-12 years, the majority of females aged 13-26 years also can benefit from vaccination.
Females not yet sexually active can be expected to receive the full benefit of vaccination. Although sexually active females in this age group might have been in fected with one or more vaccine HPV types, type-specific prevalence studies in the United States suggest that a small percentage of sexually active females have been infected with all four of the HPV vaccine types. These data, available from North American females aged 16-24 years who participated in the quadrivalent vaccine trials, are from women who were more likely to have ever had sex than similar aged females in the general U.S. population. Among those sexually active fe males, the median number of lifetime sex partners (two) was similar in trial participants and females in the general U.S. population. The vaccine does not appear to protect against persistent infection, cervical cancer precursor lesions, or genital warts caused by an HPV type that females are infected with at the time of vaccination. However, females already infected with one or more vaccine HPV types before vaccination would be protected against disease caused by the other vaccine HPV types. Therefore, although overall vaccine effectiveness would be lower when administered to a population of females who are sexually active, and would decrease with older age and likelihood of HPV exposure with increasing number of sex partners, the majority of females in this age group will derive at least partial benefit from vaccination.

# Recommendations for Use of HPV Vaccine
Recommendations for Routine Use and Catch-Up

# Routine Vaccination of Females Aged 11-12 Years
ACIP recommends routine vaccination of females aged 11-12 years with 3 doses of quadrivalent HPV vaccine. The vac cination series can be started as young as age 9 years.

# Catch-Up Vaccination of Females Aged 13-26 Years
Vaccination also is recommended for females aged 13-26 years who have not been previously vaccinated or who have not completed the full series. Ideally, vaccine should be ad ministered before potential exposure to HPV through sexual contact; however, females who might have already been ex posed to HPV should be vaccinated. Sexually active females who have not been infected with any of the HPV vaccine types would receive full benefit from vaccination. Vaccina tion would provide less benefit to females if they have already been infected with one or more of the four vaccine HPV types. However, it is not possible for a clinician to assess the extent to which sexually active persons would benefit from vaccina tion, and the risk for HPV infection might continue as long as persons are sexually active. Pap testing and screening for HPV DNA or HPV antibody are not needed before vaccina tion at any age.

# Dosage and Administration
The vaccine should be shaken well before administration. The dose of quadrivalent HPV vaccine is 0.5 mL, adminis tered intramuscularly (IM), preferably in the deltoid muscle.

# Recommended Schedule
Quadrivalent HPV vaccine is administered in a 3-dose schedule. The second and third doses should be administered 2 and 6 months after the first dose.

# Minimum Dosing Intervals and Management of Persons Who Were Incorrectly Vaccinated
The minimum interval between the first and second doses of vaccine is 4 weeks. The minimum recommended interval between the second and third doses of vaccine is 12 weeks. Inadequate doses of quadrivalent HPV vaccine or vaccine doses received after a shorter-than-recommended dosing in terval should be readministered.

# Interrupted Vaccine Schedules
If the quadrivalent HPV vaccine schedule is interrupted, the vaccine series does not need to be restarted. If the series is interrupted after the first dose, the second dose should be administered as soon as possible, and the second and third doses should be separated by an interval of at least 12 weeks. If only the third dose is delayed, it should be administered as soon as possible.

# Simultaneous Administration with Other Vaccines
Although no data exist on administration of quadrivalent HPV vaccine with vaccines other than hepatitis B vaccine, quadrivalent HPV vaccine is not a live vaccine and has no components that adversely impact safety or efficacy of other vaccinations. Quadrivalent HPV vaccine can be administered at the same visit as other age appropriate vaccines, such as the Tdap and quadrivalent meningococcal conjugate (MCV4) vaccines. Administering all indicated vaccines together at a single visit increases the likelihood that adolescents and young adults will receive each of the vaccines on schedule. Each vac cine should be administered using a separate syringe at a dif ferent anatomic site.

# Cervical Cancer Screening Among Vaccinated Females
Cervical cancer screening recommendations have not changed for females who receive HPV vaccine (Table 2). HPV types in the vaccine are responsible for approximately 70% of cervical cancers; females who are vaccinated could subse quently be infected with a carcinogenic HPV type for which the quadrivalent vaccine does not provide protection. Fur thermore, those who were sexually active before vaccination could have been infected with a vaccine type HPV before vaccination. Health-care providers administering quadriva lent HPV vaccine should educate women about the impor tance of cervical cancer screening.

# Groups for Which Vaccine is Not Licensed Vaccination of Females Aged 26 Years
Quadrivalent HPV vaccine is not licensed for use among females aged 26 years. Studies are ongoing among females aged >26 years. No studies are under way among children aged <9 years.

# Vaccination of Males
Quadrivalent HPV vaccine is not licensed for use among males. Although data on immunogenicity and safety are avail able for males aged 9-15 years, no data exist on efficacy in males at any age. Efficacy studies in males are under way.

# Special Situations Among Females Aged 9-26 Years

# Equivocal or Abnormal Pap Test or Known HPV Infection
Females who have an equivocal or abnormal Pap test could be infected with any of approximately 40 high-risk or lowrisk genital HPV types. Such females are unlikely to be in fected with all four HPV vaccine types, and they might not be infected with any HPV vaccine type. Vaccination would provide protection against infection with HPV vaccine types not already acquired. With increasing severity of Pap test find ings, the likelihood of infection with HPV 16 or 18 increases and the benefit of vaccination would decrease. Women should be advised that results from clinical trials do not indicate the vaccine will have any therapeutic effect on existing HPV in fection or cervical lesions.
Females who have a positive HC2 High-Risk test conducted in conjunction with a Pap test could have infection with any of 13 high-risk types. This assay does not identify specific HPV types, and testing for specific HPV types is not con ducted routinely in clinical practice. Women with a positive HC2 High-Risk test might not have been infected with any of the four HPV vaccine types. Vaccination would provide protection against infection with HPV vaccine types not al ready acquired. However, women should be advised that re sults from clinical trials do not indicate the vaccine will have any therapeutic effect on existing HPV infection or cervical lesions.

# Genital Warts
A history of genital warts or clinically evident genital warts indicates infection with HPV, most often type 6 or 11. How ever, these females might not have infection with both HPV 6 and 11 or infection with HPV 16 or 18. Vaccination would provide protection against infection with HPV vaccine types not already acquired. However, females should be advised that results from clinical trials do not indicate the vaccine will have any therapeutic effect on existing HPV infection or geni tal warts.

# Lactating Women
Lactating women can receive HPV vaccine.

# Immunocompromised Persons
Because quadrivalent HPV vaccine is a noninfectious vac cine, it can be administered to females who are immunosup pressed as a result of disease or medications. However, the immune response and vaccine efficacy might be less than that in persons who are immunocompetent.

# Vaccination During Pregnancy
Quadrivalent HPV vaccine is not recommended for use in pregnancy. The vaccine has not been causally associated with adverse outcomes of pregnancy or adverse events in the devel oping fetus. However, data on vaccination during pregnancy are limited. Until additional information is available, initia tion of the vaccine series should be delayed until after comple tion of the pregnancy. If a woman is found to be pregnant after initiating the vaccination series, the remainder of the 3 dose regimen should be delayed until after completion of the pregnancy. If a vaccine dose has been administered during pregnancy, no intervention is needed. A vaccine in pregnancy registry has been established; patients and health-care provid ers should report any exposure to quadrivalent HPV vaccine during pregnancy (telephone: 800-986-8999).

# Precautions and Contraindications

# Acute Illnesses
Quadrivalent HPV vaccine can be administered to persons with minor acute illnesses (e.g., diarrhea or mild upper respi ratory tract infections with or without fever). Vaccination of persons with moderate or severe acute illnesses should be de ferred until after the patient improves (124).

# Hypersensitivity or Allergy to Vaccine Components
Quadrivalent HPV vaccine is contraindicated for persons with a history of immediate hypersensitivity to yeast or to any vaccine component. Data from passive surveillance in Vaccine Adverse Event Reporting System (VAERS) indicates that recombinent yeast derived vaccines pose a minimal risk for anaphylaxic reactions in persons with a history of allergic reactions to Saccharomyces cerevisiae (baker's yeast) (125).

# Preventing Syncope After Vaccination
Syncope (i.e., vasovagal or vasodepressor reaction) can oc cur after vaccination, most commonly among adolescents and young adults (124). Among reports to VAERS for any vac cine that were coded as syncope during 1990-2004, a total of 35% of these episodes were reported among persons aged 10-18 years. Through January 2007, the second most common report to VAERS following receipt of HPV vaccine was syn cope (CDC, unpublished data, 2007). Vaccine providers should consider observing patients for 15 minutes after they receive HPV vaccine.

# Reporting of Adverse Events After Vaccination
As with any newly licensed vaccine, surveillance for rare adverse events associated with administration of quadrivalent HPV vaccine is important for assessing its safety in wide spread use. All clinically significant adverse events should be reported to VAERS at , even if causal re lation to vaccination is not certain. VAERS reporting forms and information are available electronically at http:// www.vaers.hhs.gov or by telephone (800-822-7967). Webbased reporting is available and providers are encouraged to report electronically at / VaersDataEntryintro.htm to promote better timeliness and quality of safety data.
Safety surveillance for adolescent quadrivalent HPV vac cine, Tdap, MCV4, and other vaccines is being conducted on an ongoing basis in cooperation with FDA. A vaccine in pregnancy registry has been established by Merck and Co., Inc.; patients and health-care providers should report any ex posure to quadrivalent HPV vaccine during pregnancy (tele phone: 800-986-8999).

# Areas for Research and Program Activity Related to HPV Vaccine
With licensure and introduction of quadrivalent HPV vac cine for females, monitoring impact of vaccination and vac cine safety will be needed. Research in several areas is ongoing, and research in other areas is needed.
Duration of Protection from the Quadrivalent Vaccine: Long-term data on duration of antibody response and clini cal protection will be obtained through studies conducted in the Nordic countries through the Nordic cancer registries and through other studies in the United States (111). Follow up of vaccine trial participants aged 9-15 years will continue for up to 10 years after dose 3. This will include evaluation of antibody titers and, in participants who reach their 16th birth day, evaluation of vaccine effectiveness.
Surveillance for HPV-Related Outcomes: Although it will take years to realize the impact of vaccination on cervical can cer, decreases in cervical cancer precursors and genital warts should be realized sooner. Studies are planned to monitor these lesions and other HPV-related outcomes in the United States.
Virologic Surveillance: Prevalence and incidence of HPV types in the vaccine are expected to decrease as a result of vaccination. Studies are planned to monitor HPV types in various populations and specimens.

# Safety of Vaccination:
Postlicensure studies to evaluate gen eral safety and pregnancy outcomes will be conducted by the manufacturer and independently by CDC. Monitoring will be accomplished through VAERS and CDC's Vaccine Safety Datalink, which will include surveillance of cohorts of re cently vaccinated females and evaluation of outcomes of preg nancy among those pregnant at the time of vaccination. The manufacturer will be monitoring long-term safety as part of the Nordic Cancer Registry Program (111).
Simultaneous Vaccination: Safety and immunogenicity studies of simultaneous administration of quadrivalent HPV vaccine with Tdap and MCV4 are ongoing.
Efficacy of HPV Vaccine in Men: Studies are needed to define the efficacy of HPV vaccination in preventing genital warts and anogenital intraepithelial neoplasia in men. Stud ies of the effectiveness of HPV vaccination of men in pre venting transmission to both female and male sex partners are also needed.
Cervical Cancer Screening: Recommendations for cervi cal cancer screening guidelines have not changed. Evaluation of the impact of HPV vaccination on cervical cancer screen ing provider practices and women's screening behavior is needed as well as further economic analyses.
Vaccine Delivery and Implementation: Administration of 3 doses of vaccine in adolescents will be challenging. Pro grammatic research is needed to determine optimal strategies to reach this age group.

# Vaccines for Children Program
The Vaccines for Children (VFC) program supplies vac cines to all states, territories, and the District of Columbia for use by participating providers. These vaccines are to be administered to eligible children without cost to the patients or the provider. All routine childhood vaccines recommended by ACIP are available through this program. The program saves patients and providers out-of-pocket expenses for vac cine purchases and provides cost savings to states through CDC vaccine contracts. The program results in lower vac cine prices and ensures that all states pay the same contract prices. Detailed information about the VFC program is avail able at .